Conditions: Irritable Bowel Syndrome With Constipation Chronic Idiopathic Constipation
Keywords: Immunogenicity Irritable Bowel Syndrome with Constipation Chronic Idiopathic Constipation Linaclotide Linzess
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 828
Healthy volunteers: no

Brief summary:
The primary objective of this study is to assess the potential of LINZESS® (linaclotide) treatment to induce the development of anti-drug antibodies (ADAs). The secondary objectives are to provide additional evidence supporting the long-term safety and efficacy of linaclotide in adult irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) participants and to evaluate lower doses of linaclotide.

Detailed description:
This study includes up to a 3-week Screening Period, followed by a 52-week treatment period. Participants with CIC meeting the entry criteria received linaclotide 145 μg capsules, orally, once daily and participants with IBS-C meeting the entry criteria received linaclotide 290 μg capsules, orally, once daily. Participants with intolerable Adverse Events (AEs), following resolution of the AEs, could be randomized to receive 290 μg, 145 μg, or the lower dose of 72 μg linaclotide oral capsules for IBS-C; and 145 μg or 72 μg for CIC. Participants who experienced further intolerable AEs after the randomization could be transitioned to open-label 72 μg linaclotide.

Arms:
arm 1: LINZESS® (linaclotide) 145 μg capsules, orally, once daily for up to 52 weeks for participants with CIC. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period. arm 2: LINZESS® 290 μg capsules, orally, once daily for up to 52 weeks for participants with IBS-C. If an intolerable AE occurred participants could be randomized to the Double-blind Treatment Period. arm 3: Following participation in the Open Label Treatment Period, LINZESS® 290 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with IBS-C. If an intolerable AE occurred, dose was reduced to Open Label 72 μg, if applicable. arm 4: Following participation in the Open Label Treatment Period, LINZESS® 145 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with IBS-C. If an intolerable AE occurred, dose was reduced to Open Label 72 μg, if applicable. arm 5: Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with IBS-C. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable. arm 6: Following participation in the Open Label Treatment Period, LINZESS® 145 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was reduced to 72 μg, if applicable. arm 7: Following participation in the Open Label Treatment Period, LINZESS® 72 μg capsules, orally, once daily from double-blind randomization up to Week 52 for participants with CIC. If an intolerable AE occurred, dose was maintained at Open Label 72 μg, if applicable. arm 8: Following participation in the Double-blind Treatment Period, if an intolerable AE occurred, LINZESS® 72 μg capsules, orally, once daily up to Week 52 for participants with CIC. arm 9: Following participation in the Double-blind Treatment Period, if an intolerable AE occurred, LINZESS® 72 μg capsules, orally, once daily up to Week 52 for participants with IBS-C.

Interventions: intervention 1: Linaclotide
Intervention descriptions: intervention 1: Linaclotide capsules, orally, once daily.

Protocol document:
Prot_000.pdf: 
NCT02590432 
 
Study ID: LIN‐MD‐10 
 
Title: An Open‐label, Long‐term Study to Assess the Immunogenicity of Linaclotide Administered Orally 
to Adult Patients With Irritable Bowel Syndrome With Constipation or Chronic Idiopathic Constipation 
 
 
Protocol Amendment 2 Date: 05‐Oct‐2015 
 
 
 


1.0
TITLE PAGE
Forest Research Institute, Inc., an affiliate of Actavis Inc.
Harