Clinical trial NCT02559570
Conditions: Functional Constipation in Children Ages 6-17 Years
Keywords: Functional constipation in children LINZESS
Sponsor: Forest Laboratories
Start date: 2015-11-03; Completion date: 2018-05-29
Enrollment: 173 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate dose response of the safety and efficacy of linaclotide for the treatment of functional constipation (FC), in children age 6-17 years. This study includes up to a 4-week Screening Period, and a 2 to 3-week Pretreatment Period. Participants age 6-11 years will receive oral liquid formulation and participants 12-17 years will receive solid oral capsule or liquid oral solution.

Children ages 6-11 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 FC.

Detailed description:

Arms: arm 1: Participants aged 6 to 11 or 12 to 17 years received matching placebo linaclotide (LIN), 30 minutes before evening meal, once daily for 4 weeks. Administered as liquid oral solution for participants 6 to 11 years of age and solid oral capsule or liquid oral solution for participants 12 to 17 years of age. arm 2: Participants aged 6 to 11 years with weight 18 to \<35 kg received LIN 9 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 18 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 18 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks. arm 3: Participants aged 6 to 11 years with weight 18 to \<35 kg received LIN 18 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 36 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 36 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks. arm 4: Participants aged 6 to 11 years with weight 18 to \<35 kg received LIN 36 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 6 to 11 years with weight ≥35 kg received LIN 72 ug, oral solution, 30 minutes before evening meal, once daily for 4 weeks. Participants aged 12 to 17 years received LIN 72 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks. arm 5: Participants aged 12 to 17 years received LIN 145 ug, oral solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.
Interventions: intervention 1: Placebo intervention 2: LIN Dose A intervention 3: LIN Dose B intervention 4: LIN Dose C intervention 5: LIN 145 µg
Intervention descriptions: intervention 1: Participants received matching placebo LIN liquid solution or solid capsules, orally, 30 minutes before evening meal, once daily for 4 weeks. intervention 2: Participants received LIN 9 or 18 ug liquid solution or solid capsules, orally, 30 minutes before evening meal, once daily for 4 weeks. intervention 3: Participants received LIN 18 or 36 ug liquid solution or solid capsules, orally, 30 minutes before evening meal, once daily for 4 weeks. intervention 4: Participants received LIN 36 or 72 ug liquid solution or solid capsules, orally, 30 minutes before evening meal, once daily for 4 weeks. intervention 5: Participants received LIN 145 µg, liquid solution or solid capsules, 30 minutes before evening meal, once daily for 4 weeks.

Protocol documents:
Prot_000.pdf: 
NCT02559570 
 
 
Study ID: LIN‐MD‐62 
 
 
Title: 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, Who Fulfill 
Modified Rome III Criteria for Child/Adolescent Functional Constipation (FC) 
 
 
Protocol Amendment 3 Date: 16 May 2017 
 
 
 


Protocol Amendment #3 LIN-MD-62
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1.0
TITLE PAGE
Forest Research Institute, Inc., an affiliate of Allergan.
Harborside Financial Center, Plaza V
Jersey City, NJ 07311
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, Who Fulfill Modified Rome III Criteria for 
Child/Adolescent Functional Constipation (FC)
LIN-MD-62
IND #63,290
Original Protocol Date:
15 Apr 2015
Amendment #1:
13 Aug 2015
Amendment #2:
11 Sep 2016
Amendment #3:
16 May 2017
Confidentiality Statement
This document is the property of Forest Research Institute, Inc., and may not—in full or 
part—be passed on, reproduced, published, distributed, or submitted to any regulatory 
authority without the express written permission of Forest Research Institute, Inc.


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SYNOPSIS AND SCHEDULE OF EVALUATIONS
CLINICAL STUDY SYNOPSIS: Study LIN-MD-62
Title of Study
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, Who Fulfill Modified 
Rome III Criteria for Child/Adolescent Functional Constipation (FC)
Study Sites (Country)
Approximately 50 - 100
Development Phase
2
Objective
To evaluate the dose response, safety, and efficacy of 4 weeks of treatment 
with 1 of 3 linaclotide doses (A, B, or C) or 145 ug (as an exploratory 
objective in the adolescent patients 12 - 17 years of age using the approved 
adult dose) compared with placebo in pediatric patients 6 to 17 years of age 
who fulfill modified Rome III criteria for child/adolescent functional 
constipation (FC)
Methodology
Multicenter, randomized, double-blind, placebo-controlled, parallel-group, 
safety and efficacy dose-ranging study in pediatric patients
Number of Patients
Approximately 160 patients are planned. (35 placebo patients, 35 patients per 
linaclotide dose A, B, or C, and 14-19 patients for the approved adult 
linaclotide dose, 145 ug [in the 12-17 years of age group only]), with a 
minimum of 40% of patients per age group (6-11 years and 12-17 years) .
Diagnosis and 
Main Criteria for Inclusion
Male and female pediatric patients 6 to 17 years of age with a diagnosis of FC 
based on the modified Rome III criteria for child/adolescent FC
Test Product, Dosage, and Mode of 
Administration
Patients 6 to 11 years of age: linaclotide liquid oral solution taken once daily
Patients 12 to 17 years of age: linaclotide solid oral capsule or liquid oral 
solution taken once daily
Dosage is weight–based for the 6 to 11 years of age group:
Patients 6 to 11 years of age (weight 18 to < 35 kg)

Dose A: 9 ug  

Dose B: 18 ug  

Dose C: 36 ug  
Patients 6 to 11 years of age (weight ≥ 35 kg) 

Dose A: 18 ug  

Dose B: 36 ug 

Dose C: 72 ug  
Patients 12 to 17 years of age

Dose A: 18 ug  

Dose B: 36 ug  

Dose C: 72 ug  

Approved adult dose: 145 ug (for safety and exploratory efficacy 
only)
Duration of Treatment
The study will be approximately 9 to 12 weeks in duration: up to a 4-week (14 
- 28 days) Screening Period, a 2- to 3-week (14 to 21 days) Pretreatment 
Period, followed by a 4-week (≥ 28 days) Double-blind Treatment Period, and 
finally followed by a 1-week (≥ 7 days) Post-treatment Period. 
Patients will not receive investigational product during the Pretreatment 
Period or the Post-treatment Period.


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Reference Therapy, Dosage, and 
Mode of Administration
Patients 6 to 11 years of age: matching placebo liquid oral solution taken once 
daily
Patients 12 to 17 years of age: matching placebo solid oral capsule or liquid 
oral solution taken once daily
Criteria for Evaluation
Primary Outcome Measure
Bowel movement (BM) characteristic assessments that determine the 
occurrences of spontaneous bowel movements (SBMs) (ie, BM frequency and 
rescue medication use) recorded morning and evening in either the patient- or 
interviewer-administered version of the handheld electronic diary (eDiary)
Safety Measures
Adverse event recording,
 
 
 
Statistical Methods
The primary efficacy parameter is change from baseline in 4-week overall 
SBM frequency rate (SBMs/week) during the Treatment Period. Comparison 
between each linaclotide dose (A, B, and C) and placebo will be performed 
using an analysis-of-covariance (ANCOVA) model (based on the observed 
data) with treatment and age group (6 - 11 years and 12 - 17 years of age) as 
factors and baseline value as a covariate. No multiplicity adjustment will be 
applied in this dose-ranging study.
 
 
The change-from-baseline secondary efficacy parameters (except fecal 
incontinence daytime symptoms) defined for the Treatment Period will be 
analyzed in a similar way as the primary efficacy parameter (with A, B, and C 
linaclotide dose levels and placebo) using the ANCOVA model.
 
 
The change from baseline in 4-
week fecal incontinence daytime symptoms based on evening diary will be 
summarized only based on descriptive statistics.
All safety parameters will be analyzed descriptively based on the Safety 
Population, defined as all randomized patients who receive at least 1 dose of 
double-blind investigational product. All efficacy analyses will be based on 
the Intent-to-Treat Population, defined as all patients in the Safety Population 
who have at least 1 postbaseline entry of BM assessments that determine 
occurrences of SBMs (ie, BM frequency and rescue medication use). 
 
 
 
 
 


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3.0
OVERALL TABLE OF CONTENTS
1.0
TITLE PAGE....................................................................................................................................1
3.0
OVERALL TABLE OF CONTENTS ..............................................................................................6
3.1
LIST OF IN-TEXT TABLES.............................................................................................8
3.2
LIST OF IN-TEXT FIGURES ...........................................................................................8
4.0
LIST OF ABBREVIATIONS...........................................................................................................9
5.0
ETHICAL CONSIDERATIONS....................................................................................................11
5.1
Institutional Review Board and INDEPENDENT Ethics Committee ..............................11
5.2
Ethical Conduct of the Study............................................................................................11
5.3
Patient Information and INFORMED Consent.................................................................12
5.3.1
Patient Assent Form ...........................................................................................12
5.3.2
Parent, Legal Guardian, and Legally Authorized Representative/Caregiver
Informed Consent...............................................................................................12
6.0
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ......................................14
7.0
INTRODUCTION ..........................................................................................................................15
7.1
Summary of Linaclotide Properties ..................................................................................15
7.2
Clinical Experience...........................................................................................................16
7.2.1
Other Information...............................................................................................19
8.0
STUDY OBJECTIVES...................................................................................................................20
9.0
INVESTIGATIONAL PLAN .........................................................................................................21
9.1
Overall Study Design and Plan: Description ....................................................................21
9.1.1
Screening Period.................................................................................................21
9.1.2
Pretreatment Period ............................................................................................22
9.1.3
Double-blind Treatment Period..........................................................................23
9.1.4
Post-treatment Period .........................................................................................23
9.2
Discussion of Study Design, Including the Choice of Control Groups.............................24
9.3
Selection of Study Population...........................................................................................24
9.3.1
Inclusion Criteria................................................................................................24
9.3.2
Exclusion Criteria...............................................................................................26
9.3.3
Removal of Patients from Therapy or Assessment.............................................29
9.3.4
Patient Replacement Procedures ........................................................................30
9.4
Treatments ........................................................................................................................31
9.4.1
Treatments Administered ...................................................................................31
9.4.1.1
Rescue Medication ...........................................................................31
9.4.2
Identity of Investigational Products....................................................................32
9.4.3
Method of Assigning Patients to Treatment Groups ..........................................34
9.4.4
Selection of Dosages in the Study ......................................................................34
9.4.5
Selection and Timing of Dose for Each Patient..................................................34
9.4.6
Blinding..............................................................................................................36
9.4.7
Unblinding..........................................................................................................36
9.4.8
Prior and Concomitant Therapy .........................................................................36


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9.4.9
Monitoring Treatment Compliance and Accountability.....................................37
9.5
Efficacy and Safety Variables...........................................................................................37
9.5.1
Efficacy Assessments .........................................................................................37
9.5.1.1
Primary Efficacy Assessment...........................................................37
9.5.1.2
Secondary Efficacy Assessments......................................................39
9.5.2
Safety Assessments ............................................................................................45
9.5.2.1
Adverse Events and 
..................46
9.5.2.4
Serious Adverse Events....................................................................48
9.5.2.5
Reporting Adverse Events and Serious Adverse Events ..................49
9.5.2.6
Immediate Reporting of Serious Adverse Events and 
 
.................................................................................49
9.6
Data Quality Assurance ....................................................................................................62
9.6.1
Data Monitoring .................................................................................................62
9.6.2
Data Recording and Documentation...................................................................63
9.7
Statistical Methods and Determination of Sample Size....................................................63
9.7.1
Patient Populations.............................................................................................63
9.7.1.1
Screened Population .........................................................................64
9.7.1.2
Randomized Population....................................................................64
9.7.1.3
Safety Population..............................................................................64
9.7.1.4
Intent-to-Treat Population ................................................................64
9.7.2
Patient Disposition .............................................................................................64
9.7.3
Demographics and Other Baseline Characteristics.............................................65
9.7.5
Efficacy Analyses...............................................................................................66
9.7.5.1
Primary Efficacy Parameter..............................................................68
9.7.5.2
Secondary Efficacy Parameters ........................................................69
9.7.6
Safety Analyses ..................................................................................................76
9.7.6.1
Adverse Events.................................................................................76


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9.7.8
Interim Analysis .................................................................................................78
9.7.10
Computer Methods.............................................................................................79
9.8
Changes in the Conduct of the Study or Planned Analyses ..............................................79
9.9
Protocol Deviations ..........................................................................................................80
10.0
STUDY SPONSORSHIP................................................................................................................81
10.1
Study Termination ............................................................................................................81
10.2
Reporting and Publication ................................................................................................81
11.0
INVESTIGATOR OBLIGATIONS................................................................................................82
11.1
Documentation..................................................................................................................82
11.2
Performance......................................................................................................................82
11.3
Use of Investigational Materials.......................................................................................83
11.4
Case Report Forms ...........................................................................................................83
11.5
Retention and Review of Records.....................................................................................83
11.6
Patient Confidentiality......................................................................................................84
12.0
INVESTIGATOR’S STATEMENT ...............................................................................................85
13.0
APPENDICES ................................................................................................................................86
Appendix I.
Elements of Informed Consent...........................................................................86
Appendix II.
Contact Information............................................................................................88
Appendix III.
Concomitant Medications...................................................................................89
Appendix IV.
Blood Sampling and Shipping Instructions ........................................................92
14.0
LITERATURE CITED ...................................................................................................................95
3.1
LIST OF IN-TEXT TABLES
Table 9.4.5–1.
Double-blind Dosing Regimen...........................................................................35
3.2
LIST OF IN-TEXT FIGURES


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4.0
LIST OF ABBREVIATIONS
AE
adverse event
ANCOVA
analysis of covariance
β-hCG
beta human chorionic gonadotropin
BM
bowel movement
BP
blood pressure
CFR
Code of Federal Regulations
CI
confidence interval
CIC
chronic idiopathic constipation 
CMH
Cochran-Mantel-Haenszel 
CSBM
complete spontaneous bowel movement
DSMB
Data Safety Monitoring Board
eCRF
electronic case report form
EDC
electronic data capture 
eDiary
electronic diary
FC
functional constipation
FDA
Food and Drug Administration
FGID
functional gastrointestinal disorder
FR
Federal Register
GCP
good clinical practice
GI
gastrointestinal
HIPAA
Health Insurance Portability and Accountability Act 
 
IBS
irritable bowel syndrome


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IBS-C
irritable bowel syndrome with constipation
ICF
informed consent form
ICH
International Conference on Harmonisation 
IEC
Independent Ethics Committee
IND
Investigational New Drug (application)
IRB
Institutional Review Board
ITT
intent to treat (Intent-to-Treat Population)
IWRS
interactive Web response system
LAR
legally authorized representative
LSM
least squares means
NDA
New Drug Application 
p-BSFS
Pediatric Bristol Stool Form Scale
 
 
PID
patient identification
PK
pharmacokinetic
PRO
patient reported outcome
 
 
 
SAE
serious adverse event
SAP
statistical analysis plan
SBM
spontaneous bowel movement
SOC
system organ class
TEAE
treatment-emergent adverse event
ULN
upper limit of normal


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5.0
ETHICAL CONSIDERATIONS
5.1
INSTITUTIONAL REVIEW BOARD AND INDEPENDENT 
ETHICS COMMITTEE
United States
Approval by the Institutional Review Board (IRB) before the start of the study will be the 
responsibility of the Investigator. A copy of the approval letter will be supplied to 
Forest Research Institute, Inc. (the Sponsor), along with a roster of IRB members or the 
US Department of Health and Human Services general assurance number. During the 
course of the study, the Investigator will provide timely and accurate reports to the IRB 
on the progress of the study, at intervals not exceeding 1 year (or as appropriate), and will 
notify the IRB of serious adverse events (SAEs) or other significant safety findings. The 
study protocol, informed consent form (ICF), information sheet advertisements, and 
amendments (if any) will be approved by the IRBs at the study sites in conformance with 
the US CFR, Title 21, Part 56.
Outside the United States
If performed outside the United States, this study will be carried out in full compliance 
with the guidelines of the independent ethics committee (IEC) and government agencies 
of each respective country as well as the European Union Clinical Trial Directive 
(Directive 2001/20/EC), where applicable. Before the study begins, the study site will 
require approval from an IEC and government agency. During the course of the study, the 
Sponsor or authorized representative will provide timely and accurate reports to the IEC 
on the progress of the study, at intervals not exceeding 1 year (or as appropriate) and will 
notify the IEC of SAEs or other significant safety findings. The study protocol, ICF, 
information sheet advertisements, and amendments (if any) will be approved by the IEC 
at the study site in conformance with CFR, Title 21, Part 56, the European Union Clinical 
Trial Directive (Directive 2001/20/EC), and local regulations.
5.2
ETHICAL CONDUCT OF THE STUDY
This clinical study will be conducted in accordance with the ethical principles that have 
their origins in the Declaration of Helsinki.
This clinical study will comply with the ICH Guidance on General Considerations for 
Clinical Trials (ICH-E8; 62 FR 66113, 17 Dec 1997) and Good Clinical Practice 
(ICH-E6; 62 FR 25692, 09 May 1997), as well as Part 312 of the US CFR.


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5.3
PATIENT INFORMATION AND INFORMED CONSENT
After being given an explanation of the study and before participating in any study 
procedures, each patient must provide assent, and his or her parent(s), legal guardian(s), 
or legally authorized representative (LAR) (hereafter referred to as parent/guardian/LAR) 
must provide voluntary and written informed consent in compliance with 21 CFR, Parts 
50 and 312 and give HIPAA authorization (or an equivalent of HIPAA authorization in 
non-US countries). 
The signed documents will be placed in the Investigator’s study files. The informed 
consent statement contains all the elements of informed consent listed in Appendix I of 
this protocol. A unique patient identification (PID) number will be assigned according to 
Section 9.4.3.
5.3.1
Patient Assent Form
To participate in the study, the patient will read, assent to an understanding of, sign the 
assent form, and be made aware they can withdraw from the study at any time. Patients 
who are unable to read the assent form will have the statements read to them. If the 
patient cannot sign the form, a witness will be allowed to provide written verification of 
oral assent. A copy of the signed assent will be given to the patient’s 
parent/guardian/LAR.
5.3.2
Parent, Legal Guardian, and Legally Authorized 
Representative/Caregiver Informed Consent
Written informed consent will be obtained from the patient’s parent/guardian/LAR before 
the patient participates in any study-related procedure. To provide consent for the 
patient’s participation in the study, the patient’s parent/guardian/LAR will read, assent to 
an understanding of, and sign an instrument of informed consent or other locally 
applicable regulations and authorization form after having had an opportunity to discuss 
the forms with the Investigator before signing. The parent/guardian/LAR will be made 
aware that the patient may withdraw from the study at any time and will receive a copy of 
the signed ICF. Patients who reach the age of majority (ie, 18 years of age in most 
jurisdictions) during the course of the study are required to re-consent.


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A caregiver is a person identified as able and willing to provide safety and efficacy 
information about the patient and oversee the administration of investigational product 
and completion of the daily electronic diary (eDiary), and may be a different individual 
than the parent/guardian/LAR. The caregiver must commit to accompany the patient to 
each study visit. To be eligible for the study, the caregiver, whether or not he or she is the 
parent/guardian/LAR, must read and sign the caregiver consent or a combined 
parent/legal guardian/caregiver permission ICF document. If the parent/guardian/LAR is 
the caregiver, he or she will be asked to sign both the parent/legal guardian permission 
(ICF) and the caregiver consent or a combined parent/legal guardian/caregiver permission 
(ICF). The parent/guardian/LAR or caregiver who supervises the patient in the 
completion of the eDiary or administers the interviewer-administered version should be 
the same individual throughout the course of the study. If a caregiver is replaced during 
the study, each caregiver must provide separate ICF/caregiver consents and be given a 
signed copy of his or her caregiver consent.


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6.0
INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE
This study will be performed at approximately 50 - 100 study sites.
The Investigator is responsible for ensuring that an investigation is conducted according 
to the signed Investigator statement, the investigational plan, GCP guidelines, and 
applicable regulations; for protecting the rights, safety, and welfare of patients under the 
Investigator’s care; and for the control of investigational products under investigation. An 
Investigator shall obtain the informed consent of each human patient prior to the patient 
enrolling in the study and/or prior to participating in any study-related activity. 
The Investigator at each site must meet their obligations to the patients, ethics committee, 
Sponsor, and regulatory authorities by maintaining oversight and control of the study’s 
conduct and the study staff. It is the responsibility of the Investigator to ensure that any 
and all delegated duties be assigned to qualified staff by education, experience, and 
licensure (in accordance with local regulations) and that the Investigator oversight is 
documented and assessment of their capabilities and performance consistent with the 
study investigational plan. The Investigator at each site will be responsible for the 
management of the study, including maintaining the study file and the patient records, 
corresponding with the IRB, and completing the electronic case report forms (eCRFs).


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7.0
INTRODUCTION
Functional gastrointestinal disorders (FGIDs) are common conditions of the digestive 
system in which symptoms cannot be explained by the presence of structural or tissue 
abnormalities (Hyams, 1999). The Rome criteria were developed to classify the FGIDS in 
adults and children based on clinical symptoms.   
Functional constipation (FC) is a common FGID in childhood, with an estimated 
prevalence of 3% worldwide. It is often associated with infrequent and/or painful 
defecation, fecal incontinence, and abdominal pain. It often causes significant distress to 
the child and family, and has a significant impact on healthcare costs. Children who 
experience painful bowel movements (BMs) may avoid defecation as long as possible, 
thereby exacerbating the constipation-associated symptoms. At present, the most widely 
accepted definitions for childhood FC are the Rome III definitions. Abdominal pain is a 
frequent associated symptom, but its presence is not considered necessary for FC 
(Tabbers et al, 2014). 
Present guidelines (Constipation Guideline Committee, 2006) for the treatment of 
childhood functional constipation recommend a number of agents for disimpaction and 
relief of constipation, including polyethylene glycol (PEG), other osmotic laxatives (eg, 
lactulose), lubricants (eg, mineral oil), stimulant laxatives, and enemas. However, some 
of these agents may be challenging to administer to children (Hyman et al, 2014), and a 
meta-analysis revealed that only 61% of treated children fully recovered from 
constipation by 6 to 12 months after presentation (Pijpers et al, 2010). In addition, there 
are no FDA approved products for FC in children. Thus, effective treatment alternatives 
are needed to provide symptomatic relief in children and adolescents with functional 
constipation, and the safety and efficacy of such alternatives should be demonstrated in 
adequate and well controlled studies in children.
7.1
SUMMARY OF LINACLOTIDE PROPERTIES
Linaclotide, a 14-amino acid peptide that acts on the apical surface of epithelial cells in 
the intestinal lumen to stimulate guanylate cyclase subtype C, is approved in the United 
States for the treatment of adults with IBS-C and with chronic idiopathic constipation 
(CIC) (Linzess, 2013) and in the European Union for moderate to severe IBS-C. By 
activating guanylate cyclase subtype C, orally administered linaclotide has been found to 
increase both intestinal fluid secretion and intestinal transit and to also decrease visceral 
pain in animal models. Linaclotide has minimal oral bioavailability (≤ 0.2%) in several 
animal species (Bryant et al, 2010; Eutamene et al, 2010). Refer to the Investigator’s 
Brochure for a more detailed description of the chemistry, pharmacology, efficacy, and 
safety of linaclotide, based on studies conducted in animals, healthy volunteers, and in 
adult patients with IBS-C and CIC (Investigator’s Brochure, 2016).


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7.2
CLINICAL EXPERIENCE
Linaclotide has been developed by the Sponsor and Ironwood Pharmaceuticals Inc. for 
the treatment of CIC and IBS-C in adults. The clinical development program for 
linaclotide that culminated in FDA and European Medicines Agency (EMA) approvals 
included the following North American studies in adult patients:

4 large double blind, placebo-controlled Phase 3 registration studies (2 IBS-C studies 
[LIN-MD-31 and MCP-103-302] and 2 CIC studies [LIN-MD-01 and 
MCP-103-303])

2 long term adult safety studies (LIN-MD-02 and MCP-103-305), each with 78-week 
Treatment Periods
In addition, 2 randomized, double-blind, placebo-controlled, parallel-group, North 
American studies: Phase 3b study (LIN-MD-04) and Phase 3 study (MCP-103-309) have 
been completed.
The 2 IBS-C studies (LIN-MD-31 and MCP-103-302) evaluated the safety and efficacy 
of linaclotide 290 ug (the adult dose subsequently approved by FDA) administered as a 
solid oral capsule for 12 or 26 weeks, respectively. In these studies, linaclotide 
demonstrated statistically significant and clinically meaningful improvements in patients’ 
constipation symptoms and abdominal pain, and met all the pre-specified primary and 
secondary endpoints. Study MCP-103-302 demonstrated improvement in abdominal and 
bowel symptoms at 12 weeks that was maintained throughout 26 weeks of treatment. 
Study LIN-MD-31 included a 4-week double blind, randomized withdrawal period 
immediately following the 12-week treatment period to assess the potential for rebound 
worsening of bowel or abdominal symptoms. The results from the randomized 
withdrawal period showed that there was no evidence of development of tolerance, nor 
was there evidence of rebound worsening of bowel or abdominal symptoms relative to 
baseline once the linaclotide was discontinued. The most common adverse event (AE) 
was diarrhea occurring in approximately 20% of IBS-C patients in both studies. Overall, 
there was no obvious pattern in the types of SAEs experienced in either the placebo or 
linaclotide group. There were no SAEs of diarrhea. 


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The 2 CIC studies (LIN-MD-01 and MCP-103-303) evaluated the safety and efficacy of 
linaclotide 145 ug (the adult dose subsequently approved by FDA for this indication) and 
linaclotide 290 ug administered as solid oral capsules. Both the 145-ug and 290-ug doses 
demonstrated statistically significant and clinically meaningful improvement in 
constipation and abdominal symptoms, and met all pre-specified primary and secondary 
endpoints. The most common AE in CIC patients was diarrhea occurring in 16% of 
patients treated with the 145-ug dose, and 14.2% of patients treated with the 290 ug dose. 
There were no SAEs of diarrhea although diarrhea was reported in 1 patient along with 
SAEs of dehydration and orthostatic hypotension. There were no clinically relevant
differences between the 2 linaclotide dose groups in the incidence of diarrhea 
treatment-emergent adverse events (TEAEs), severe diarrhea TEAEs, or diarrhea that 
resulted in discontinuation from the studies.
 
 
 
 
 
 
 
 
 
 
 
Long-term studies LIN-MD-02 and MCP-103-305 included 78-week treatment periods to 
evaluate the long-term safety of linaclotide in IBS-C and CIC adult patients. Both studies 
included patients who completed 1 of the linaclotide Phase 2 or 3 studies, or completed 
the Pretreatment Period of 1 of the Phase 3 double-blind studies, but failed to meet 
specific inclusion or exclusion criteria to be randomized.
 
 
 
 
 
In both 
Study MCP-103-305 and Study LIN-MD-02, the most commonly reported AE was 
diarrhea, which occurred in approximately 30% of CIC patients and IBS-C patients in 
both studies. Neither study reported SAEs of diarrhea.


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The completed Phase 3b study (LIN-MD-04) was a randomized, double-blind, placebo 
controlled, parallel-group, study. Linaclotide at doses of 145 ug/day and 290 ug/day was 
administered orally for 12 weeks to 487 randomized adult patients with CIC and 
prominent abdominal bloating at baseline (ie, bloating ≥ 5.0 on an 11-point numerical 
rating scale). No new safety trends or concerns were identified. There were no deaths 
during the study and no SAEs of diarrhea.
The completed Phase 3 study (MCP-103-309) was a randomized, double-blind, 
placebo-controlled, parallel-group study in patients with CIC at baseline. Linaclotide at 
doses of 72 ug/day and 145 ug/day was administered orally for 12 weeks to 1223 
randomized adult patients. No new safety trends or concerns were identified. There were 
no deaths during the study and no SAEs of diarrhea. One patient in the linaclotide 145-ug 
group experienced an SAE of colitis that was considered by the investigator to be 
possibly related to study drug.
Safety data from these adult studies showed that, except for diarrhea, the proportion of 
patients reporting a TEAE was similar between placebo and, in the CIC studies, each 
linaclotide dose group, and the incidence of TEAEs was not dose-related. With the 
exception of the gastrointestinal (GI) system organ class (SOC), the occurrence of 
TEAEs in the CIC and IBS-C patients was balanced across treatment groups in each SOC 
for the adult Phase 3 placebo-controlled studies. Diarrhea was the most common TEAE 
in linaclotide-treated CIC and IBS-C patients, consistent with its pharmacology; however 
diarrhea was rarely associated with serious sequelae such as dehydration, fecal 
incontinence, or defecation urgency. 
SAEs were infrequent and balanced across treatment arms within each indication. An 
analysis of the SAEs across the entire clinical development program revealed no pattern 
to suggest that linaclotide causes any specific serious condition.
Minor abnormalities in laboratory, vital sign, or ECG parameters were observed rarely; 
overall, there were no clinically meaningful differences between linaclotide and placebo 
treatment groups for any of these parameters in the Phase 3 placebo-controlled studies in
adults.
The following registration studies were conducted outside of North America:
•
ICP-103-307: A Phase 3 international, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group efficacy and safety trial of linaclotide orally 
administered once daily for 12 weeks to patients with IBS-C in China, Australia, 
New Zealand, the US, and Canada. A total of 839 patients were randomized into 1 
of 2 treatment groups: linaclotide 290 ug (417 patients) or placebo (422 patients)


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•
0456-CL-0031: A 2-part study, Part 1 was a multicenter, randomized, double-
blind, placebo-controlled, parallel-group Phase 3 trial of linaclotide orally 
administered once daily for 12 weeks to patients with IBS-C in Japan.
 
 
Both IBS-C studies evaluated the safety and efficacy of double-blind linaclotide 
administered as a solid oral capsule for 12 weeks. In these studies, linaclotide 
demonstrated statistically significant and clinically meaningful improvements in patients’ 
constipation symptoms and abdominal pain, and met all the prespecified primary 
endpoints. Statistically significant improvements were achieved for linaclotide versus 
placebo in multiple prespecified abdominal and bowel symptom secondary endpoints, 
including bloating and abdominal pain/discomfort. The most common adverse event 
(AE) was diarrhea, which occurred in 9-12% of linaclotide patients. Overall, there was no 
obvious pattern in the types of SAEs experienced in either the placebo or linaclotide 
groups. There were no SAEs of diarrhea.
7.2.1
Other Information
Linaclotide is contraindicated in pediatric patients up to 6 years of age. This is because in 
nonclinical studies, administration of a single, clinically relevant adult oral dose of 
linaclotide caused deaths due to dehydration in young (Day 7 postpartum) juvenile mice. 
Supplemental subcutaneous fluid administration prevented death after linaclotide 
administration in neonatal mice, and significantly higher doses (≥ 10 times the clinically 
relevant adult dose) were tolerated in older juvenile mice without supplemental fluid 
administration.
In post-marketing experience, severe diarrhea AEs associated with dizziness, syncope, 
hypotension and electrolyte abnormalities (hypokalemia and hyponatremia) requiring 
hospitalization or intravenous fluid administration have been reported in patients 
treated with linaclotide.
This study will be the first to evaluate the safety and efficacy of linaclotide relative to 
placebo in pediatric patients, 6 to 17 years of age, with FC.


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8.0
STUDY OBJECTIVES
The objective of this study is to evaluate the dose response, safety, and efficacy of 
4 weeks of treatment with 1 of 3 linaclotide doses (A, B, or C) or 145 ug (as an 
exploratory objective in the adolescent patients 12 - 17 years of age using the approved 
adult dose) compared with placebo in pediatric patients 6 to 17 years of age who fulfill 
modified Rome III criteria for child/adolescent FC. 


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9.0
INVESTIGATIONAL PLAN
9.1
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION
This clinical study will be a multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, safety and efficacy study comparing 1 of 3 linaclotide doses (A, B, and C) 
or 145 ug (only patients 12 - 17 years of age) with placebo in pediatric patients, 6 to 
17 years of age, with a diagnosis of FC based on modified Rome III Child/Adolescent 
Criteria (ie, who fulfill modified Rome III criteria for child/adolescent FC). The study 
will include a total of 6 visits and will be approximately 9 to 12 weeks in duration 
(Figure 9.1.4–1). Approximately 160 patients with FC will be enrolled in this study.

Screening Period (14 to 28 days) 

Pretreatment Period (14 to 21 days)

Double-blind Treatment Period (hereinafter referred to as Treatment Period) (at least 
28 days [4 weeks] on treatment)

Post-treatment Period (at least 7 days [1 week] after the Week 4 End-of-Treatment 
Visit)
9.1.1
Screening Period
After obtaining assent and informed consent, patient eligibility for entry into the study 
will be determined (Sections 9.3.1 and 9.3.2). The Screening Period will begin up to 
7 weeks before Randomization (Visit 3/Day 1) and will last for 14 to 28 days. Patients 
will not receive any investigational product during the Screening Period. Consented 
patients will be assigned a unique PID number via interactive Web response system 
(IWRS) (Section 9.4.3) and will be given a single dose of placebo (liquid oral solution for 
patients 6 to 11 years of age and solid oral capsule or liquid oral solution for patients 12 
to 17 years of age) to swallow to confirm their ability and willingness to swallow the 
investigational product. Patients 6 - 11 years of age who fail the swallow test for the 
liquid oral solution will be considered screen failures. Patients 12 - 17 years of age who 
choose or are assigned to the solid oral capsule formulation will repeat the swallow test 
for placebo solid oral capsule during the Pretreatment Period. There should be at least a 
1-week interval between the swallow tests performed for placebo solid oral capsules 
during the Screening Period and the Pretreatment Period.


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9.1.2
Pretreatment Period
The Pretreatment Period will occur up to 3 weeks before Randomization (Visit 3/Day 1) 
and will last for 14 to 21 days. Patients will not receive investigational product during the 
Pretreatment Period. Patients 12 to 17 years of age who choose or are assigned to the 
solid oral capsule formulation during the Screening Period will be provided a single dose 
of placebo solid oral capsule to repeat the swallow test. There should be at least a 1-week 
interval between the swallow tests performed for placebo solid oral capsules during the 
Screening Period and the Pretreatment Period. Baseline symptoms will be assessed and 
inclusion/exclusion criteria will be reviewed. Patients and caregivers will receive full 
training on the use and completion of the eDiary, and the decision regarding whether a 
patient can complete the eDiary on his/her own or if he/she requires assistance will be 
made at the discretion of the caregiver and carried through to study completion. 
Additionally, caregivers of patients 6 to 11 years of age will be trained on completing the 
observer-completed global items once weekly on the eDiary. Throughout this protocol, 
eDiary is understood to refer to the patient- or interviewer- administered version of the 
patient reported outcome (PRO) diary on a handheld electronic device. The eDiary will 
be completed by all patients (or caregivers) twice daily throughout the Pretreatment 
Period. During the Pretreatment Period, compliance with the eDiary will be defined as 
completion of both morning and evening assessments for 10 out of the 14 days 
immediately preceding the Randomization Visit and must be documented before patients 
are included in the Double-blind Treatment Period.
IWRS registration during the Pretreatment Period will include protocol-permitted rescue 
medication assignment (ie, senna [oral] or bisacodyl [oral or rectal])
 
 


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9.1.3
Double-blind Treatment Period
Patients will complete at least 4 weeks of investigational product treatment during the 
double-blind Treatment Period (referred to as Treatment Period). Three study visits will 
occur during the Treatment Period: a Randomization Visit (Visit 3/Day 1), a Week 2 
Visit (Visit 4, approximately Day 15) and a Week 4 End-of-Treatment-Period Visit 
(Visit 5, approximately Day 29). Randomization will occur on the first day of the 
Treatment Period. Based on randomization, patients will receive placebo or linaclotide. 
The first dose of investigational product will be administered at the study site following 
randomization (Visit 3/Day 1).
Randomization will be stratified by age group (6 - 11 years of age and 12 - 17 years of 
age) with a minimum of 40% of patients within each age group. Patients 6 to 11 years of 
age will be randomized to linaclotide doses (A, B, or C) or placebo in a 1:1:1:1 
allocation. Patients 12 to 17 years of age will be randomized to linaclotide doses (A, B, or 
C, or the approved adult dose, 145 ug) or placebo in a 1:1:1:1:1 allocation
(Table 9.4.5–1).
Patients will complete the eDiary twice daily throughout the Treatment Period and must 
complete at least 4 weeks of treatment before arriving at the study site for the Week 4 
Visit (Visit 5).
9.1.4
Post-treatment Period
The End-of-Study Visit (Visit 6/Post-treatment Visit) must occur at least 7 days after the 
Week 4 Visit (Visit 5). Patients will not receive investigational product during the 
Post-treatment Period, but will continue to complete the eDiary twice daily throughout 
the Post-treatment Period.  
The figure below provides a schematic of the study design. The Schedule of Evaluations 
is presented in Section 2.0. Detailed descriptions of each study visit can be found in 
Section 9.5.1.


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9.2
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE 
OF CONTROL GROUPS
A multicenter, randomized, double-blind, placebo-controlled, parallel-group, safety and 
efficacy dose-ranging study design was chosen based on prior studies that established 
linaclotide efficacy and safety in adult patients with CIC. Additionally, this study was 
designed with reference to the FDA Guidance for Industry E11 Clinical Investigation of 
Medicinal Products in the Pediatric Population. In this pediatric study, Investigators will 
enroll patients 6 to 17 years of age who fulfill modified Rome III for child/adolescent FC.
The linaclotide doses selected for use in this study were based on prior studies in adult 
patients with CIC, current product labeling for the treatment of CIC in North America (ie, 
US, Canada, and Mexico for both indications in adult patients), and communications with 
the FDA. 
9.3
SELECTION OF STUDY POPULATION
9.3.1
Inclusion Criteria
To be eligible to participate in the study, patients must meet the following criteria:
1. Patient must provide written or verbal informed assent and the parent/guardian/LAR 
and caregiver must provide written informed consent before the initiation of any 
study-specific procedures (Section 5.3)


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2. Patient is a male or female outpatient, weighing ≥18 kg, 6 to 17 years of age 
(inclusive) at the time the patient provides assent for the study and 
parent/guardian/LAR has provided signed consent
3. Patient is able to read and/or understand the assessments in the eDiary. If the patient 
is 6 to 11 years of age and does not meet this criterion, the interviewer-administered 
version of the eDiary must be used and the parent/guardian/LAR or caregiver who 
will be administering the interviewer-administered version of the eDiary must 
undergo training 
 
 
 
 
 
6. Patient meets modified Rome III criteria for child/adolescent FC: For at least 
2 months before the Screening Visit, the patient has had 2 or fewer defecations (with 
each defecation occurring in the absence of any laxative, suppository, or enema use 
during the preceding 24 hours) in the toilet per week
In addition, at least once per week, patient meets 1 or more of the following: 
a.
History of retentive posturing or excessive volitional stool retention
b. History of painful or hard bowel movements (BMs)
c.
Presence of a large fecal mass in the rectum
d. History of large diameter stools that may obstruct the toilet
e.
At least one episode of fecal incontinence per week
7. Patient is willing to discontinue any laxatives used before the Pretreatment Visit in 
favor of the protocol-permitted rescue medicine (Appendix III)


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9. Patient has an average of fewer than 3 spontaneous BMs (SBMs) per week during the 
14 days before the randomization day and up to the randomization (including the 
morning eDiary assessments reported before administration of first dose of 
double-blind investigational product on the randomization day). An SBM is defined 
as a BM that occurs in the absence of laxative, enema, or suppository use on the 
calendar day of the BM or the calendar day before the BM 
10. Patient or parent/guardian/LAR or caregiver is compliant with eDiary by completing 
both the morning and evening assessments for 10 out of the 14 days immediately 
preceding the Randomization Visit (Section 9.1.2)
9.3.2
Exclusion Criteria
Patients who meet any of the following criteria will not be eligible to participate in the 
study:
1. Patient meets Rome III criteria for Child/Adolescent IBS: At least once per week for 
at least 2 months before the Screening Visit, the patient has experienced abdominal 
discomfort (an uncomfortable sensation not described as pain) or pain associated with 
2 or more of the following at least 25% of the time: 
a.
Improvement with defecation 
b.
Onset associated with a change in frequency of stool
c.
Onset associated with a change in form (appearance) of stool


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2. Patient reports having more than 1 loose, mushy stool (eDiary-recorded stool 
consistency of 6 on the Pediatric Bristol Stool Form Scale [p-BSFS]) or any watery 
stool (eDiary-recorded stool consistency of 7 on the p-BSFS) with any SBM that 
occurred in the absence of laxative use on the calendar day of the BM or the calendar 
day before the BM during the 14 days before the randomization day and up to the 
randomization (including the morning eDiary assessments reported before 
administration of first dose of double-blind investigational product on the 
randomization day)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7. Patient required manual disimpaction anytime prior to randomization  or disimpaction
during in-patient hospitalization within 1 year prior to randomization
 
 
 
 
 
 
 


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17. Patient is unable to tolerate the placebo prior to randomization
 
 
9.3.3
Removal of Patients from Therapy or Assessment
A premature discontinuation will occur when a patient who gave voluntary assent and 
whose parent/guardian/LAR and caregiver gave consent ceases participation in the study, 
regardless of circumstances, before the completion of the study visits and procedures. 
Patients will be prematurely discontinued from the study for reasons of safety including 
those who experience an SAE considered by the Investigator or the Sponsor to be related 
to investigational product. Patients will also be prematurely discontinued from the study 
for evidence of significant volume depletion and/or significant electrolyte and/or ECG 
abnormalities that are considered by the Investigator or Sponsor to be related to diarrhea 
related to the investigational product (ie, treatment-related AEs of special interest 
[Sections 9.5.2.1.1 and 9.5.2.6]). The Investigator should contact the Study Physician if 
there is any question whether the criteria for an AE of special interest have been met and 
the patient should be discontinued from the study. 


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Patients can also be prematurely discontinued from the study after careful consideration 
for one of the following reasons:

Screen Failure (Failure to meet inclusion/exclusion criteria) 

Withdrawal of consent

AE

Lack of Efficacy

Protocol violation 

Non-compliance with investigational product

Lost to follow-up

Study terminated by Sponsor 

Site terminated by Sponsor

Other
All randomized patients who prematurely discontinue from the study, regardless of cause, 
should be seen for the assessments to be completed at the End-of-Treatment Visit 
(Week 4/Visit 5). The end-of-treatment assessments are defined as completion of the 
evaluations scheduled for all patients at Week 4 (Visit 5). In addition to the 
end-of-treatment assessments, all patients discontinuing the study prematurely should 
enter the Post-treatment Period and complete a Post-treatment Visit (Visit 6). 
Patients who discontinue from the study and do not return to the study site for Visit 5 
and/or Visit 6 must be requested in writing to return to the study site for procedures in 
Visit 5 or Visit 6 and return any unused investigational product and the handheld eDiary. 
A copy of the letter, together with the source documentation, will be kept in the 
Investigator’s files. The reason for premature discontinuation from the study will be 
recorded on the Study Termination Page of the eCRF. Study site staff will be contacted 
by the Sponsor after each premature discontinuation to ensure proper characterization of 
the reason for discontinuation is captured.
9.3.4
Patient Replacement Procedures
Patients in this study who prematurely discontinue treatment will not be replaced.


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9.4
TREATMENTS
Patients meeting the eligibility criteria during Visit 3 (Day 1) will be randomized in a 
double-blind fashion to linaclotide or placebo (Table 9.4.5–1). 
Randomization will be stratified by age group:

Patients 6 to 11 years of age will be randomized to linaclotide doses (A, B, or C dose) 
or placebo in a 1:1:1:1 allocation 

Patients 12 to 17 years of age will be randomized to linaclotide doses (A, B, or C 
dose or the approved adult dose, 145 ug) or placebo in a 1:1:1:1:1 allocation
9.4.1
Treatments Administered
Investigational product in the form of liquid oral solution or solid oral capsules will be
packaged in bottles and provided by the Sponsor. Patients will be supplied with blinded 
investigational product and will be instructed to take their assigned dose orally, once 
daily as a single dose, 30 minutes before their evening meal. Confirmation will be 
recorded in the source documents that the dosing regimen and dosing instructions were 
discussed with the patient and caregiver and that written dosing instructions were 
provided. 
Throughout the study, it is recommended that patients take the investigational product at 
approximately the same time each day (Section 9.4.5).
9.4.1.1
Rescue Medication
During the Pretreatment and Treatment Periods, a patient may use dispensed, 
protocol-permitted laxatives as rescue medication
 
 
Protocol-permitted rescue medication will be a choice of senna (oral) or bisacodyl (oral 
or rectal) that will be dispensed according to the Schedule of Evaluations (Section 2.0). 
 
 
 
 
 
 


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9.4.2
Identity of Investigational Products
All investigational products (linaclotide and placebo) will be supplied to the site by the 
Sponsor. 
 
 
 
 
 
 
 
 
Immediately before dispensing the investigational product, the Investigator or designee 
will write the patient’s initials (where applicable), PID number, and dispensing date on 
the label.
 
 Immediately before dispensing the rescue 
medication, the Investigator or designee will write the patient’s initials (where 
applicable), PID number, and dispensing date on the label.
Label requirements listed above will be modified per country-specific requirements. 
Investigational products in bottles containing solid oral capsules must be stored at the 
study site in an appropriate secure area (eg, a locked cabinet in a locked room) at 
 
 
 
 
Investigational products in bottles containing liquid oral solution
 
 
 
 


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The Investigator or designee is responsible for recording the receipt and use of all 
investigational products supplied and for ensuring the supervision of the storage and 
allocation of these supplies. All unused investigational products and dispensed protocol-
permitted rescue medications must be returned; and, whenever investigational products 
and dispensed protocol-permitted rescue medications are returned, unit counts must be 
performed (Section 9.4.9). All investigational products and dispensed rescue medications 
must be accounted for. At the end of the study, all unused investigational products, empty 
investigational product/dispensed rescue medication packages and unused rescue 
medications should be returned to the Sponsor or the local distributor at the address 
provided in the Study Reference Binder.


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9.4.3
Method of Assigning Patients to Treatment Groups
After a patient and parent/LAR/caregiver sign the assent/permission/consent at the first 
Screening Visit (Visit 1), study personnel will register the patient in the IWRS, and the 
system will assign the patient a sequential PID number. The first patient entered in the 
system at each study site will be assigned the first number in the sequence by the system. 
 
 
This PID number will be 
used to identify the patient throughout the study (ie, at all study phases). 
The study site must contact the IWRS at screening in order to obtain the kit number for 
the investigational product that will be dispensed to the patient throughout the study. 
Confirmation of the investigational product number will be faxed or e-mailed (per the 
study site’s preference) to the study site following each assignment. A detailed 
description of IWRS procedures is contained in the IWRS Manual in the Study Reference 
Binder.
9.4.4
Selection of Dosages in the Study
The doses chosen for this dose-ranging pediatric study are based on results obtained in 
the adult linaclotide clinical development program. In the adult program, 145 ug once 
daily was approved for CIC. Pediatric patients 6 to 11 years of age will be dosed using a 
weight-based approach; patients will receive 1 of 3 linaclotide doses. For patients who 
weigh < 35 kg, the doses administered will correspond to about 0.25 to 0.5, 0.5 to 1, or 
1 to 2 ug/kg. For patients who weigh ≥ 35 kg, the doses will not exceed 0.5, 1, or 2 ug/kg. 
Pediatric patients 12 to 17 years of age will receive 1 of 4 linaclotide dose levels. The 
approved adult dose level of 145 ug for CIC will be evaluated to obtain safety data in 
older pediatric patients (Table 9.4.5–1). 
9.4.5
Selection and Timing of Dose for Each Patient
All investigational products will be administered orally as a single daily dose taken 
30 minutes before the evening meal on a consistent, ongoing basis.


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Patients who continue to meet all eligibility criteria on Visit 3 (Day 1) will be assigned a 
randomization number, dispensed the corresponding double-blind investigational 
product, and receive their first dose of investigational product at the study site. Patients 
6 to 11 years of age will receive 1 or more bottles containing the liquid oral solution. 
Patients 12 to 17 years of age will receive 1 or more bottles containing solid oral capsules 
or liquid oral solution, based on choice or assignment. Patients will be instructed to take 
their assigned dose orally as a single daily dose at approximately the same time each day, 
30 minutes before their evening meal. Any alternate schedule must be approved and 
documented by the Investigator.
Dosage will be determined by weight for patients 6 to 11 years of age (18 to < 35 kg or 
≥35 kg) (Table 9.4.5–1). 
Patients will be instructed to return the empty/partially used bottle at the next study visit 
whether there is any remaining investigational product or if the bottle is empty. 
Investigational product will be dispensed as per the schedule shown in Section 2.0.
Table 9.4.5–1.
Double-blind Dosing Regimen
4-Week Treatment Period
Age Group
Weight
Linaclotide
Dose A 
Linaclotide
Dose B 
Linaclotide
Dose C 
Approved Adult 
Dose
Patients 6 -11 yearsa
18- < 35 kg
9 ug
18 ug
36 ug
—
placebo
placebo
placebo
—
≥ 35 kg
18 ug
36 ug
72 ug
—
placebo
placebo
placebo
—
Patients 12 -17 yearsb
18 ug
36 ug
72 ug
145 ugc
placebo
placebo
placebo
placebo
a
Patients 6 to 11 years of age will receive linaclotide or placebo in a liquid oral solution.
b
Patients 12 to 17 years of age will receive linaclotide or placebo in a solid oral capsule or a liquid oral solution.
c
Approved dose is for safety and exploratory efficacy only.


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The Investigator may allow a patient to stop taking investigational product for up to 
3 days because of an intolerable AE. If the Investigator believes that the patient is unable 
to resume dosing after 3 days, or requires a suspension of dosing on more than 
1 occasion, the Investigator is required to contact the Study Physician to discuss the 
patient’s continued participation in the study.
9.4.6
Blinding
A list of patient randomization codes will be generated by Statistical Programming and 
implemented by the IWRS vendor (an electronic version will be stored on a secure 
server). This list will identify each patient by randomization number and include the 
patient’s corresponding treatment assignment.
9.4.7
Unblinding
Any unblinding at the study site level should be done only in an emergency that requires 
for the investigational product to be identified for the medical management of the patient. 
The Investigator has to notify the study physician immediately (Appendix II) and a full 
written explanation must be provided if the blind is broken. Before the investigational 
product is unblinded, every attempt should be made to discuss the case with the Study 
Physician. Breaking the code at the study site will immediately disqualify the patient 
from further participation in the study.
Treatment codes may be broken by Patient Safety for regulatory reporting purposes. In 
such cases, the study staff will be kept blinded and the patient will not need to be 
disqualified from the study. Representatives of the bioanalytical team may be unblinded 
prior to database lock in support of PK sample analysis. The unblinding of the 
bioanalytical representatives is to be carried out in a secure manner following the 
Sponsor’s standard operating procedures. Extreme care will be taken to ensure no other 
individuals outside the bioanalytical team will be unblinded.
For IWRS Unblinding
In an emergency, the Investigator can obtain the treatment assignment of any patient at 
his or her study site through the IWRS. In an emergency, the Investigator will access the 
IWRS to break the blind and record the unblinding in the eCRF.
9.4.8
Prior and Concomitant Therapy
A list of example medications that are allowed and not allowed as concomitant 
medications for either episodic or chronic use is provided in Appendix III. Medication 
history during the previous 3 months will be recorded at Screening (Visit 1) in the eCRF. 
Thereafter, any changes in concomitant medications or any new medications (other than 
dispensed, protocol-permitted rescue medications) will be recorded in the eCRF.


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9.4.9
Monitoring Treatment Compliance and Accountability
Investigational product accountability and compliance during any period will be closely 
monitored. 
 
 
 
 
 
 Treatment
compliance will be assessed through patient/caregiver and study site staff discussion at 
study visits and recorded on the eCRF. Every effort will be made to collect all unused 
investigational product at the final visit. 
9.5
EFFICACY AND SAFETY VARIABLES
9.5.1
Efficacy Assessments
All efficacy assessments will be determined by responses entered in the eDiary twice 
daily (morning eDiary and evening eDiary). Patients and caregivers must be able to read 
and understand the eDiary as a condition for study participation (inclusion criterion 3). If 
the patient is 6 to 11 years of age and has difficulty reading and understanding the eDiary 
without help, the interviewer-administered version of the eDiary must be used and the 
parent/guardian/LAR or caregiver who will be administering the interviewer-
administered version of the eDiary must undergo training. At the start of the Pretreatment 
Period, patients and caregivers will receive full training in the use and completion of the 
eDiary at the study visit in which they are given the eDiary. The parent/guardian/LAR or 
caregiver who supervises the patient in the completion of the eDiary or administers the 
interviewer-administered version should be the same individual throughout the course of 
the study (Section 5.3.2). 
9.5.1.1
Primary Efficacy Assessment
The primary efficacy assessments used to determine the change from baseline in 4-week 
overall SBM frequency rate during the Treatment Period (primary efficacy parameter) are 
the occurrences of SBMs (ie, BM frequency and rescue medication use) determined by 
the overall assessment of BM frequency as recorded in the eDiary. A SBM is a BM that 
occurs in the absence of laxative, suppository, or enema use on the calendar day of the 
BM or the calendar day before the BM. Patients will report their BM frequency (the 
number of BMs each day) and report their use of rescue medication by responding to the 
following: 


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Bowel Movement Frequency

Morning eDiary
From bedtime last night until now, how many times did you poop (and poop came 
out)? 
o
Enter number of times

Evening eDiary
From when you got up this morning until now, how many times did you poop (and 
poop came out)? 
o
Enter number of times
If response is > 0 BMs, then the patient answers the following question for each BM 
reported:
When did you poop today?
o
In the morning (from when you woke up until lunch)
o
In the afternoon (from lunch until dinner)
o
In the evening (from dinner until bedtime)
o
I don't know
Rescue medication use

Morning eDiary
From bedtime last night until now, did you take any medicine to help you poop, other 
than the study medicine? 
o
Yes
o
No

Evening eDiary
From when you got up this morning until now, did you take any medicine to help you 
poop, other than the study medicine?
o
Yes
o
No
If the response is ‘yes”, then the patient answers the following question:
When did you take the medicine (NOT your study medicine) to help you poop?
o
In the morning (from when you woke up until lunch)
o
In the afternoon (from lunch until dinner)
o
In the evening (from dinner until bedtime)
o
I don't know


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9.5.1.2
Secondary Efficacy Assessments
In addition to the primary efficacy assessment, 6 secondary efficacy assessments are 
included in the study regarding abdominal symptoms, BM characteristics, and fecal 
incontinence that will be determined by the daily assessments recorded in the eDiary. 
Abdominal Pain – Daytime
For this parameter, patients will rate their abdominal pain by responding to the following
in the evening eDiary:

From when you got up this morning until now, did your tummy hurt at all?
o
Yes
o
No
If “yes”, then patient answers the following question:

How much did your tummy hurt? 
1 = a tiny bit
2 = a little 
3 = some 
4 = a lot
Stool Consistency (Pediatric Bristol Stool Form Scale)
Stool consistency of each BM will be based on the p-BSFS (Appendix V). The BSFS is a 
well-accepted and widely used measurement of stool consistency (Lewis and Heaton, 
1997). The p-BSFS was developed by the Sponsor and Ironwood Pharmaceuticals based 
on the original BSFS and was refined based on qualitative research with pediatric patients 
with FC and IBS-C. Patients will use the p-BSFS 7-point ordinal scale to rate their stool 
consistency:
"Use the card provided to choose the poop that is most like the poop you had."
Type 1 = looks like small hard lumps or balls, like pebbles
Type 2 = looks like fat sausage shape but lumpy and hard
Type 3 = looks like a sausage but with cracks on it
Type 4 = looks like a sausage or snake, smooth and soft
Type 5 = looks like chicken nuggets, soft smooth blobs 
Type 6 = looks like oatmeal, fluffy mushy pieces 
Type 7 = looks like a milkshake, watery
99 - I don’t know 
Straining With Bowel Movement
Patients will assess the degree of straining by responding to the following:

When you pooped, how hard did you push?


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0 = not hard at all
1 = I pushed a tiny bit hard
2 = I pushed a little hard
3 = I pushed hard
4 = I pushed very hard
Abdominal Bloating - Daytime
For this parameter, patients will record their assessment of abdominal bloating by 
responding to the following in the evening eDiary:

From when you got up this morning until now, did your tummy FEEL big and full?  
o
Yes
o
No 
o
I don’t know what you mean
o
I don’t remember
If “yes” then patient answers the following question:

How big and full did your tummy FEEL?
1 = a tiny bit
2 = a little 
3 = medium 
4 = very
Complete Spontaneous Bowel Movement/Incomplete Evacuation 
A complete spontaneous bowel movement (CSBM) is an SBM that is associated with a 
sense of complete evacuation. Patients will record their assessment of the sensation of 
incomplete evacuation by responding to the following: 

When you pooped, did it feel like there was more poop left inside that didn’t come 
out?
o
Yes
o
No
Fecal Incontinence - Daytime
Patients will record their episodes of fecal incontinence by responding to the following 
evening assessments.
- From when you got up this morning until now, did you have a pooping accident 
(even a little)? 
o
Yes


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o
No
- From when you got up this morning until now, did you have any poop marks or 
stains on your underwear? 
o
Yes
o
No 
o
I don’t know
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9.5.2
Safety Assessments
Patients must be evaluated by a physician or an appropriately trained health care 
professional at every visit and the evaluation must be documented. The procedures 
discussed below will be completed at the designated visits. Safety assessments should not 
be administered to the patient unless the patient is accompanied by his or her consented  
caregiver.


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9.5.2.1
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product (ICH-E2A).
For the purpose of the site’s data collection responsibilities, any untoward event that was 
reported from the time written consent was obtained until 30 days after the final protocol-
defined study visit (or the last known dose of investigational product if the final visit does 
not occur) is to be considered an AE.
 
  
Examples of AEs are as follows:

Changes in the general condition of the patient

Subjective symptoms offered by or elicited from the patient

Objective signs observed by the Investigator or other study site personnel

All diseases that occur after signing the informed consent, including any change in 
severity or frequency of preexisting disease

All clinically relevant abnormalities in laboratory values or clinically relevant 
physical findings that occur during the study schedule
Please note medical procedures scheduled prior to consenting, but occurring during the 
study should not be captured as AEs, but should be listed in the medical history if related 
to a pre-existing condition.
 
 
 
 
 


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9.5.2.4
Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose:

Results in death

Is life threatening

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions, or

Is a congenital anomaly/birth defect
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based on appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in patient 
hospitalization, or the development of investigational product dependency or drug abuse.
Emergency room visits that do not result in hospitalization should be evaluated for one of 
the other serious outcomes to determine whether they qualify as SAEs.
Preplanned hospitalizations (e.g., elective procedures for preexisting conditions that did 
not worsen, such as cosmetic surgery and hysterectomy) are excluded from SAE 
reporting.


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9.5.2.5
Reporting Adverse Events and Serious Adverse Events
At each visit, patients are to be queried regarding any AEs or SAEs that have occurred 
since the previous visit. Patients will be asked to volunteer information with a nonleading 
question such as, “How do you feel since your last visit?” Study site personnel will 
record all pertinent information in the patient’s eCRF. Any AEs reported in diaries will 
also be reported on the relevant eCRF page.
All AEs must be recorded on the appropriate AE reporting page of the patient’s eCRF 
whether or not they are considered causally related to the investigational product.
For every AE, the Investigator must:

Provide an assessment of the seriousness of the event (ie, is it an SAE?), as well as 
the severity and causal relationship

Document all actions taken with regard to the investigational product

Detail any other treatment measures taken for the AE

Document the outcome of the AE
In addition, patients are to be reminded, as described in the ICF and in accordance with 
Section 9.5.2.1, to notify site personnel of any AEs occurring during the 30 day poststudy 
period. Any AEs reported by the patient (or patient representative) during this period are 
to be recorded in the eCRF.
Any AEs that are ongoing at the time of the final protocol-defined study visit will be 
followed until the condition returns to prestudy status, has resolved, or has stabilized. If a 
follow-up visit is deemed necessary for appropriate safety surveillance, it will take place 
within 30 days of the final protocol-defined study visit.
9.5.2.6
Immediate Reporting of Serious Adverse Events 
 
The Sponsor is required to inform worldwide regulatory authorities of SAEs that meet 
specific criteria. Therefore, the Sponsor must be notified immediately regarding any SAE 
that occurs after informed consent is obtained.
Within 24 hours of learning of any AE that meets one of the criteria for an SAE, the 
study site personnel must report the event to Forest Global Drug Safety on the SAE Form 
for Clinical Trials. The Sponsor’s Study Physician may also be notified by telephone.
If, during follow-up, any non-serious AE worsens and eventually meets the criteria for an 
SAE, that AE should be recorded as a new SAE. 


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The site must transmit the SAE Form for Clinical Trials to the SAE fax number shown 
below. Even if an initial report is made by telephone, the SAE Form for Clinical Trials 
completed with all available details must still be faxed within 24 hours of knowledge of 
the event at the study site.
Supplemental information should be submitted as soon as available and may include 
laboratory results, radiology reports, progress notes, hospital admission and emergency 
room notes, holding and observation notes, discharge summaries, autopsy reports, and 
death certificates.
The Investigator is expected to take all therapeutic measures necessary for resolution of 
the SAE. Any medications or procedures necessary for treatment of the SAE must be 
recorded on the appropriate pages of the patient’s eCRF. All SAEs are to be followed by 
the study staff until resolution or until the SAE is deemed stable. The Sponsor may 
contact the study site to solicit additional information or follow up on the event.
Fax the SAE Form for Clinical Trials to the Sponsor.
 
 
 
 
 
9
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9.6
DATA QUALITY ASSURANCE
9.6.1
Data Monitoring
Before any patient enters the study, a representative of the Sponsor will meet with the 
Investigator and the study site staff to review the procedures to be followed during the 
study. Electronic data capture (EDC) functionality training is provided via computer-
based training to train Investigators and authorized designees on recording the data in the 
eCRFs using the EDC system. After the first patient is enrolled, the Sponsor’s 
representative, a Regional Site Manager or designee, will periodically monitor the 
progress of the study by conducting on-site visits. This Regional Site Manager or 
designee will review query statuses remotely, possibly warranting more frequent 
communication and/or site visits with the Investigator and the study site staff. The 
Investigator will make available to the Regional Site Manager or designee source 
documents (written notes and electronic medical records, if used), signed consent forms, 
and all other study-related documents. The Investigator and the study site staff will be 
responsible for data entry of patient data into the eCRFs via the EDC system, resolving 
data queries generated via the EDC system and providing missing or corrected data. The 
Investigator or designee will be responsible for approving all changes performed on the 
data, and endorsing the patient data within the EDC system. This approval method will 
include applying an electronic signature linked to a uniquely assigned username and 
password that together will represent a traditional handwritten signature used in the past.
The study site staff will be fully trained by a representative of the eDiary vendor on the 
use of the eDiary and how to train patients and caregivers in the use of the eDiary 
(ie, how to complete their daily and weekly assessments and download their data). The 
study site staff will then be responsible for ensuring that all patients and caregivers 
enrolled in the study are given full training and support materials in relation to the 
completion of the eDiary. 


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9.6.2
Data Recording and Documentation
Data collection will involve the use of the Sponsor’s EDC system, to which only 
authorized personnel will have access. Patient’s data are to be entered into the EDC 
system by the Investigator or designee using their assigned EDC user account. After data 
entry into the EDC system by the Investigator or designee, a combination of manual and 
programmatic edit checks will be used to review the data for completeness, logic, and 
adherence to study protocol. As a result of these edits checks, data monitoring and 
reviews; queries may be electronically issued to the site and should be answered 
electronically via the EDC system.
Each query will carry identifying information (assigned username, date and time) to 
assist the Sponsor and the Investigator on the origin of the data clarification request and 
the response provided by the Investigator. All data changes made to the patient’s data via 
a data query will be approved by the Investigator prior to final database lock.
After all data have been reviewed and all issues have been resolved, the database will be 
locked.
All data collected in the context of this study will be stored and evaluated per regulatory 
requirements and applicable guidance for electronic records. Also, data will be stored and 
evaluated in such a way as to guarantee patient confidentiality in accordance with the 
legal stipulations applying to confidentiality of data. Study records (eg, copies of eCRFs, 
laboratory reports, patient diaries, regulatory documents) will be retained at the site, 
along with adequate source documentation, according to FDA and ICH requirements. All 
study records must be available for inspection by the Sponsor, its authorized 
representatives, and the FDA or other health authorities.
 
 
 
9.7
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
9.7.1
Patient Populations
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9.7.1.1
Screened Population
The Screened Population will consist of all patients who undergo the Screening Visit 
(Visit 1) and receive a PID number.
9.7.1.2
Randomized Population
The Randomized Population will consist of all patients in the Screened Population who 
are randomized to a treatment group in the study.
9.7.1.3
Safety Population
The Safety Population will consist of all patients in the Randomized Population who took 
at least 1 dose of double-blind investigational product.
9.7.1.4
Intent-to-Treat Population
The Intent-to-Treat (ITT) Population will consist of all patients in the Safety Population 
who had at least 1 postbaseline entry on BM characteristic assessments that determine 
occurrences of SBMs (ie, BM frequency and rescue medication use).
9.7.2
Patient Disposition
The number of patients in each of the study populations described in Section 9.7.1 will be 
summarized overall, by treatment group, 
 
The number of screen failures (ie, patients who enter the Screening Period but not the 
Pretreatment Period) and patients ineligible for randomization (ie, patients who enter the 
Pretreatment Period but are not randomized at Visit 3), along with the associated reasons 
for failure, will be tabulated overall
 


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The number and percentage of patients who complete the Double-blind Treatment Period 
(ie, the Treatment Period) and the number and percentage of patients who prematurely 
discontinue during the Treatment Period will be presented by treatment group and overall 
for Randomized Population 
. The 
reasons for premature discontinuation from the Treatment Period as recorded on the study 
termination page of the eCRFs will be summarized (number and percentage) by treatment 
group and overall for the Randomized Population. Patients who complete the Treatment 
Period and patients who prematurely discontinue during the Treatment Period for their 
corresponding reasons will also be summarized by treatment group
 
 
 
9.7.3
Demographics and Other Baseline Characteristics
Demographic parameters (e.g., age, race, ethnicity, sex, weight) and other baseline 
characteristics will be summarized by treatment group for the Safety and 
ITT Populations. 
 
 
 
 
.
 
 
 
 
 
 
 
 
 
 


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9.7.5
Efficacy Analyses
Efficacy analyses will be based on the ITT Population. 


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Baseline values for efficacy parameters will be derived from the eDiary in the 
Pretreatment Period, specifically the period of time from 14 days before randomization 
up to the time of randomization. The baseline weekly SBM or CSBM rate will be derived 
based on the total number of SBMs or CSBMs a patient had during this period. Baseline 
stool consistency and straining based on combined morning and evening assessments will 
be calculated as the observed weighted average of the nonmissing daily values during this 
period; the nonmissing daily value will be the average of nonmissing morning and/or 
evening assessments associated with the corresponding (ie, morning and/or evening) 
SBMs by the patient on that specific day.
 
. The sum of the 
weights during this period will be used in the denominator to calculate the observed 
weighted average of the nonmissing daily values. 
 
 
 
 
 
 Baseline 
abdominal pain or bloating daytime symptoms, based on evening 
 
 assessment, will be calculated as the average of the 
nonmissing patient scores reported in the evening 
Baseline fecal 
incontinence daytime symptoms, based on evening assessment, will be calculated as the 
average of nonmissing patient scores reported in the evening diary.
Since the BM-related assessments and abdominal-symptom assessments in this study will 
be assessed twice daily via eDiary entries for efficacy parameters that will be derived 
based on the combined morning and evening assessments; a patient’s daily score (based 
on combined morning and evening assessments) will be defined as the daily average (of 
the morning score and the evening score), except SBM and CSBM frequency. In case 
only the morning assessment score or only the evening assessment score is available, the 
available morning (or the available evening) assessment score will be taken as the 
patient’s daily score.
An observed-cases approach to missing postbaseline data will be applied. The overall 
analysis (incorporating both age groups) including placebo and linaclotide doses (A, B, 
and C) will be the analysis to evaluate the main objective of this study.
 
 
All statistical tests will be 2-sided hypothesis tests performed at the 5% level 
of significance. All confidence intervals (CIs) will be 2-sided 95% CI, unless stated 
otherwise. No multiplicity adjustment will be applied in this dose-ranging study. Nominal 
p-values will be provided for the efficacy parameters as a measure of strength of 
association between the endpoint and the treatment effect.


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9.7.5.1
Primary Efficacy Parameter
The primary efficacy parameter is the change from baseline in 4-week overall SBM
frequency rate (SBMs/week) during the Treatment Period. The numerator of the SBM 
rate (SBMs/week) during the Treatment Period will be derived based on the total number 
of SBMs a patient reported during this period in the morning and evening eDiaries.
For the primary efficacy parameter, comparison between each linaclotide dose (A, B, and 
C) and placebo will be performed using an analysis of covariance (ANCOVA) model 
with treatment and age group (6 - 11 years of age and 12 - 17 years of age) as factors and 
baseline value as a covariate. Least squares means (LSMs) for each treatment group, 
differences in LSMs between each linaclotide treatment group versus placebo, associated 
2-sided 95% CIs for these differences in LSMs, and the corresponding statistical test
p-values will be reported.
 
 
 
 
 
 
 
 
 
 
 


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9.7.5.2
Secondary Efficacy Parameters
Six change from baseline parameters are secondary efficacy parameters in this study. 
Their description and analyses are provided below.
Change From Baseline in 4-Week Abdominal Pain Daytime Symptoms Based on 
Evening Assessment
Abdominal pain scores will be collected twice daily in the eDiary: in the morning when 
a patient wakes up and in the evening at bedtime. Patients are asked to rate their 
abdominal pain from the time the patient wakes up until bedtime as part of the evening 
assessment, and a 5-point rating scale is derived from the patient’s responses. The 
patient’s 4-week abdominal pain daytime symptoms during the Treatment Period are 
defined as the average of the nonmissing daily abdominal pain daytime symptoms 
reported in evening assessments in the eDiary during the 4-week Treatment Period.
Change From Baseline in 4-Week Stool Consistency
Stool consistency will be collected twice daily in the eDiary, in the morning when a 
patient wakes up and in the evening at bedtime, and measured using the 7-point p-BSFS. 
The patient’s p-BSFS score in the 4-week Treatment Period will be the observed 
weighted average of the daily p-BSFS scores (using weight of 1 for full day and 0.5 for 
half day) and the denominator in the observed weighted average will be the sum of the 
weights during this period. The daily p-BSFS score will be the average of nonmissing 
morning and/or evening assessments of the p-BSFS score from the SBMs reported by the 
patient on that specific day during the Treatment Period
Change From Baseline in 4-Week of Severity of Straining
Straining with each BM will be collected twice daily in the eDiary, in the morning when 
a patient wakes up and in the evening at bedtime, and measured using a 5-point scale. 
The patient’s straining score in the 4-week Treatment Period will be the observed 
weighted average of daily straining score (using weight of 1 for full day and 0.5 for half 
day) and the denominator in the observed weighted average will be the sum of the 
weights during this period. The daily score for the Treatment Period will be the average 
of the nonmissing morning and/or evening assessments of the straining score from the 
SBMs reported by the patient on that specific day during the Treatment Period.
Change From Baseline in 4-Week Abdominal Bloating Daytime Symptoms Based on 
Evening Assessment
Abdominal bloating will be collected twice daily in the eDiary, in the morning when a 
patient wakes up and in the evening at bedtime. Patients are asked to rate their abdominal 
bloating from the time the patient wakes up until bedtime as part of the evening 
assessment, and a 5-point rating scale is derived from the patient’s responses. The 
patient’s 4-week abdominal bloating daytime symptoms during the Treatment Period are 
defined as the average of the nonmissing daily abdominal bloating daytime symptoms 
reported in evening assessments in the eDiary during the 4-week Treatment Period.


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Change From Baseline in 4-Week Overall CSBM Frequency Rate (CSBMs/week) 
During the Treatment Period
A patient’s 4-week overall CSBM frequency rate will be the CSBM rate (CSBMs/week) 
calculated over the 4-week Treatment Period. The numerator of the CSBM rate 
(CSBMs/week) during the 4-week Treatment Period will be derived based on the total 
number of CSBMs a patient reported during this period in his/her morning and 
evening eDiary.
Change From Baseline in 4-Week Fecal Incontinence Daytime Symptoms Based on 
Evening Assessment 
Fecal incontinence will be collected daily in the evening eDiary. Patients are asked two 
questions (as discussed in Section 9.5.1.3) to cover the interval from when the patient 
wakes up until bedtime as part of the evening assessment. Any "yes" response in either of 
these questions will be counted as presence of fecal incontinence. The patient’s 4-week 
fecal incontinence daytime symptoms during the Treatment Period are defined as the 
average of the nonmissing daily fecal incontinence daytime symptoms reported in 
evening assessments in the eDiary during the 4-week Treatment Period.
Analysis Method for Change-From-Baseline Parameters
For each change-from-baseline parameter (except change from baseline in 4-week fecal 
incontinence daytime symptoms based on evening assessment), each linaclotide dose 
group (A, B, and C) will be compared with the placebo group using an ANCOVA model 
with treatment (linaclotide doses A, B, and C, and placebo) and age group (6 - 11 years of 
age and 12 - 17 years of age) as factors and baseline value as a covariate. LSMs for each 
treatment group, differences in LSMs between each linaclotide treatment group versus 
placebo, associated 2-sided 95% CIs for these differences in LSMs, and the 
corresponding statistical test p-values will be reported. 
 
 
 
Change from baseline in 4-week fecal incontinence daytime symptoms based on 
evening assessment will be summarized based on descriptive statistics by treatment 
group.
 
 
 
 


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In addition, stool consistency and straining during the analysis period (based on morning 
and evening assessments) will also be derived as the mean of the patient’s non-missing, 
SBM-associated scores during the analysis period (similar to LIN-MD-31 and MCP-103-
302 adult studies).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9.7.6
Safety Analyses
The safety analysis will be performed using the Safety Population. The safety summaries 
will be provided by treatment group overall
 
 The safety parameters will include AEs, 
 
 
9.7.6.1
Adverse Events
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
Version 18.0 or newer. 
An AE (classified by preferred term) that occurs during the Treatment Period will be 
considered a TEAE if it was not present before the date of the first dose of double-blind 
investigational product or was present before the date of the first dose of double-blind 
investigational product and increased in severity during the Treatment Period. If more 
than 1 AE is reported before the date of the first dose of double-blind investigational 
product and coded to the same preferred term, the AE with the greatest severity will be 
used as the benchmark for comparison with the AEs occurring during the Treatment 
Period that were also coded to that preferred term. An AE that occurs more than1 day 
after the date of the last dose of double-blind investigational product will not be counted 
as a TEAE.
The number and percentage of patients reporting TEAEs in each treatment group will be 
tabulated by SOC and preferred term;
 
 
 
 
The incidence of common (≥ 5% of patients in any treatment group) TEAEs, on-therapy 
SAEs, 
 
 
. In addition, the incidence of fatal on-
therapy SAEs (ie, events that caused death) will be summarized separately by treatment 
group and preferred term. 


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9.7.8
Interim Analysis
No interim analysis is planned for this study. 


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9.7.10
Computer Methods
Statistical analyses will be performed using 
 
9.8
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSES
Any amendment to this protocol will be provided to the Investigator in writing by the 
Sponsor. No protocol amendment may be implemented (with the exceptions noted below) 
before it has been approved by the IRB/IEC and the signature page, signed by the 
Investigator, has been received by the Sponsor. If the protocol is amended to eliminate or 
reduce the risk to patients, the amendment may be implemented before IRB/IEC review 
and approval. However, the IRB/IEC must be informed in writing of such an amendment, 
and approval must be obtained within reasonable time limits. 


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9.9
PROTOCOL DEVIATIONS 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures that is under the Investigator’s responsibility and oversight (as defined by 
regulations) without prior written IRB/IEC approval or favorable opinion of an 
appropriate amendment and that does not have a major impact on the patient’s rights, 
safety, or well-being, or on the integrity and authenticity of the study data. Deviations 
may include, but are not limited to, departure from inclusion/exclusion criteria, allowed 
concomitant medications, dosing or duration of treatment, failure to follow withdrawal 
criteria or perform the required assessments at specified time points, scheduling of visits 
not in accordance with specifications. 
Deviating from the protocol is permitted only if absolutely necessary for the safety or 
clinical management of the patients and must immediately be reported to the Sponsor. 
Protocol deviations should be reported to the Sponsor (either verbally or electronically) in 
a timely manner from the day of discovery.
Protocol deviations that may impact patient’s rights (eg, failure to obtain informed 
consent prior to initiating study procedures), safety, or well-being (eg, deviations that 
resulted in an SAE, exposure during pregnancy),or the integrity and authenticity of the 
study data should be reported to the Sponsor within 24 hours, if possible. 
The IRB/IEC must be notified according to the criteria and time period dictated by the 
IRB/IEC associated with this study. 


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10.0
STUDY SPONSORSHIP
This study is sponsored by Forest Research Institute, Inc. in partnership with Ironwood 
Pharmaceuticals, Inc.
10.1
STUDY TERMINATION
The Sponsor reserves the right to terminate the study in its entirety or at a specific study 
site before study completion. 
10.2
REPORTING AND PUBLICATION
All data generated in this study are the property of the Sponsor. An integrated clinical and 
statistical report will be prepared at the completion of the study.
Publication of the results by the Investigator will be subject to mutual agreement between 
the Investigator and the Sponsor and will follow the Sponsor’s standard operating 
procedures on publications.


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11.0
INVESTIGATOR OBLIGATIONS
11.1
DOCUMENTATION
The Investigator must provide the following to the Sponsor before the start of the study:

A completed and signed Form FDA 1572. If, during the course of the study, any 
changes are made that are not reflected on Form FDA 1572, a new Form FDA 1572 
must be completed and returned to the Sponsor for submission to the FDA

A fully executed contract

The curricula vitae for the Investigator and all Subinvestigators listed on Form FDA 
1572, including a copy of each physician’s license

A copy of the original IRB/EC approval for conducting the study. If the study is 
ongoing, renewals must be submitted at yearly intervals. All subsequent 
modifications must be submitted and approved by the IRB/EC, as stated in 
Section 5.1

A copy of the IRB/EC-approved ICF

A copy of the HIPAA authorization form, or other local privacy applicable forms

A list of the IRB/EC members or the US Department of Health and Human Services 
general assurance number

A copy of the laboratory certifications and reference ranges

The Investigator’s Statement page in this protocol signed and dated by the 
investigator

Financial disclosure agreement completed and signed by the Investigator and all 
Subinvestigators listed on Form FDA 1572. The Investigator and all Subinvestigators 
will provide an updated financial disclosure agreement to the Sponsor 1 year after the 
completion of the study
11.2
PERFORMANCE
The Investigator must demonstrate reasonable efforts to obtain qualified patients for the 
study.


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11.3
USE OF INVESTIGATIONAL MATERIALS
The Investigator will acknowledge that the investigational product supplies are 
investigational and as such must be used strictly in accordance with the protocol and only 
under the supervision of the Investigator or Subinvestigators listed on Form FDA 1572. 
The investigational products must be stored in a secured place and must be locked. At 
study initiation, a representative from the Sponsor will inventory the investigational 
products at the site. The Investigator must maintain adequate records documenting the 
receipt and disposition of all study supplies. The Sponsor will supply forms on which to 
record the date the investigational products were received and a dispensing record in 
which to record each patient’s use. All unused investigational products must be returned 
to the Sponsor. It is the Investigator’s responsibility to ensure that patients return their 
investigational product.
11.4
CASE REPORT FORMS
All patient data relating to the study will be recorded on eCRFs to be provided by the 
Sponsor through the EDC system. The investigator is responsible for verifying that all 
data entries in the eCRFs are accurate and correct by electronically signing the completed 
eCRF casebook submitted to the Sponsor. The investigator must maintain and retain 
accurate documentation that supports the information entered into the EDC system for 
source document verification and possible regulatory inspection.
11.5
RETENTION AND REVIEW OF RECORDS
Records and documents pertaining to the conduct of this study, including eCRFs, source 
documents, consent forms, regulatory documents, clinical laboratory results, calibration 
logs, or reports (including, but not limited to, all local and central laboratory results and 
ECG reports), and medication inventory records in all formats (including, but not limited 
to, written, electronic, magnetic, and optical records, and scans, x-rays, and ECGs) must 
be retained by the Investigator for a period of at least 15 years after study completion 
unless local regulations or institutional policies require a longer retention period or 
otherwise notified in writing by the Sponsor. 
No study records shall be destroyed without notifying the Sponsor and providing the 
Sponsor the opportunity to arrange long-term storage for such study records or 
authorizing in writing the destruction of records after the required retention period.


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The Investigator must permit access to any documentation relating to the study upon 
request of the Sponsor or applicable regulatory authorities. If the Investigator for the 
study retires, relocates, or for other reasons withdraws from the responsibility of keeping 
the study records, custody must be transferred to a suitable alternate custodian employee 
of the institution or to a suitably qualified and responsible third party. The Sponsor must 
be notified in writing of the name and address of the new custodian in advance of the 
transfer.
For countries falling within the scope of the ICH guidelines, the sponsor-specific 
essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirement(s) or if needed by the sponsor.
In addition, for countries not falling within the scope of the ICH guidelines, local 
regulatory requirements should be followed regarding the retention of clinical study 
documentation.
For Canadian study sites only: All records and documents pertaining to the conduct of the 
study must be retained for a 25-year period in accordance with the Canadian Food and 
Drugs Act and Regulations. 
11.6
PATIENT CONFIDENTIALITY
All patient records will only be identified by initials (where applicable) and PID number. 
Patients’ names are not to be transmitted to the Sponsor. The Investigator will keep a 
master patient list on which the PID number and the full name, address, and telephone 
number of each patient are listed.


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12.0
INVESTIGATOR’S STATEMENT
I agree to conduct the study in accordance with this protocol amendment (LIN-MD-62, 
Amendment #3, dated 16 May 2017) and with all applicable government regulations and 
good clinical practice guidance.
_______________________________________
_____/_____/______
Investigator’s Signature
Date
_______________________________________
Investigator’s Name


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13.0
APPENDICES
APPENDIX I.
ELEMENTS OF INFORMED CONSENT
Procedures will comply with 21 CFR, Parts 50 and 312. Signed informed consent will be 
obtained from each patient participating in a clinical research study or from the patient’s 
parent/guardian/LAR. This consent must include the following items:

A statement that the study involves research and an explanation of the purposes of the 
research; a description of the procedures to be followed and the identification of any 
procedures that are experimental; and the expected duration of the patient’s 
participation

A description of any reasonably foreseeable risks or discomforts to the patient

A description of any benefits to the patient or to others that may reasonably be 
expected from the research. If the patient is to be paid for participating in the study, 
the consent form must state the amount that he/she will receive and the schedule of 
payment (to ensure neither coercion nor undue influence)

A disclosure of appropriate alternative procedures or courses of treatment, if any, that 
might be advantageous to the patient

A statement describing the extent, if any, to which confidentiality of records 
identifying the patient will be maintained and noting the possibility that the FDA; the 
Sponsor, the IRB; or an authorized contract research organization may inspect the 
records

For research involving more than minimal risk, an explanation of whether any 
medical treatment is available if injury occurs and, if so, what it consists of or where 
further information may be obtained

An explanation of whom to contact, including the relevant telephone number, for 
answers to pertinent questions about the research and the research patient’s rights and 
whom to contact in the event of a research-related injury to the patient. (Note: In 
some cases, it may be necessary to identify a person other than the investigator as the 
contact. The guidance of the IRB/EC may be required)

A statement that participation is voluntary, that refusal to participate will involve no 
penalty or loss of benefits to which the patient is otherwise entitled, and that the 
patient may discontinue participation at any time without penalty or loss of benefits to 
which the patient is otherwise entitled


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
A statement that the particular treatment or procedures may involve risks to the 
patient (or to the embryo or fetus if the patient is, or may become, pregnant) that are 
at present unforeseeable

The expected circumstances for which the patient’s participation may be terminated 
by the investigator without regard to the patient’s consent

Any additional costs to the patient that may result from participation in the research

The consequences of a patient’s decision to withdraw from the research and 
procedures for an orderly termination of the patient’s participation

A statement that significant new findings developed during the course of the research 
that may relate to the patient’s willingness to continue participation will be provided 
to the patient

The approximate number of patients involved in the study

A statement of consent (eg, “I agree to allow (my child) to participate . . .”)

A place for the patient’s parent/guardian/LAR signature and date of signing

A statement indicating that information about this study has been, or will be, entered 
into a databank that is publicly accessible at www.ClinicalTrials.gov.
A copy of the signed consent form must be given to the patient’s parent/guardian/LAR.
In addition, the patient will be asked to provide assent that will include a statement 
agreeing to participate in the study.


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APPENDIX II.
CONTACT INFORMATION 
Contact information for the Sponsor’s personnel is maintained in the Study Reference 
Binder.


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APPENDIX III.
CONCOMITANT MEDICATIONS
Rescue Medication
Rescue medication will be provided
 
Laxative, 
suppository, or enema use must be documented with all other concomitant medication 
use in the eDiary.
Protocol-permitted rescue medicine, which will be selected by and dispensed to patients, 
will be a choice of senna (oral) or bisacodyl (oral or rectal). During the Pretreatment, 
Treatment, and Post-treatment Periods, patients may use dispensed, protocol-permitted 
laxatives (ie, senna or bisacodyl) as rescue medicine 
 
 
 
 
 
 
Prohibited Medications
All medicines listed in the sections below 
 will be 
excluded during the Pretreatment, Treatment and Post-treatment Periods. 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX IV.
BLOOD SAMPLING AND SHIPPING INSTRUCTIONS
Blood collection procedure
Blood and urine samples will be collected, handled, and processed according to the 
instructions provided in the Central Laboratory Manual.
Sample shipping guide from the study center to the central laboratory
Samples will be shipped from the study site to the central laboratory on the day of 
collection or as specified in the Central Laboratory Manual. The central laboratory will 
provide packaging, labeling, and shipping instructions. 


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14.0
LITERATURE CITED
Bryant AP, Busby RW, Bartolini WP, et al. Linaclotide is a potent and selective 
guanylate cyclase C agonist that elicits pharmacological effects locally in the 
gastrointestinal tract. Life Sci 2010;86:760-5. 
Constipation Guideline Committee of the North American Society for Pediatric 
Gastroenterology, Hepatology and Nutrition. Evaluation and treatment of constipation in 
infants and children: Recommendations of the North American Society for Pediatric 
Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 
2006;43(3):e1-13.
Eutamene H, Bradesi S, Larauche M, et al. Guanylate cyclase C-mediated antinociceptive 
effects of linaclotide in rodent models of visceral pain. Neurogastroenterol Motil 
2010;22:312-e84.
Hyams JS. Functional gastrointestinal disorders. Curr Opin Pediatr1999;11:375-8.
Hyman PE, DiLorenzo C, Prestridge LL, et al. Lubiprostone for the treatment of 
functional constipation in children. J Pediatr Gastroenterol Nutr.2014;58:283-91.
Lewis SJ, and Heaton KW. Stool form scale as a useful guide to intestinal transit time. 
Scand J Gastroenterol 1997;32:920-24.
Linaclotide: Investigator’s brochure. Edition 11. Cambridge, MA: Ironwood 
Pharmaceuticals, Inc; 2016 Nov 22. 
Pijpers MA, Bongers ME, Benninga MA, et al. Functional constipation in children: A 
systematic review on prognosis and predictive factors. J Pediatr Gastroenterol Nutr 
2010;50:256–68.
Study LIN-MD-01: a phase III, randomized, double-blind, placebo-controlled, 
parallel-group trial of linaclotide administered orally for 12 weeks in patients with 
chronic constipation. Jersey City, NJ: Forest Research Institute, Inc; 2010 Jun 2. 
Study LIN-MD-02: an open-label, long-term safety study of oral linaclotide administered 
to patients with chronic constipation or irritable bowel syndrome with constipation. 
Jersey City, NJ: Forest Research Institute, Inc; 2012 Nov 5.
Study LIN-MD-04: a phase 3b, randomized, double-blind, placebo-controlled, 
parallel-group trial of linaclotide administered orally for 12 weeks to patients with 
chronic constipation and prominent abdominal bloating at baseline. Jersey City, NJ: 
Forest Research Institute, Inc; 2014 March 14.


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Study LIN-MD-31: a phase III, randomized, double-blind, placebo-controlled, 
parallel-group trial of linaclotide administered orally for 12 weeks followed by a 4-week 
randomized withdrawal period in patients with irritable bowel syndrome with 
constipation. Jersey City, NJ: Forest Research Institute, Inc; 2011 May 10.
Study MCP-103-201: a randomized, multicenter, double-blind, placebo-controlled, dose-
range-finding, parallel-group, phase 2 trial of oral linaclotide acetate administered to 
patients with chronic constipation. Cambridge, MA: Ironwood Pharmaceuticals, Inc: 
2009 Aug 07.
Study MCP-103-302: a phase 3, randomized, double-blind, placebo-controlled, 
parallel-group trial of linaclotide administered orally for 26 weeks in patients with 
irritable bowel syndrome with constipation. Cambridge, MA: Ironwood Pharmaceuticals, 
Inc: 2011 May 24.
Study MCP-103-303: a phase 3, randomized, double-blind, placebo-controlled, 
parallel-group, trial of linaclotide administered orally for 12 weeks followed by a 4-week 
randomized withdrawal period in patients with chronic constipation. Cambridge, MA: 
Ironwood Pharmaceuticals, Inc; 2010 May 7.
Study MCP-103-305: an open-label, long-term safety study of oral linaclotide 
administered to patients with chronic constipation or irritable bowel syndrome with 
constipation. Cambridge, MA: Ironwood Pharmaceuticals, Inc;2012 Oct 18.
Study MCP-103-309: a Phase 3, Randomized, Double-blind, Placebo controlled, Parallel-
group Trial of Linaclotide (72 ug or 145 ug) Administered Orally for 12 Weeks to 
Patients with Chronic Idiopathic Constipation. Cambridge, MA: Ironwood 
Pharmaceuticals, Inc; 2010 Feb 10.
Tabbers MM, DiLorenzo C, Berger MY, et al. Evaluation and treatment of functional 
constipation in infants and children: Evidence-based recommendations from ESPGHAN 
and NASPGHAN. J Pediatr Gastroenterol Nutr 2014;58:258-74.
Varni JW, Burwinkle TM, Berrin SJ, et al. The PedsQL in pediatric cerebral palsy: 
reliability, validity, and sensitivity of the Generic Core Scales and Cerebral Palsy 
Module. Dev Med Child Neurol Jun 2006;48(6):442-9.
Varni JW, Burwinkle TM, Jacobs JR, et al. The PedsQL in type 1 and type 2 diabetes: 
reliability and validity of the Pediatric Quality of Life Inventory Generic Core Scales and 
type 1 Diabetes Module. Diabetes Care Mar 2003;26(3):631-7.
Varni JW, Burwinkle TM, Katz ER, et al. The PedsQL in pediatric cancer: reliability and 
validity of the Pediatric Quality of Life Inventory Generic Core Scales, Multidimensional 
Fatigue Scale, and Cancer Module. Cancer Apr 1 2002;94(7):2090-106.


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Varni JW, Burwinkle TM, Rapoff MA, et al. The PedsQL in pediatric asthma: reliability 
and validity of the Pediatric Quality of Life Inventory generic core scales and asthma 
module. J Behav Med Jun 2004;27(3):297-318.
Varni JW, Burwinkle TM, Seid M. The PedsQL 4.0 as a school population health 
measure: feasibility, reliability, and validity. Qual Life Res Mar 2006;15(2):203-15.
Varni JW, Seid M, Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric Quality 
of Life Inventory version 4.0 generic core scales in healthy and patient populations. 
Med Care Aug 2001;39(8):800-12.
Varni JW, Seid M, Smith Knight T, et al. The PedsQL in pediatric rheumatology: 
reliability, validity, and responsiveness of the Pediatric Quality of Life Inventory Generic 
Core Scales and Rheumatology Module. Arthritis Rheum Mar 2002;46(3):714-25.


Protocol Amendment #3 - Summary of Changes LIN-MD-62
Forest Research Institute, Inc.
Forest Research Institute, Inc., an affiliate of Allergan.
Harborside Financial Center, Plaza V
Jersey City, NJ 07311
SUMMARY OF CHANGES TO PROTOCOL 
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, Who Fulfill Modified Rome III Criteria for 
Child/Adolescent Functional Constipation (FC)
LIN-MD-62
IND #63,290
Original Protocol Date:
15 Apr 2015
Amendment #1:
13 Aug 2015
Amendment #2:
11 Sep 2016
Amendment #3:
16 May 2017
Confidentiality Statement
This document is the property of Forest Research Institute, Inc., and may not—in full or 
part—be passed on, reproduced, published, distributed, or submitted to any regulatory 
authority without the express written permission of Forest Research Institute, Inc.


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1.0
INTRODUCTION
In response to protocol comments provided by the FDA on 12 Jun 2015, Amendment #1 
to the original protocol was completed 13 Aug 2015. In a subsequent effort to stimulate 
enrollment into the study and to respond to European regulatory advice, Amendment #2 
was completed on 11 Sep 2016. In order to comply fully with FDA instructions relating 
to follow-up to adverse events, and to incorporate additional FDA feedback, Amendment 
#3 was developed.
Amendment #1 specified the following changes to the original protocol LIN-MD-62,
dated 15 Apr 2015:

to allow patients 12-17 years of age to select liquid oral solution as an alternative 
to the previously specified solid oral capsules
 

to include a repeat swallow test for patients who receive capsules to assess those 
patients’ ability to swallow capsules on 2 occasions a minimum of 1 week apart
 
 
 
 
.
Amendment #2 specified the following changes to protocol LIN-MD-62 as previously 
amended, dated 13 Aug 2015: 

to change the name of the sponsor

to increase the number of study sites

to correct the duration of treatment

to update Sections 9.1.2, 9.3.1, 9.5.5.2, and 9.5.5.3 to require compliance with 
eDiary on 8 out of 14 days 

to supplement clinical experience information with details of recently completed 
studies
 

to clarify inclusion criterion #5 and to allow fecal incontinence as part of Rome 
III criteria in #6


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
to clarify exclusion criteria # 7

to broaden the text describing rescue medications and use of IWRS 

to remove the use of patient’s initials (where applicable)

to clarify monitoring of treatment compliance and accountability

to reorder the secondary efficacy assessments, to add fecal incontinence as a 
secondary efficacy assessment, and to move abdominal pain-daytime from the 
additional efficacy assessments to the secondary efficacy assessments
 

to clarify the AE time window definition and to update SAE reporting contact 
information
 
 
 
 
 
 
 
 
In addition, minor clarifications of previous text were made in several sections of the 
document.
Amendment #3 specifies the following changes to protocol LIN-MD-62 as previously 
amended, dated 11 Sep 2016: 

to update the Synopsis (Statistical Methods) regarding fecal incontinence data 
summarization

to update Section 7.1 with the new Investigator’s Brochure date

to update Section 7.2.1 to supplement clinical experience information with details 
of recent post-marketing experience

to update Sections 9.1.2, 9.3.1, 9.5.5.2, and 9.5.5.3 to require compliance with 
eDiary on at least 10 of 14 days

to update the footnote to Table 9.4.2-1 with correct abbreviation description for 
NF (National Formulary)


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
to update Section 14.0 with the new Investigator’s Brochure date and version 
number
 
Not summarized here, minor clarifications of previous text were made in several sections 
of the document.


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2.0
GLOBAL CHANGES
None.


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3.0
SECTIONS DELETED
None.


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4.0
SECTIONS ADDED
None.


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5.0
REVISIONS
5.1
SECTION 2.0 SYNOPSIS AND SCHEDULE OF 
EVALUATIONS (STATISTICAL METHODS)
Rationale: The synopsis (Statistical Methods) has been revised to indicate that fecal 
incontinence daytime symptoms based on evening diary will be only summarized based 
on descriptive statistics.
The second paragraph of statistical methods has been updated and now reads as 
follows: 
The change-from-baseline secondary efficacy parameters (except fecal incontinence 
daytime symptoms) defined for the Treatment Period will be analyzed in a similar way as 
the primary efficacy parameter (with A, B, and C linaclotide dose levels and placebo) 
using the ANCOVA model. An exploratory analysis with the approved adult linaclotide 
dose, 145 ug, within the 12 to 17 year age group will be provided. The change from 
baseline in 4-week fecal incontinence daytime symptoms based on evening diary will be 
summarized only based on descriptive statistics.
5.2
SECTION 7.1, SUMMARY OF LINACLOTIDE PROPERTIES
Rationale: The Investigator’s Brochure has been updated.
The last sentence of the section now reads as follows: 
Refer to the Investigator’s Brochure for a more detailed description of the chemistry, 
pharmacology, efficacy, and safety of linaclotide, based on studies conducted in animals, 
healthy volunteers, and in adult patients with IBS-C and CIC (Investigator’s Brochure, 
20152016).
5.3
SECTION 7.2.1, OTHER INFORMATION
Rationale: Updated post-marketing experience has become available.
A second paragraph that reads as follows has been added to this section:
In post-marketing experience, severe diarrhea AEs associated with dizziness, syncope, 
hypotension and electrolyte abnormalities (hypokalemia and hyponatremia) requiring 
hospitalization or intravenous fluid administration have been reported in patients treated 
with linaclotide.


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5.4
SECTION 9.1.2 PRETREATMENT PERIOD
Rationale: Compliance with the eDiary has been made more stringent at FDA request.
The last sentence of the first paragraph now reads as follows: 
During the Pretreatment Period, compliance with the eDiary will be defined as 
completion of both morning and evening assessments for 8 10 out of the 14 days 
immediately preceding the Randomization Visit and must be documented before patients 
are included in the Double-blind Treatment Period.
5.5
SECTION 9.3.1 INCLUSION CRITERIA
Rationale: Compliance with the eDiary has been made more stringent at FDA request.
Inclusion criterion #10 now reads as follows: 
Patient or parent/guardian/LAR or caregiver is compliant with eDiary by completing both 
the morning and evening assessments for 8 10 out of the 14 days immediately preceding 
the Randomization Visit (Section 9.1.2)
5.6
TABLE 9.4.2-1 INVESTIGATIONAL PRODUCT 
FORMULATION
Rationale: Previous erroneous footnote text has been corrected.
The footnote text now reads as follows: 
NF = National Formulary nonformulary
 
 
.
 


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5.11
SECTION 9.7.5.1 , PRIMARY EFFICACY PARAMETER
Rationale: Additional sensitivity analysis has been added for primary efficacy parameter 


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A new sentence in the second paragraph that reads as follows has been added to this 
section: 
 
5.12
SECTION 9.7.5.2 , SECONDARY EFFICACY PARAMETERS
(ANALYSIS METHOD FOR CHANGE-FROM-BASELINE 
PARAMETERS)
Rationale: Clarified analysis for change from baseline in 4-week fecal incontinence 
daytime symptoms based on evening assessment.
 
New sentences in the first and second paragraphs, and a new third paragraph, that 
read as follows have been added to this section: 
For each change-from-baseline parameter (except change from baseline in 4-week fecal 
incontinence daytime symptoms based on evening assessment), each linaclotide dose 
group (A, B, and C) will be compared with the placebo group using an ANCOVA model 
with treatment (linaclotide doses A, B, and C, and placebo) and age group (6 - 11 years of 
age and 12 - 17 years of age) as factors and baseline value as a covariate.
Change from baseline in 4-week fecal incontinence daytime symptoms based on evening 
assessment will be summarized based on descriptive statistics by treatment group.
 
 
 
 
 
 
5.13
SECTION 14.0 LITERATURE CITED
Rationale: The Investigator’s Brochure has been updated.
The reference notation now reads as follows: 


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Linaclotide: Investigator’s brochure. Edition 1011. Cambridge, MA: Ironwood 
Pharmaceuticals, Inc; 2015 May 152016 Nov 22. 
 
 
 
 
 


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6.0
INVESTIGATOR’S STATEMENT
I agree to conduct the study in accordance with this protocol amendment (LIN-MD-62, 
Amendment #3, dated 16 May 2017) and with all applicable government regulations and 
good clinical practice guidance.
_______________________________________
_____/_____/______
Investigator’s Signature
Date
_______________________________________
Investigator’s Name


Protocol Amendment #2 - Summary of Changes LIN-MD-62
Forest Research Institute, Inc.
Forest Research Institute, Inc., an affiliate of Allergan.
Harborside Financial Center, Plaza V
Jersey City, NJ 07311
SUMMARY OF CHANGES TO PROTOCOL 
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, Who Fulfill Modified Rome III Criteria for 
Child/Adolescent Functional Constipation (FC)
LIN-MD-62
IND #63,290
Original Protocol Date:
15 Apr 2015
Amendment #1:
13 Aug 2015
Amendment #2:
11 Sep 2016
Confidentiality Statement
This document is the property of Forest Research Institute, Inc., and may not—in full or 
part—be passed on, reproduced, published, distributed, or submitted to any regulatory 
authority without the express written permission of Forest Research Institute, Inc.


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1.0
INTRODUCTION
In response to protocol comments provided by the FDA on 12 Jun 2015, Amendment #1 
to the original protocol was completed 13 Aug 2015. In a subsequent effort to stimulate 
enrollment into the study and to respond to European regulatory advice, Amendment #2 
was planned.
Amendment #1 specified the following changes to the original protocol LIN-MD-62,
dated 15 Apr 2015:

to allow patients 12-17 years of age to select liquid oral solution as an alternative 
to the preciously specified solid oral capsules
 

to include a repeat swallow test for patients who receive capsules to assess those 
patients’ ability to swallow capsules on 2 occasions a minimum of 1 week apart
 
 
 
 and minor clarifications of previous text were made in 
several sections.
Amendment #2 specifies the following changes to protocol LIN-MD-62 as previously 
amended, dated 13 Aug 2015: 

to change the name of the sponsor

to increase the number of study sites

to correct the duration of treatment

to supplement clinical experience information with details of recently completed 
studies
 

to merge the Parent, Legal Guardian, and Legally Authorized Representative
informed consent text with the Caregiver Informed Consent

to clarify inclusion criterion #5 and to allow fecal incontinence as part of Rome 
III criteria in #6

to clarify exclusion criteria # 7

to broaden the text describing rescue medications and use of IWRS 

to remove the use of patient’s initials (where applicable)


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
to reorder the secondary efficacy assessments, to add fecal incontinence as a 
secondary efficacy assessment, and to move abdominal pain-daytime from the 
additional efficacy assessments to the secondary efficacy assessments
 
 
 
 
 

to update Sections 9.7.5, 9.7.5.2, 9.7.5.3, 9.7.6.1, and 9.7.6.4 to clarify various 
definitions and analysis methods, to add assessment of the secondary efficacy 
parameter related to fecal incontinence, and to move abdominal pain daytime 
symptoms from the additional efficacy parameters to the secondary efficacy 
parameters

to update Section 11.5 adding document retention details for countries covered by 
ICH
In addition, minor clarifications of previous text were made in several sections of the 
document. The protocol section numbers in the headings of this amendment are those of 
the previous version of the protocol. 


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2.0
GLOBAL CHANGES
2.1
EDIARY COMPLIANCE
Inclusion criterion #10 which addresses required compliance with use of the eDiary has 
been relaxed to allow more flexibility in use of the eDiary. 
Inclusion criterion #10 now reads as follows, and all mentions of the requirement for 
eDiary compliance throughout the protocol have been altered accordingly:
Patient or parent/guardian/LAR or caregiver is compliant with eDiary by completing both 
the morning and evening assessments for 10 8 out of the 14 days immediately preceding 
the Randomization Visit (Section 9.1.2)
 
 
 
 
 
 
2.3
USE OF IWRS AND PATIENT INITIALS
The text around use of patient initials and use of the IWRS has been made more generic 
to allow for study execution in differing jurisdictions.
Text in Sections 2.0, 9.4.1.1, 9.4.2, 9.5.5.2, 9.5.5.3, 9.5.5.4, 9.5.5.5, and 11.6 that refers 
to patient initials or use of the IWRS has been adjusted using the words “where 
applicable”. 


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3.0
SECTIONS DELETED
The heading and text for Section 5.3.3, Caregiver Consent has been deleted. The text 
from this section has been merged into the previous section: 5.3.2  Parent, Legal 
Guardian, and Legally Authorized Representative/Caregiver Informed Consent.
Caregiver Consent
A caregiver is a person identified as able and willing to provide safety and efficacy 
information about the patient and oversee the administration of investigational product 
and completion of the daily electronic diary (eDiary), and may be a different individual 
than the parent/guardian/LAR. The caregiver must commit to accompanying the patient 
to each study visit. To be eligible for the study, the caregiver, whether or not he or she is 
the parent/guardian/LAR, must read and sign the caregiver consent and meet the relevant 
inclusion/exclusion criteria. If the parent/guardian/LAR is the caregiver, he or she will be 
asked to sign both the parent/legal guardian permission (ICF) and the caregiver consent. 
The parent/guardian/LAR or caregiver who supervises the patient in the completion of 
the eDiary or administers the interviewer-administered version should be the same 
individual throughout the course of the study. If a caregiver is replaced during the study, 
each caregiver must provide separate ICF/caregiver consents and be given a signed copy 
of his or her caregiver consent.


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4.0
SECTIONS ADDED
A new section heading: “Section 7.2.1. Other Information” was added to the Introduction
in order to aid organization.


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5.0
REVISIONS
5.1
SECTION 1.0, TITLE PAGE
Rationale: The name of the sponsor has changed from Actavis to Allergan.
The sponsor line on this page now reads as follows:
Forest Research Institute, Inc., an affiliate of Actavis, IncAllergan. 
5.2
SECTION 2.0, SYNOPSIS AND SCHEDULE OF EVALUATION, 
Study Sites 
Rationale: The number of estimated study sites has been increased. 
The Study Sites row now reads as follows:
Approximately 50 - 100
 
 
 
 
 
. 
 
 
 
 
 


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5.4
SECTION 5.3.2 PARENT, LEGAL GUARDIAN, AND 
LEGALLY AUTHORIZED REPRESENTATIVE/CAREGIVER
INFORMED CONSENT
Rationale: The text for parent and caregiver consent (formerly in 2 separate sections) has 
been merged into a single section. 
The last paragraph of the section now reads as follows:
A caregiver is a person identified as able and willing to provide safety and efficacy 
information about the patient and oversee the administration of investigational product 
and completion of the daily electronic diary (eDiary), and may be a different individual 
than the parent/guardian/LAR. The caregiver must commit to accompany the patient to 
each study visit. To be eligible for the study, the caregiver, whether or not he or she is the 
parent/guardian/LAR, must read and sign the caregiver consent or a combined 
parent/legal guardian/caregiver permission ICF document. If the parent/guardian/LAR is 
the caregiver, he or she will be asked to sign both the parent/legal guardian permission 
(ICF) and the caregiver consent or a combined parent/legal guardian/caregiver permission 
(ICF). The parent/guardian/LAR or caregiver who supervises the patient in the 
completion of the eDiary or administers the interviewer-administered version should be 
the same individual throughout the course of the study. If a caregiver is replaced during 
the study, each caregiver must provide separate ICF/caregiver consents and be given a 
signed copy of his or her caregiver consent.
5.5
SECTION 6.0 INVESTIGATORS AND STUDY 
ADMINISTRATIVE STRUCTURE
Rationale: The number of estimated study sites has been increased.


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The first sentence of the section now reads as follows:
This study will be performed at approximately 50 – 100 study sites.
5.6
SECTION 7.1 SUMMARY OF LINACLOTIDE PROPERTIES
Rationale: The Investigator Brochure has been updated. 
The last sentence of the section now reads as follows:
Refer to the Investigator’s Brochure for a more detailed description of the chemistry, 
pharmacology, efficacy, and safety of linaclotide, based on studies conducted in animals, 
healthy volunteers, and in adult patients with IBS-C and CIC (Investigator’s Brochure, 
20142015).
5.7
SECTION 7.2 CLINICAL EXPERIENCE 
Rationale: New information about recently completed studies has become available. 
The first, second, ninth, thirteenth, and fourteenth paragraphs of the section now read
as follows:
Linaclotide has been developed by the Sponsor and Ironwood Pharmaceuticals, Inc. for 
the treatment of CIC and IBS-C in adults. The clinical development program for 
linaclotide that culminated in FDA and European Medicines Agency (EMA) approvals 
included the following North American studies in adult patients:

4 large double-blind, placebo-controlled Phase 3 registration studies (2 IBS-C studies 
[LIN-MD-31 and MCP-103-302] and 2 CIC studies [LIN-MD-01 and MCP-103-303]) 

2 long-term adult safety studies (LIN-MD-02 and MCP-103-305), each with 78-week 
treatment periods
In addition, a 2 randomized, double-blind, placebo-controlled, parallel-group, North 
American studies: Phase 3b study in patients with CIC (LIN-MD-04) and Phase 3 study 
(MCP-103-309) was recentlyhave been completed.
The completed Phase 3 study (MCP-103-309) was a randomized, double-blind, placebo 
controlled, parallel-group study in patients with CIC at baseline. Linaclotide at doses of 
72 ug/day and 145 ug/day was administered orally for 12 weeks to 1223 randomized 
adult patients. No new safety trends or concerns were identified. There were no deaths 
during the study and no SAEs of diarrhea. One patient in the linaclotide 145-ug group 
experienced an SAE of colitis that was considered by the investigator to be possibly 
related to study drug.
The following registration studies were conducted outside of North America:


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•
ICP-103-307: A Phase 3 international, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group efficacy and safety trial of linaclotide orally 
administered once daily for 12 weeks to patients with IBS-C in China, Australia, New 
Zealand, the US, and Canada. A total of 839 patients were randomized into 1 of 2 
treatment groups: linaclotide 290 ug (417 patients) or placebo (422 patients)
•
0456-CL-0031: A 2-part study, Part 1 was a multicenter, randomized, double-
blind, placebo-controlled, parallel-group Phase 3 trial of linaclotide orally administered 
once daily for 12 weeks to patients with IBS-C in Japan.
 
 
Both IBS-C studies evaluated the safety and efficacy of double-blind linaclotide 
administered as a solid oral capsule for 12 weeks. In these studies, linaclotide 
demonstrated statistically significant and clinically meaningful improvements in patients’ 
constipation symptoms and abdominal pain, and met all the prespecified primary 
endpoints. Statistically significant improvements were achieved for linaclotide versus 
placebo in multiple prespecified abdominal and bowel symptom secondary endpoints, 
including bloating and abdominal pain/discomfort. The most common adverse event 
(AE) was diarrhea, which occurred in 9-12% of linaclotide patients. Overall, there was no 
obvious pattern in the types of SAEs experienced in either the placebo or linaclotide 
groups. There were no SAEs of diarrhea.
5.8
SECTION 9.1.1 SCREENING PERIOD (PAGE 23)
Rationale: The order of paragraph 1 has been adjusted for clarity.
The first paragraph of this section now reads as follows:
After obtaining assent and informed consent, patient eligibility for entry into the study 
will be determined (Sections 9.3.1 and 9.3.2). The Screening Period will begin up to 7 
weeks before Randomization (Visit 3/Day 1) and will last for 14 to 28 days. Patients will 
not receive any investigational product during the Screening Period. After obtaining 
assent and informed consent (Section 5.3), patient eligibility for entry into the study will 
be determined (Sections 9.3.1 and 9.3.2). Consented patients will be assigned a unique 
PID via interactive Web response system (IWRS) (Section 9.4.3) and will be given a 
single dose of placebo (liquid oral solution or solid oral capsule for patients 7 to 11 years 
of age, and solid oral capsule for patients 12 to 17 years of age) to swallow to confirm 
their ability and willingness to swallow the investigational product. Patients who choose 
or are assigned to the solid oral capsule formulation will repeat the swallow test for solid 
oral capsule during the Pretreatment Period. There should be at least a 1-week interval 
between the swallow tests performed for placebo solid oral capsules during the Screening 
Period and the Pretreatment Period.


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5.9
SECTION 9.1.2 PRETREATMENT PERIOD
Rationale: The text around rescue medications and use of the IWRS has been made more 
generic.
The second paragraph of this section now reads as follows:
IWRS registration during the Pretreatment Period will include protocol-permitted rescue 
medication assignment (ie, senna [oral] syrup [known as Senokot syrup in Canada], 
bisacodyl tablets, or bisacodyl [oral or rectal]suppositories) and random assignment to 1 
of 4 pharmacokinetic (PK) sampling schedules in a 1:1:1:1 allocation. 
5.10
SECTION 9.3.1, INCLUSION CRITERIA
 
 
 
5.11
SECTION 9.3.1, INCLUSION CRITERIA 
Rationale: Assessment of fecal incontinence has been added to inclusion criterion #6.
Inclusion criterion #6 now reads as follows:
Patient meets modified Rome III criteria for child/adolescent FC: For at least 2 months 
before the Screening Visit, the patient has had 2 or fewer defecations (with each 
defecation occurring in the absence of any laxative, suppository, or enema use during the 
preceding 24 hours) in the toilet per week
In addition, at least once per week, patient meets 1 or more of the following: 
a.
History of retentive posturing or excessive volitional stool retention
b. History of painful or hard bowel movements (BMs)
c.
Presence of a large fecal mass in the rectum


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d. History of large diameter stools that may obstruct the toilet
e.
At least one episode of fecal incontinence per week
5.12
SECTION 9.3.2, EXCLUSION CRITERIA 
Rationale: Exclusion criterion #7 has been made more stringent to exclude patients who 
have required disimpaction.
Exclusion criterion #7 now reads as follows:
Patient has required manual disimpaction anytime prior to randomization or hospital-
based disimpaction during in-patient hospitalization any timewithin 1 year prior to 
randomization
5.13
SECTION 9.4.1.1, RESCUE MEDICATION (PAGE 31)
Rationale: The text around rescue medications and use of the IWRS has been made more 
generic.
The second and third paragraphs of this section now read as follows:
Protocol-permitted rescue medication will be a choice of senna (oral) syrup (known as 
Senokot syrup in Canada), bisacodyl 5-mg tablets, or bisacodyl (oral or rectal) 10-mg 
suppositories (5-mg and 10-mg suppositories are available in Canada) that will be 
dispensed according to the Schedule of Evaluations (Section 2.0). 
 
 
 
 
 
5.14
SECTION 9.4.9, MONITORING TREATMENT COMPLIANCE 
AND ACCOUNTABILITY
Rationale: The method of assessing treatment compliance has been upgraded. 
The first and second paragraphs of this section now read as follows:


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Investigational product compliance accountability and compliance during any period will 
be closely monitored. 
 
 
 
 
 
 
Ttreatment compliance will be assessed through patient/caregiver and study site staff 
discussion at study visits and recorded on the eCRF. Every effort will be made to collect 
all unused investigational product at the final visit. 
Investigational product accountability will be monitored by counting the number of solid 
oral capsules/weighing the bottle of liquid oral solution returned. Study sites will be 
provided a scale for weighing the bottles of liquid oral solution and instructed how to 
properly obtain and record the weight.  
5.15
SECTION 9.5.1.2 SECONDARY EFFICACY ASSESSMENTS  
Rationale: The secondary efficacy assessments have been reordered to match Section 
9.7.5.2, to move assessment of Abdominal Pain-Daytime from the section on Additional 
Efficacy Assessments, and to include assessment of Fecal Incontinence-Daytime.
The first, fourth, and last paragraphs of the section now read as follows:
In addition to the primary efficacy assessment, 6 secondary efficacy assessments are 
included in the study regarding abdominal symptoms,BM characteristics, and BM 
characteristics, and fecal incontinence abdominal symptoms that will be determined by 
the twice daily assessments recorded in the eDiary. 
Abdominal Pain – Daytime
For this parameter, patients will rate their abdominal pain by responding to the following
in the evening eDiary:

From when you got up this morning until now, did your tummy hurt at all?
o
Yes
o
No


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If “yes”, then patient answers the following question:

How much did your tummy hurt? 
1 = a tiny bit
2 = a little 
3 = some 
4 = a lot
Abdominal Bloating - Daytime
For this parameter, patients will record their assessment of abdominal bloating by 
responding to the following in the evening eDiary:

From when you got up this morning until now, did your tummy FEEL big and full?  
1 = yes
0 = no 
98 = I don’t know what you mean
99 = I don’t remember
If “yes” then patient answers the following question:

How big and full did your tummy FEEL?
1 = a tiny bit
2 = a little 
3 = medium 
4 = very
Fecal Incontinence - Daytime
Patients will record their episodes of fecal incontinence by responding to the following 
evening assessments.
- From when you got up this morning until now, did you have a pooping accident 
(even a little)? 
o
Yes
o
No
- From when you got up this morning until now, did you have any poop marks or 
stains on your underwear? 
o
Yes
o
No
o
I don't know
The following abdominal symptoms will be assessed:


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5.17
SECTION 9.5.2.1, ADVERSE EVENTS AND 
 
Rationale: The AE time window description has been adjusted (lengthened) to align with 
previous linaclotide studies. 
Paragraph 2 of this section now reads as follows:
For the purpose of the site’s data collection responsibilities, any untoward event that was 
reported from the time written consent was obtained until 1 day30 days after the final 
protocol-defined study visit ( or the last known dose of investigational product (if the 
final visit does not occur) is to be considered an AE. Particular attention must be given to 
the AE of diarrhea, which was the most frequently reported AE in the adult linaclotide 
program. Please refer to Section 9.5.2.5 for details about AE reporting.  
5.18
SECTION 9.5.2.6. IMMEDIATE REPORTING OF SERIOUS 
ADVERSE EVENTS AND EVENTS OF SPECIAL INTEREST
 
 
 


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5.25
SECTION 9.7.2, PATIENT DISPOSITION
Rationale: Use of Fisher’s exact test to compare rates of premature discontinuations has 
been removed.
The third sentence of the third paragraph of this section has been deleted:
The percentage of premature discontinuations will be compared overall and for each 
discontinuation reason between treatment groups using the Fisher exact test.
 
 
 
 
 
 
 
 
 
 


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5.28
SECTION 9.7.5, EFFICACY PARAMETERS
Rationale: The baseline fecal incontinence daytime symptoms, based on evening 
assessment, have been added. 
The last sentence of the second paragraph of this section now reads as follows:
Baseline fecal incontinence daytime symptoms, based on evening assessment, will be 
calculated as the average of nonmissing patient scores reported in the evening diary.
5.29
SECTION 9.7.5.2, SECONDARY EFFICACY PARAMETERS
Rationale: Two secondary efficacy assessments have been added to this section. Change 
from Baseline in 4-Week Abdominal Pain Daytime Symptoms Based on Evening 
Assessment has been moved from additional efficacy parameters to the secondary 
section, and a new paragraph on Fecal Incontinence-Daytime has been added. The fourth
secondary efficacy parameter (Change from Baseline in 4-Week Abdominal Bloating 
Daytime Symptoms Based on Evening Assessment) has been clarified, and the additional 
derivation for stool consistency and straining parameters has been clarified. 
The first and second paragraphs of this section now read as follows:


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Four Six change from baseline parameters are secondary efficacy parameters in this 
study. Their description and analyses are provided below.
Change From Baseline in 4-Week Abdominal Pain Daytime Symptoms Based on 
Evening Assessment
Abdominal pain scores will be collected twice daily in the eDiary: in the morning when a 
patient wakes up and in the evening at bedtime. Patients are asked to rate their abdominal 
pain using a 4-point ordinal scale from the time the patient wakes up until bedtime as part 
of the evening assessment, and a 5-point rating scale is derived from the patient’s 
responses at bedtime. The patient’s 4-week abdominal pain daytime symptoms during the 
Treatment Period are defined as the average of the nonmissing daily abdominal pain 
daytime symptoms reported in evening assessments in the eDiary during the 4-week 
Treatment Period.
The fifth and seventh paragraphs of this section now read as follows:
Change From Baseline in 4-Week Abdominal Bloating Daytime Symptoms Based 
on Evening Assessment
Abdominal bloating will be collected twice daily in the eDiary, in the morning when a 
patient wakes up and in the evening at bedtime. Patients are asked to rate their abdominal 
bloating using a 4-point scale from the time the patient wakes up until bedtime as part of 
the evening assessment, and a 5-point rating scale is derived from the patient’s responses
at bedtime. The patient’s 4-week abdominal bloating daytime symptoms during the 
Treatment Period are defined as the average of the nonmissing daily abdominal bloating 
daytime symptoms reported in evening assessments in the eDiary during the 4-week 
Treatment Period.
Change From Baseline in 4-Week Fecal Incontinence Daytime Symptoms Based on 
Evening Assessment 
Fecal incontinence will be collected daily in the evening eDiary. Patients are asked two 
questions (as discussed in Section 9.5.1.3) to cover the interval from when the patient 
wakes up until bedtime as part of the evening assessment. Any "yes" response in either of 
these questions will be counted as presence of fecal incontinence. The patient’s 4-week 
fecal incontinence daytime symptoms during the Treatment Period are defined as the 
average of the nonmissing daily fecal incontinence daytime symptoms reported in 
evening assessments in the eDiary during the 4-week Treatment Period.
The last paragraph of this section now reads as follows:
In addition, stool consistency and straining during the analysis period (based on morning 
and evening assessments) will also be derived as the mean of the patient’s non-missing, 
SBM-associated scores during the analysis period (similar to LIN-MD-31 and MCP-103-
302 adult studies).


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5.31
SECTION 9.7.6.1, ADVERSE EVENTS
Rationale: Information about the dictionary used has been updated. The method of 
summarization for TEAEs has been clarified. 
The first paragraph of this section now reads as follows:
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
Version 1718.0 or newer. 
The third paragraph of this section now reads as follows:


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The number and percentage of patients reporting TEAEs in each treatment group will be 
tabulated by SOC and preferred term;
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.33
SECTION 11.5, RETENTION AND REVIEW OF RECORDS 
(PAGE 85)
Rationale: Information has been added about document retention details for countries 
covered by ICH.  
The fourth and fifth paragraphs of this section now read as follows:
For countries falling within the scope of the ICH guidelines, the sponsor-specific 
essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirement(s) or if needed by the sponsor.


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In addition, for countries not falling within the scope of the ICH guidelines, local 
regulatory requirements should be followed regarding the retention of clinical study 
documentation.
5.34
APPENDIX III. CONCOMITANT MEDICATIONS, (PAGE 88)
Rationale: The text around rescue medications has been made more generic.
The second paragraph of this section now reads as follows:
Protocol-permitted rescue medicine, which will be selected by and dispensed to patients, 
will be a choice of senna (oral)syrup (known as Senokot syrup in Canada), bisacodyl 5-
mg tablets, or bisacodyl (oral or rectal) 10-mg suppositories (5-mg and 10-mg 
suppositories are available in Canada). During the Pretreatment, Treatment, and Post-
treatment Periods, patients may use dispensed, protocol-permitted laxatives (ie, senna 
syrup [known as Senokot syrup in Canada], bisacodyl tablets, or bisacodyl suppositories) 
as rescue medicine 
 
 
 
 
 
5.35
SECTION 14.0, LITERATURE CITED (PAGE 94)
Rationale: The Investigator’s brochure has been updated. 
The seventh reference of this section now reads as follows:
Linaclotide: Investigator’s brochure. Edition 810. Cambridge, MA: Ironwood 
Pharmaceuticals, Inc; 2014 2015 Mar 28May 15. 


Protocol Amendment #2 - Summary of Changes LIN-MD-62
Forest Research Institute, Inc.
Page 27
Summary of Changes for Protocol Amendment #2
11 Sept 2016
6.0
INVESTIGATOR’S STATEMENT
I agree to conduct the study in accordance with this protocol amendment (LIN-MD-62, 
Amendment #2, dated 11 Sep 2016) and with all applicable government regulations and 
good clinical practice guidance.
_______________________________________
_____/_____/______
Investigator’s Signature
Date
_______________________________________
Investigator’s Name


Forest Research Institute, Inc., an affiliate of Actavis, Inc.
Harborside Financial Center, Plaza V
Jersey City, NJ 07311
SUMMARY OF CHANGES TO PROTOCOL 
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, Who Fulfill Modified Rome III Criteria for 
Child/Adolescent Functional Constipation (FC)
LIN-MD-62
IND #63,290
Original Protocol Date:
15 Apr 2015
Amendment #1:                     13 Aug 2015 
Confidentiality Statement
This document is the property of Forest Research Institute, Inc., and may not—in full or 
part—be passed on, reproduced, published, distributed, or submitted to any regulatory 
authority without the express written permission of Forest Research Institute, Inc.
 
Forest Research Institute, Inc. 
Page 1 of 23
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1.0
INTRODUCTION
In response to protocol comments provided by the FDA on 12 Jun 2015, Amendment #1 
to the original protocol was planned. Amendment #1 specifies the following changes to 
the original protocol LIN-MD-62, dated 15 Apr 2015: (1) to allow patients 12-17 years of 
age to select liquid oral solution as an alternative to the preciously specified solid oral
capsules;
 
) to include a repeat swallow 
test for patients who receive capsules to assess those patients’ ability to swallow capsules 
on 2 occasions a minimum of 1 week apart; and 
 
 
and minor clarifications of 
previous text have been made in several sections.
The page and protocol section numbers in the headings of this amendment are those of 
the previous version of the protocol. 
 
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2.0
GLOBAL CHANGES
The following changes have been made globally to the protocol:

Linaclotide capsules are referred to as solid oral capsules

Linaclotide oral solution is referred to as liquid oral solution
 
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3.0
SECTIONS DELETED
None
 
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4.0
SECTIONS ADDED
 
 
:
 
 
 
 
  
 
).
 
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5.0
REVISIONS
5.1
SECTION 2.0, SYNOPSIS AND SCHEDULE OF 
EVALUATIONS (PAGE 2)
Rationale: The synopsis has been amended to reflect the addition of liquid oral solution 
as an alternate formulation for older patients, to clarify the text of the pharmacokinetic 
analysis, to clarify the statistical methods. The schedule of evaluations has been amended 
for clarity, to add a second swallow test for capsules, and to add an additional possible 
timepoint for the PK draw.
The beginning of the row Test Product, Dosage, and Mode of Administration now 
reads as follows:
Patients 6 to 11 years of age: linaclotide liquid oral solution taken once daily
Patients 12 to 17 years of age: linaclotide solid oral capsule or liquid oral solution taken 
once daily
The row Reference Therapy, Dosage, and Mode of Administration now reads as 
follows:
Patients 6 to 11 years of age: matching placebo liquid oral solution taken once daily
Patients 12 to 17 years of age: matching placebo solid oral capsule or liquid oral solution 
taken once daily
 
 
The last paragraph of the row Statistical Methods now reads as follows:
 
 
 
 
 
 
 
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5.2
SECTION 7.0, INTRODUCTION (PAGE 20)
Rationale: This section has been amended to clarify the wording.
The first paragraph of this section now reads as follows:
Functional gastrointestinal disorders (FGIDs) are common conditions of the digestive 
system in which symptoms cannot be explained by the presence of a structural or tissue 
abnormality abnormalities (Hyams, 1999). The Rome criteria were developed to classify 
the FGIDS in adults and children based on clinical symptoms.
 
Forest Research Institute, Inc. 
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5.3
SECTION 9.1.1, SCREENING PERIOD (PAGE 25)
Rationale: This section has been amended to reflect addition of liquid oral solution as an 
alternate formulation for older patients and to clarify details of the swallow test.
The first paragraph of this section now reads as follows:
The Screening Period will begin up to 7 weeks before Randomization (Visit 3/Day 1) and 
will last for 14 to 28 days. Patients will not receive any investigational product during the 
Screening Period. After obtaining assent and informed consent, patient eligibility for 
entry into the study will be determined (Sections 9.3.1 and 9.3.2). Consented patients will 
be assigned a unique PID number via interactive Web response system (IWRS) 
(Section 9.4.3) and will be given a single dose of placebo (liquid formulation oral 
solution for patients 6 to 11 years of age and solid oral capsule or liquid oral solution for 
patients 12 to 17 years of age) to swallow to confirm their ability and willingness to 
swallow the investigational product. Patients 6 to 11 years of age who fail the swallow 
test for the liquid oral solution will be considered screen failures. Patients 12 to 17 years 
of age who choose or are assigned to the solid oral capsule formulation will repeat the
swallow test for placebo solid oral capsule during the Pretreatment Period. There should 
be at least a 1-week interval between the swallow tests performed for placebo solid oral 
capsules during the Screening Period and the Pretreatment Period.
5.4
SECTION 9.1.2, PRETREATMENT PERIOD (PAGE 26)
Rationale: This section has been amended to reflect addition of liquid oral solution as an 
alternate formulation for older patients, to clarify details of the swallow test, to clarify 
training on use of the eDiary, to clarify the definition of eDiary compliance, to clarify the 
name of one of the rescue medications,
.
 
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This section now reads as follows:
The Pretreatment Period will occur up to 3 weeks before Randomization (Visit 3/Day 1) 
and will last for 14 to 21 days. Patients will not receive investigational product during the 
Pretreatment Period. Patients 12 to 17 years of age who choose or are assigned to the 
solid oral capsule formulation during the Screening Period will be provided a single dose 
of placebo solid oral capsule to repeat the swallow test. There should be at least a 1-week 
interval between the swallow tests performed for placebo solid oral capsules during the 
Screening Period and the Pretreatment Period. Baseline symptoms will be assessed and 
inclusion/exclusion criteria will be reviewed. Patients and caregivers will become 
familiar with receive full training on the use and completion of the eDiary, and the 
decision regarding whether a patient can complete the eDiary on his/her own or if he/she 
requires assistance will be made at the discretion of the caregiver and carried through to 
study completion. Additionally, caregivers of patients 6 to 11 years of age will be trained 
on completing the observer-completed global items once weekly on the eDiary. 
Throughout this protocol, eDiary is understood to refer to the patient- or interviewer-
administered version of the patient reported outcome (PRO) diary on a handheld 
electronic device. The eDiary will be completed by all patients (or caregivers) twice daily
throughout the Pretreatment Period. During the Pretreatment Period, compliance with the 
eDiary will be defined as completion of both morning and evening assessments for 10 out 
of the 14 days immediately preceding the Randomization Visit and must be documented 
before patients are included in the Double-blind Treatment Period.
IWRS registration during the Pretreatment Period will include protocol-permitted rescue 
medication assignment (ie, senna syrup [known as Senokot syrup in Canada], bisacodyl 
tablets, or bisacodyl suppositories)
 
 
 
 
 
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5.6
SECTION 9.3.1, INCLUSION CRITERIA (PAGE 28)
Rationale: Inclusion criterion 6 has been amended to clarify the requirements for meeting 
modified Rome III criteria. Inclusion criterion 9 has been amended to clarify details of 
the timing of the assessments of SBMs. Inclusion criterion 10 has been amended to
clarify the definition of eDiary compliance.
Inclusion criterion 6 now reads as follows:
6.
Patient meets modified Rome III criteria for child/adolescent FC: at least once per 
week for For at least 2 months before the Screening Visit, the patient has had 2 or 
fewer defecations (with each defecation occurring in the absence of any laxative, 
suppository, or enema use during the preceding 24 hours) in the toilet per week 
and in
In addition, at least once per week, patient meets 1 or more of the following: 
a.
History of retentive posturing or excessive volitional stool retention
b.
History of painful or hard bowel movements (BMs)
c.
Presence of a large fecal mass in the rectum
d.
History of large diameter stools that may obstruct the toilet
 
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Inclusion criterion 9 now reads as follows:
9.
Patient has an average of fewer than 3 spontaneous BMs (SBM SBMs) per week 
during the 14 days before the start of the Treatment Period the randomization day 
and up to the randomization (including the morning eDiary assessments reported 
before administration of first dose of double-blind investigational product on the
randomization day). An SBM is defined as a BM that occurs in the absence of 
laxative, enema, or suppository use on the calendar day of the BM or the calendar 
day before the BM
Inclusion criterion 10 now reads as follows:
10.
Patient or parent/guardian/LAR or caregiver is compliant with eDiary by 
completing both the morning and evening assessments for 10 out of the 14 days
immediately preceding Randomization Visit during the Pretreatment Period
(Sections 9.1.2 and 9.7.4.2)
5.7
SECTION 9.3.2, EXCLUSION CRITERIA (PAGE 29)
Rationale: Exclusion criterion 2 has been amended to clarify details of the timing of the 
assessments for stool consistency and frequency. Exclusion criterion 10 has been 
amended to insert details from Appendix III. Exclusion criterion 17 has been amended to 
clarify that failing the swallow test at any point is exclusionary.
Exclusion criterion 2 now reads as follows:
2.
Patient reports having more than 1 loose, mushy stool (eDiary-recorded stool 
consistency of 6 on the Pediatric Bristol Stool Form Scale [p-BSFS]) or any watery 
stool (eDiary-recorded stool consistency of 7 on the p-BSFS) with any SBM that 
occurred in the absence of laxative use on the calendar day of the BM or the 
calendar day before the BM during the 14 days before the start of the Treatment 
Period the randomization day and up to the randomization (including the morning 
eDiary assessments reported before administration of first dose of double-blind 
investigational product on the randomization day)
Exclusion criterion 10 now reads as follows:
 
 
 
 
 
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Exclusion criterion 17 now reads as follows:
17.
Patient is unable to tolerate the placebo during the Screening Period prior to 
randomization
5.8
SECTION 9.3.3, REMOVAL OF PATIENTS FROM THERAPY 
OR ASSESSMENT (PAGE 32)
Rationale: This section has been amended to make reference to Section 9.5.2.1.1.
The first paragraph of this section now reads as follows:
A premature discontinuation will occur when a patient who gave voluntary assent and 
whose parent/guardian/LAR and caregiver gave consent ceases participation in the study, 
regardless of circumstances, before the completion of the study visits and procedures. 
Patients will be prematurely discontinued from the study for reasons of safety including 
those who experience an SAE considered by the Investigator or the Sponsor to be related 
to investigational product. Patients will also be prematurely discontinued from the study 
for evidence of significant volume depletion and/or significant electrolyte and/or ECG 
abnormalities that are considered by the Investigator or Sponsor to be related to diarrhea 
related to the investigational product (ie, treatment-related AEs of special interest 
[Section Sections 9.5.2.1.1 and 9.5.2.6]). The Investigator should contact the Study 
Physician if there is any question whether the criteria for an AE of special interest have 
been met and the patient should be discontinued from the study.
5.9
SECTION 9.4.1.1, RESCUE MEDICATION (PAGE 34)
Rationale: This section has been amended to clarify the name of one of the rescue 
medications and to include availability of a second bisacodyl presentation for sites 
in Canada.
The second paragraph of this section now reads as follows:
Protocol-permitted rescue medication will be a choice of senna syrup (known as Senokot
syrup in Canada), bisacodyl 5-mg tablets, or bisacodyl 10-mg suppositories (5-mg and 
10-mg suppositories are available in Canada) that will be dispensed according to the 
Schedule of Evaluations (Section 2).
 
 
 
 
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5.11
SECTION 9.4.5, SELECTION AND TIMING OF DOSE FOR 
EACH PATIENT (PAGE 37)
Rationale: This section has been amended to reflect addition of liquid oral solution as an 
alternate formulation for older patients.
The second paragraph of this section now reads as follows:
Patients who continue to meet all eligibility criteria on Visit 3 (Day 1) will be assigned a 
randomization number, dispensed the corresponding double-blind investigational 
product, and receive their first dose of investigational product at the study site. Patients 
will receive a bottle(s) containing the liquid oral solution (for patients 6 to 11 years of 
age) or solid oral capsules (for patients 12 to 17 years of age). Patients 6 to 11 years of 
age will receive 1 or more bottles containing the liquid oral solution. Patients 12 to 
17 years of age will 1 or more bottles containing solid oral capsules or liquid oral 
solution, based on choice or assignment. Patients will be instructed to take their assigned 
dose orally as a single daily dose at approximately the same time each day, 30 minutes 
before their evening meal. Any alternate schedule must be approved and documented by 
the Investigator.
Footnote b of Table 9.4.5–1 now reads as follows:
b
Patients 12 to 17 years of age will receive linaclotide or placebo in a solid oral 
capsule or a liquid oral solution.
 
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5.12
SECTION 9.5.1.2, SECONDARY EFFICACY ASSESSMENTS 
(PAGE 42)
Rationale: This section has been amended to more accurately describe use of the 
Pediatric-BSFS tool.
The fourth paragraph in this section now reads as follows:
"Use the card to your left provided to choose the poop that is most like the poop you 
had."
Type 1 = looks like small hard lumps or balls, like pebbles
Type 2 = looks like fat sausage shape but lumpy and hard
Type 3 = looks like a sausage but with cracks on it
Type 4 = looks like a sausage or snake, smooth and soft
Type 5 = looks like chicken nuggets, soft smooth blobs 
Type 6 = looks like oatmeal, fluffy mushy pieces 
Type 7 = looks like a milkshake, watery
99 - I don’t know 
 
 
 
 
5.14
SECTION 9.5.2.1, ADVERSE EVENTS (PAGE 48)
Rationale: This section has been amended to accommodate the newly added section on 
AE of special interest.
The heading of this section now reads as follows: 
9.5.2.1
Adverse Events 
 
Forest Research Institute, Inc. 
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This second paragraph of this section now reads as follows:
For the purpose of the site’s data collection responsibilities, any untoward event that was 
reported from the time written consent was obtained until 1 day after the last known dose 
of investigational product (if the final visit does not occur) is to be considered an AE.
 
The next to last paragraph of this section has been omitted:
Particular attention must be given to AEs of diarrhea, which was the most frequently
reported AE in the adult linaclotide program, and AEs of special interest (volume 
depletion and/or significant electrolyte and/or ECG abnormalities considered related to
diarrhea) (Sections 9.3.3 and 9.5.2.6).
5.15
SECTION 9.5.2.6, IMMEDIATE REPORTING OF SERIOUS 
ADVERSE EVENTS 
 
 
 
 
 
 
 
 
 
 
 
 
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5.22
SECTION 9.7.5.1, PRIMARY EFFICACY PARAMETER
(PAGE 69)
Rationale: This section has been amended to refer the reader to the Statistical Analysis 
Plan for information about the sensitivity analysis.
 
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The second paragraph now reads as follows:
For the primary efficacy parameter, comparison between each linaclotide dose (A, B, and 
C) and placebo will be performed using an analysis of covariance (ANCOVA) model 
with treatment and age group (6 - 11 years of age and 12 - 17 years of age) as factors and 
baseline value as a covariate. Least squares means (LSMs) for each treatment group, 
differences in LSMs between each linaclotide treatment group versus placebo, associated 
2-sided 95% CIs for these differences in LSMs, and the corresponding statistical test 
p-values will be reported
 
 
 
 
 
 
5.25
APPENDIX III, CONCOMITANT MEDICATIONS (PAGE 89)
Rationale: This appendix has been amended to correct the name of one of the rescue 
medications and to include availability of a second bisacodyl presentation for sites in 
Canada.
 
Forest Research Institute, Inc. 
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The second paragraph now reads follows:
Protocol-permitted rescue medicine, which will be selected by and dispensed to patients, 
will be a choice of senna syrup (known as Senokot syrup in Canada), bisacodyl 5-mg 
tablets, or bisacodyl 10-mg suppositories (5-mg and 10-mg suppositories are available in 
Canada).
 
 
 
 
 
Forest Research Institute, Inc. 
Page 22 of 23
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6.0
INVESTIGATOR’S STATEMENT
I agree to conduct the study in accordance with this protocol amendment (LIN-MD-62, 
Amendment #1, dated XX Aug 2015) and with all applicable government regulations and 
good clinical practice guidance.
_______________________________________
_____/_____/______
Investigator’s Signature
Date
_______________________________________
Investigator’s Name
 
Forest Research Institute, Inc. 
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SAP_001.pdf: 
NCT02559570 
 
 
Study ID: LIN‐MD‐62 
 
 
Title: 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, Who Fulfill 
Modified Rome III Criteria for Child/Adolescent Functional Constipation (FC) 
 
 
Statistical Analysis Plan Amendment 2 Date: 28 June 2018 
 
 
 


Allergan Sales,LLC                                                                                                                                                                            1
Linaclotide
LIN-MD-62 Statistical Analysis Plan (Amendment #2)
28 June 2018
1
TITLE PAGE
Allergan Sales, LLC
5 Giralda Farms
Madison, NJ 07940
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, Who Fulfill Modified Rome III Criteria for Child/Adolescent Functional 
Constipation (FC)
LIN-MD-62
STATISTICAL ANALYSIS PLAN 
Final: 23 May 2016
Amendment #1:  1 Nov 2017
Amendment #2: 28 June 2018
Confidentiality Statement
This document is the property of Forest Research Institute (an affiliate of Allergan) and may 
notin full or partbe passed on, reproduced, published, distributed to any person, or 
submitted to any regulatory authority without the express written permission of Allergan.


Allergan Sales,LLC                                                                                                                                                                        2
Linaclotide (LINZESS)
LIN-MD-62 Statistical Analysis Plan (Amendment #2)
28 June 2018
2
TABLE OF CONTENTS
1
TITLE PAGE .................................................................................................... 1
2
TABLE OF CONTENTS.................................................................................. 2
2.1
IN-TEXT TABLES ........................................................................................... 4
3
LIST OF ABBREVIATIONS ........................................................................... 5
4
INTRODUCTION ............................................................................................ 6
5
OBJECTIVES................................................................................................. 10
6
PATIENT POPULATIONS............................................................................. 10
6.1
Screened Population........................................................................................ 10
6.2
Randomized Population.................................................................................. 10
6.3
Safety Population............................................................................................ 10
6.4
Intent-to-Treat Population................................................................................11
7
PATIENT DISPOSITION................................................................................11
8
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ....... 12
10
EFFICACY ANALYSES................................................................................ 14
10.1
Primary Efficacy Parameter............................................................................ 15
10.2
Secondary Efficacy Parameters ...................................................................... 18
11
SAFETY ANALYSES .................................................................................... 26
11.1
Adverse Events ............................................................................................... 26


Allergan Sales,LLC                                                                                                                                                                        3
Linaclotide (LINZESS)
LIN-MD-62 Statistical Analysis Plan (Amendment #2)
28 June 2018
13
INTERIM ANALYSIS.................................................................................... 33
15
STATISTICAL SOFTWARE.......................................................................... 34
16
DATA HANDLING CONVENTIONS........................................................... 34
16.3.4
Stool frequency............................................................................................... 37
16.3.5
Stool Consistency............................................................................................ 39
16.3.6
Severity of Straining ....................................................................................... 40
16.3.7
Abdominal Bloating........................................................................................ 41
16.3.8
Abdominal Pain .............................................................................................. 43
16.3.9
Fecal Incontinence .......................................................................................... 45
17
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL.......................... 53
18
HISTORY OF CHANGES.............................................................................. 53
19
REFERENCES ............................................................................................... 56


Allergan Sales,LLC                                                                                                                                                                        4
Linaclotide (LINZESS)
LIN-MD-62 Statistical Analysis Plan (Amendment #2)
28 June 2018
2.1
IN-TEXT TABLES
Table 4–1
Double-blind Dosing Regimen ......................................................................... 7
 
 


Allergan Sales,LLC                                                                                                                                                                        5
Linaclotide (LINZESS)
LIN-MD-62 Statistical Analysis Plan (Amendment #2)
28 June 2018
3
LIST OF ABBREVIATIONS 
AE
adverse event
ANCOVA
analysis of covariance
BM
bowel movement
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CSBM
complete spontaneous bowel movement
eCRF
electronic case report form
eDiary
electronic diary
FC
functional constipation
ITT
intent to treat
IP
investigational product
LSMs 
Least squares means
MAR
missing at random
MI
multiple imputation
MMRM
mixed-effects model for repeated measures
OC
observed cases
p-BSFS
pediatric Bristol Stool Form Scale
 
PID
patient identification
SAE
serious adverse event
SAP
statistical analysis plan
SBM
spontaneous bowel movement
TEAE
treatment-emergent adverse event


Allergan Sales,LLC                                                                                                                                                                        6
Linaclotide (LINZESS)
LIN-MD-62 Statistical Analysis Plan (Amendment #2)
28 June 2018
4
INTRODUCTION
This statistical analysis plan (SAP) provides a more technical and detailed elaboration of the 
statistical analyses of the efficacy and safety data as outlined and/or specified in the final 
protocol of Study LIN-MD-62 (version dated 15 Apr, 2015) and the most recent amendment 
(version 1 dated 13 Aug, 2015). Specifications of tables, figures, and data listings are contained 
in a separate document. 
Study LIN-MD-62 is a Phase II, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group safety and efficacy study comparing 1 of 3 linaclotide doses (A, B, and C) or 
145 ug (only patients 12 - 17 years of age) with placebo in pediatric patients, 6 to 17 years of 
age, with a diagnosis of functional constipation (FC) based on modified Rome III 
Child/Adolescent Criteria (ie, who fulfill modified Rome III criteria for child/adolescent FC).
The study will include a total of 6 visits and will be approximately 9 to 12 weeks in duration that 
includes 4 study periods as follows:

Screening Period (14 to 28 days)

Pretreatment Period (14 to 21 days)

Double-blind Treatment Period (hereinafter referred to as Treatment Period) (at least 
28 days [4 weeks] on treatment)

Post-treatment Period (at least 7 days [1 week] after the Week 4 End-of-Treatment Visit)
Approximately 160 patients with FC are planned to be randomized in this study. Randomization 
will be stratified by age group (6 - 11 years of age versus 12 - 17 years of age) with a minimum 
of 40% of patients within each age group. Patients 6 to 11 years of age will be randomized to 
linaclotide doses (A, B, or C) or placebo in a 1:1:1:1 allocation. Patients 12 to 17 years of age 
will be randomized to linaclotide doses (A, B, or C, or the approved adult dose, 145 ug) or 
placebo in a 1:1:1:1:1 allocation. 
Dosage will be determined by weight for patients 6 to 11 years of age (18 to <35 kg or >= 35 kg) 
as shown below in Table 4–1.


Allergan Sales,LLC                                                                                                                                                                        7
Linaclotide (LINZESS)
LIN-MD-62 Statistical Analysis Plan (Amendment #2)
28 June 2018
Table 4–1
Double-blind Dosing Regimen
4-Week Treatment Period
Age Group
Weight
Linaclotide
Dose A 
Linaclotide
Dose B 
Linaclotide
Dose C 
Approved Adult 
Dose
Patients 6 -11 yearsa
18- < 35 kg
9 ug
18 ug
36 ug
—
placebo
placebo
placebo
—
≥ 35 kg
18 ug
36 ug
72 ug
—
placebo
placebo
placebo
—
Patients 12 -17 yearsb
18 ug
36 ug
72 ug
145 ugc
placebo
placebo
placebo
placebo
a Patients 6 to 11 years of age will receive linaclotide or placebo in a liquid oral solution.
b Patients 12 to 17 years of age will receive linaclotide or placebo in a solid oral capsule or a liquid oral solution.
c Approved dose is for safety and exploratory efficacy only.
Patients will complete the electronic diary (eDiary) twice daily (morning and evening) 
throughout the Pretreatment Period, Treatment Period, and Post-treatment Period and must 
complete at least 4 weeks of treatment before arriving at the study site for the Week 4 Visit 
(Visit 5). Patients will not receive investigational product (IP) during the Post-treatment Period, 
but will continue to complete the eDiary twice daily throughout the Post-treatment Period.
 
 
 
 
 
 
Adverse events (AEs) will be monitored at every visit 
 
 


Allergan Sales,LLC                                                                                                                                                                        8
Linaclotide (LINZESS)
LIN-MD-62 Statistical Analysis Plan (Amendment #2)
28 June 2018


Allergan Sales,LLC                                                                                                                                                                        9
Linaclotide (LINZESS)
LIN-MD-62 Statistical Analysis Plan (Amendment #2)
28 June 2018


Allergan Sales,LLC                                                                                                                                                                        10
Linaclotide (LINZESS)
LIN-MD-62 Statistical Analysis Plan (Amendment #2)
28 June 2018
5
OBJECTIVES
The objective of this study is to evaluate the dose response, safety, and efficacy of 4 weeks of 
treatment with 1 of 3 linaclotide doses (A, B, or C) or 145 ug (as an exploratory objective in the 
adolescent patients 12 - 17 years of age using the approved adult dose) compared with placebo in 
pediatric patients 6 to 17 years of age who fulfill modified Rome III criteria for child/adolescent 
FC.
6
PATIENT POPULATIONS
6.1
Screened Population
The Screened Population will consist of all patients who undergo the Screening Visit (Visit 1) 
and receive a patient identification (PID) number.
6.2
Randomized Population
The Randomized Population will consist of all patients in the Screened Population who are 
randomized to a treatment group in the study.
6.3
Safety Population
The Safety Population will consist of all patients in the Randomized Population who took 
at least 1 dose of double-blind investigational product (IP).
All summaries in this population will be provided based on the treatment each patient was 
randomized to receive. If patient received treatment other than randomized treatment, actual 
treatment received will be determined based on the study treatment received for majority of the 


Allergan Sales,LLC                                                                                                                                                                        11
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double-blind treatment period. If there is a tie, higher dose will be considered for actual 
treatment for that patient.  Actual treatment will be listed for the patients in the listing related to 
treatment dosing information and additional summary of treatment emergent adverse events 
(TEAEs) will be provided if there is a difference between planned randomized treatment and 
actual treatment for more than one patient.
6.4
Intent-to-Treat Population
The Intent-to-Treat (ITT) Population will consist of all patients in the Safety Population who had 
at least 1 postbaseline entry on bowel movement (BM) characteristic assessments that determine 
occurrences of spontaneous bowel movements (SBMs) (ie, BM frequency and rescue medication 
use).
7
PATIENT DISPOSITION
The number and percentage of patients in 3 study populations (Randomized, Safety, and ITT) 
will be summarized overall, by treatment group, 
, and study center; 
 
 
 
 
 
. The number and percentage of 
patients who complete the double-blind Treatment Period and Post-treatment Period and of 
patients who prematurely discontinue during the same period will be presented for each 
treatment group and pooled across treatment groups for the Randomized Population. The reasons 
for premature discontinuation from the double-blind study period or Post-treatment Period as 
recorded in the eCRF will be summarized (number and percentage) by treatment group for the 
Randomized Population.
 
 
 


Allergan Sales,LLC                                                                                                                                                                        12
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8
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS
Demographic parameters (age; age group [6-11 and 12-17 years (inclusive)]; race; ethnicity; sex) 
and baseline characteristics (weight; height; and body mass index, calculated as weight 
[kg]/(height [m])2) will be summarized descriptively by treatment group for the Safety and ITT 
Populations. 
 
 
 
 
 
 
 Continuous variables will be 
summarized by number of patients and mean, standard deviation (SD), median, minimum, and 
maximum values. Categorical variables will be summarized by number and percentage of 
patients. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Allergan Sales,LLC                                                                                                                                                                        13
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Allergan Sales,LLC                                                                                                                                                                        14
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10 EFFICACY ANALYSES
Efficacy analyses will be based on the ITT Population.
Baseline values for efficacy parameters will be derived from the eDiary and eCRF data collected 
in the Pretreatment Period, specifically the period of time from 14 days before randomization up 
to the time of randomization. A spontaneous bowel movement (SBM) is a bowel movement 
(BM) that occurs in the absence of laxative, suppository, or enema use on the calendar day of the 
BM or the calendar day before the BM. A complete spontaneous bowel movement (CSBM) is an 
SBM that is associated with a sense of complete evacuation.
The baseline SBM and CSBM weekly rates, stool consistency, straining, and abdominal 
symptoms (pain and bloating) will be derived as discussed in Section 16.3. 
 
 
 
 
 The derivation of each efficacy parameter is discussed in 
Section 16.3 unless otherwise mentioned in Section 10.
A patient’s baseline stool consistency and straining cannot be assessed if the patient does not 
have at least 1 SBM during the Pretreatment Period. For patients who report 0 SBMs during a 
study period, the consistency and straining assessments will be considered missing for that study 
period in the analyses. Patients with missing baseline consistency and straining will be excluded 
from the respective consistency and straining analyses that involve change from baseline.


Allergan Sales,LLC                                                                                                                                                                        15
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An observed-cases (OC) approach to missing postbaseline data will be applied. 
 
 
The overall analysis (incorporating both age groups) including placebo and linaclotide doses 
(A, B, and C) will be the analysis to evaluate the main objective of this study.
 
 All 
statistical tests will be 2-sided hypothesis tests performed at the 5% level of significance. All 
confidence intervals (CIs) will be 2-sided 95% CI, unless stated otherwise. No multiplicity 
adjustment will be applied in this dose-ranging study. Nominal p-values will be provided for the 
efficacy parameters as a measure of strength of association between the endpoint and the 
treatment effect.
 
 
 
 
10.1
Primary Efficacy Parameter
The primary efficacy parameter is the change from baseline in 4-week overall spontaneous bowel 
movement (SBM) frequency rate (SBMs/week) during the Treatment Period. The SBM rate per 
week during the Treatment Period will be derived based on the total number of SBMs a patient 
reported during this period in the morning and evening assessments on the eDiary. The details of 
the derivation of this efficacy parameter are provided in Section 16.3.
For the primary efficacy parameter, comparison between each linaclotide dose (A, B, and C) and 
placebo will be performed using an analysis of covariance (ANCOVA) model with treatment and 
age group (6 - 11 years of age and 12 - 17 years of age) as factors and baseline value as a 
covariate. Least squares means (LSMs) for each treatment group, differences in LSMs between 
each linaclotide treatment group versus placebo, associated 2-sided 95% CIs for these differences 
in LSMs, and the corresponding statistical test p-values will be reported. 
 
 
.
 
 
 


Allergan Sales,LLC                                                                                                                                                                        16
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Allergan Sales,LLC                                                                                                                                                                        17
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Allergan Sales,LLC                                                                                                                                                                        18
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10.2
Secondary Efficacy Parameters
The secondary efficacy parameters are as follows:

Change from baseline in 4-week abdominal pain daytime symptoms based on evening 
assessment

Change from baseline in 4-week stool consistency

Change from baseline in 4-week of severity of straining

Change from baseline in 4-week abdominal bloating daytime symptoms based on evening 
assessment

Change from baseline in 4-week overall complete spontaneous bowel movement 
frequency rate (CSBM/week) during the Treatment Period

Change from baseline in 4-week fecal incontinence daytime symptoms based on evening 
assessment
The derivation of each secondary efficacy parameter is discussed in Section 16.3.
For each change-from-baseline secondary efficacy parameter (except fecal incontinence), each 
linaclotide dose group (A, B, and C) will be compared with the placebo group using an 
ANCOVA model with treatment (linaclotide doses A, B, and C, and placebo) and age group 
(6 - 11 years of age and 12 - 17 years of age) as factors and baseline value as a covariate. LSMs 
for each treatment group, differences in LSMs between each linaclotide treatment group versus 
placebo, associated 2-sided 95% CIs for these differences in LSMs, and the corresponding 
statistical test p-values will be reported. 
 
 


Allergan Sales,LLC                                                                                                                                                                        19
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Change from baseline in 4-week fecal incontinence daytime symptoms based on evening 
assessment will be summarized descriptively by treatment group (linaclotide doses A, B, C, and 
placebo). Fecal incontinence measurement will be available only for those patients who were 
randomized following the implementation of fecal incontinence assessment in the protocol 
(amendment #3). 
 
 
 
 
In addition, the 4-week stool consistency and severity of straining scores will be derived 
following the approach used in adult studies as discussed in Section 16.3 (Sections 16.3.5 and 
16.3.6, respectively). Change from baseline in 4-week stool consistency and severity of straining 
scores derived based on adult derivation will also be analyzed following the same approach as 
discussed above for overall ITT Population.
 
 
 
 
 
 
 
 
 
 
 
 
 


Allergan Sales,LLC                                                                                                                                                                        20
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Allergan Sales,LLC                                                                                                                                                                        21
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Allergan Sales,LLC                                                                                                                                                                        22
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Allergan Sales,LLC                                                                                                                                                                        23
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Allergan Sales,LLC                                                                                                                                                                        24
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Allergan Sales,LLC                                                                                                                                                                        25
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Allergan Sales,LLC                                                                                                                                                                        26
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
 
11 SAFETY ANALYSES
The safety analysis will be performed using the Safety Population. 
 
 
 
 
 
 
 
 
 
11.1
Adverse Events
Adverse events will be coded by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities, version 18.0 or newer.
An AE will be considered a treatment-emergent adverse event (TEAE) if it was present after the 
first dose of IP or was present before the date of the first dose of IP and increased in severity 
after the first dose of IP. If more than 1 AE was reported before the first dose of IP and coded to 
the same preferred term, the AE with the greatest severity will be used for comparison with the 
AEs occurring during the Treatment Period. An AE that occurs more than 1 day after the date of 
the last dose of IP will not be considered as a TEAE.
The number and percentage of patients reporting TEAEs in each treatment group will be 
tabulated 
, by system organ class and preferred term, 
 
 
 
 
 
 
 


Allergan Sales,LLC                                                                                                                                                                        27
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The incidence of common (≥5% of patients in any treatment group) TEAEs will be summarized 
by system organ class, preferred term, and treatment group. 
 
The overall summary of AEs will also be provided by treatment group.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Allergan Sales,LLC                                                                                                                                                                        28
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Allergan Sales,LLC                                                                                                                                                                        29
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Allergan Sales,LLC                                                                                                                                                                        30
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Allergan Sales,LLC                                                                                                                                                                        31
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Allergan Sales,LLC                                                                                                                                                                        32
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Allergan Sales,LLC                                                                                                                                                                        33
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13 INTERIM ANALYSIS
No interim analysis is planned for this study.
 
 
 
 
 
 
 
 
 
 
 
 


Allergan Sales,LLC                                                                                                                                                                        34
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15 STATISTICAL SOFTWARE
Statistical analyses will be performed using version 
 
16 DATA HANDLING CONVENTIONS
 
 
 
 
 
 
 
 
 


Allergan Sales,LLC                                                                                                                                                                        35
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Allergan Sales,LLC                                                                                                                                                                        36
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Allergan Sales,LLC                                                                                                                                                                        37
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.
16.3.4 Stool frequency
Spontaneous Bowel Movement (SBM)
A SBM is a BM that occurs in the absence of laxative, suppository, or enema use on the calendar 
day of the BM or the calendar day before the BM.
 
 
 
 
 
 
 
In the evening diary, if patients responded “yes” for RM use question but missed to report the 
timing of RM use or replied ‘I don’t know” for the timing of RM use, the missing or “I don’t 
know” response will be coded as “Yes” for all the periods in the evening diary. 
 
 
 
 
Complete Spontaneous Bowel Movement/Incomplete Evacuation
A complete spontaneous bowel movement (CSBM) is an SBM that is associated with a sense of 
complete evacuation.


Allergan Sales,LLC                                                                                                                                                                        38
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Stool Frequency Rates 
The components for calculating a patient’s stool frequency rates (SBM/CSBM weekly rates) for 
a given period are as follows:

The number of BMs that occurred during that specific period

The number of those BMs that were SBMs

The number of those SBMs that were CSBMs

The number of days during that specific period:

Randomization day with evening diary will be considered as a half day for the 
double-blind Treatment Period.

Randomization day with morning and/or clinic diary will be considered as a half day for 
the Pretreatment Period.

The day after last dose will be considered as a half day for the double-blind Treatment 
Period and for the Post-treatment Period. 
Duration of an Analysis Week
With respect to a patient’s scheduled analysis weeks, the term duration is used. In regard to the 
duration of a week, it is expected that 1 or more of a patient’s “weeks” may not be exactly 7 days 
in duration (eg, a patient may withdraw or discontinue early from the trial, may have half day 
data with diary entries, or may have missing diary day). Deviations from the 7 days norm are 
structural in nature; and, as such, the calculations of the weekly rates of SBMs or CSBMs will 
incorporate the actual days contributed within the time period (week or specific phase).
Weekly Stool Frequency Rate Calculations
The weekly frequency rate for SBMs (CSBMs) will be based on the total number of SBMs 
(CSBMs) occurring based on the diary entries during that time period, adjusting for differences 
in the length of the time period. Weekly stool frequency rates for each specific period will be 
calculated as follows:

Weekly Frequency Rate (Specific Period) =
 	
  	 (  ) 
	    

   
	   
X 7


Allergan Sales,LLC                                                                                                                                                                        39
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16.3.5 Stool Consistency
Patients will use the pediatric Bristol Stool Form Scale (p-BSFS) 7-point ordinal scale to rate 
their stool consistency:
"Use the card provided to choose the poop that is most like the poop you had."
Type 1 = looks like small hard lumps or balls, like pebbles
Type 2 = looks like fat sausage shape but lumpy and hard
Type 3 = looks like a sausage but with cracks on it
Type 4 = looks like a sausage or snake, smooth and soft
Type 5 = looks like chicken nuggets, soft smooth blobs
Type 6 = looks like oatmeal, fluffy mushy pieces
Type 7 = looks like a milkshake, watery
99 - I don’t know
Stool consistency will be collected twice daily in the eDiary, in the morning when a patient 
wakes up and in the evening at bedtime, and measured using the 7-point p-BSFS. The patient’s 
p-BSFS score in the specific period will be the observed weighted average of the daily p-BSFS 
scores 
 and the denominator in the observed 
weighted average will be the sum of the weights during this period. The daily p-BSFS score will 
be the average of nonmissing morning and/or evening assessments of the p-BSFS score from the 
SBMs reported by the patient on that specific day during that corresponding period. 


Allergan Sales,LLC                                                                                                                                                                        40
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In addition, stool consistency (p-BSFS) scores during an analysis period will also be derived to 
be consistent with derivation in adult studies as mean of patient’s non-missing, SBM-associated 
p-BSFS scores during the analysis period. 
16.3.6 Severity of Straining
Degree of straining will be assessed via patient’s responses to the following:
When you pooped, how hard did you push?
0 = not hard at all
1 = I pushed a tiny bit hard
2 = I pushed a little hard
3 = I pushed hard
4 = I pushed very hard
Straining will be collected twice daily in the eDiary, in the morning when a patient wakes up and 
in the evening at bedtime, and measured using a 5-point scale. The patient’s straining score in the 
specific analysis period will be the observed weighted average of daily straining score 
 
 and the denominator in the observed weighted 
average will be the sum of the weights during this period. The daily score will be the average of 
the nonmissing morning and/or evening assessments of the straining score from the SBMs 
reported by the patient on that specific day during the analysis period.
 


Allergan Sales,LLC                                                                                                                                                                        41
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In addition, straining scores during an analysis period will also be derived to be consistent with 
derivation in adult studies as mean of patient’s non-missing, SBM-associated straining scores 
during the analysis period.
16.3.7 Abdominal Bloating
Abdominal bloating will be collected twice daily in the eDiary, in the morning when a patient 
wakes up and in the evening at bedtime via patient’s responses to the following questions. 
Patient will record their assessment of abdominal bloating by responding to the following in the 
evening diary:
From when you got up this morning until now, did your tummy FEEL big and full?
1 = yes
0 = no
98 = I don’t know what you mean
99 = I don’t remember
If “yes” then patient answers the following question using 4-point scale:
How big and full did your tummy FEEL?
1 = a tiny bit
2 = a little
3 = medium
4 = very


Allergan Sales,LLC                                                                                                                                                                        42
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The patient’s abdominal bloating daytime/
 symptoms during the analysis period are 
defined as the average of the nonmissing daily abdominal bloating daytime
 symptoms 
reported in evening
 assessments in the eDiary during the analysis period based on the 
scores of 0, 1, 2, 3, and 4. 
 
 
 
 
 
 
 


Allergan Sales,LLC                                                                                                                                                                        43
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16.3.8 Abdominal Pain
Abdominal pain scores will be collected twice daily in the eDiary: in the morning when a patient 
wakes up and in the evening at bedtime via patient’s responses to the following questions. 
Patient will record their assessment of abdominal pain by responding to the following in the 
evening diary:
From when you got up this morning until now, did your tummy hurt at all?
o Yes
o No
If “yes”, then patient answers the following question using a 4-point scale:

How much did your tummy hurt?
1 = a tiny bit
2 = a little
3 = some
4 = a lot


Allergan Sales,LLC                                                                                                                                                                        44
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To calculate patient’s 4-week abdominal pain score, responses “no” will be coded as ‘0’. The 
patient’s 4-week abdominal pain daytime
 symptoms during the specific period are 
defined as the average of the nonmissing daily abdominal pain daytime
 symptoms 
reported in evening/
 assessments in the eDiary during specific period based on scores of 
0, 1, 2, 3, and 4.
 
 
 
 
 
 
 
  
 
 


Allergan Sales,LLC                                                                                                                                                                        45
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16.3.9 Fecal Incontinence
Fecal incontinence will be collected once daily in evening diary for those patients who will be 
randomized after the implementation of Amendment #3 (version 3.0 dated 16 May 2017) of the 
protocol. 
Patients will be asked to record their episodes of fecal incontinence by responding to the 
following evening assessments.
- From when you got up this morning until now, did you have a pooping accident
(even a little)?
o Yes
o No
From when you got up this morning until now, did you have any poop marks or
stains on your underwear?
o Yes
o No
o I don’t know
If patients answered “Yes” for any of the above questions, patients will be considered to have 
fecal incontinence. In any analysis period, Fecal incontinence daytime symptoms, based on the 
evening assessment, will be calculated as the average of nonmissing patient scores reported in 
the evening diary during the analysis period.


Allergan Sales,LLC                                                                                                                                                                        46
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Allergan Sales,LLC                                                                                                                                                                        47
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Allergan Sales,LLC                                                                                                                                                                        48
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3
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Allergan Sales,LLC                                                                                                                                                                        49
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Allergan Sales,LLC                                                                                                                                                                        50
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Allergan Sales,LLC                                                                                                                                                                        51
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Allergan Sales,LLC                                                                                                                                                                        52
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Allergan Sales,LLC                                                                                                                                                                        53
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).
17 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL
 
 
18 HISTORY OF CHANGES
Following changes have been made in this SAP Amendment:
 
 
 
 
 
 
. 
 
 


Allergan Sales,LLC                                                                                                                                                                        54
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Following changes have been made in SAP Amendment #1 to be consistent with amended 
protocol (version 3.0) dated 16 May 2017.
 
 
 

Section 10.2: Addition of a new secondary efficacy parameter of change from baseline in 
4-week fecal incontinence daytime symptoms based on evening assessment and shifting 
the change from baseline in 4-week abdominal pain daytime symptoms based on evening 
assessment to secondary efficacy parameter from additional efficacy parameter.
Other changes are the followings:
 
 
 
 
 
 
 


Allergan Sales,LLC                                                                                                                                                                        55
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.

 
 

Section 18.0 has been added to document the history of changes in this amendment. 
Following section numbers have been updated as a result. 


Allergan Sales,LLC                                                                                                                                                                        56
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19 REFERENCES
Carpenter, J.R., Kenward, M.G. Missing data in randomized controlled trials- a practical guide; 
2007. p 119-138; Free Downloadable at registered users area www.missingdata.org.uk.
Kenward, M.G., Roger, J.H. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics 1997;53:983-97.


Allergan Sales,LLC                                                                                                                                                                        57
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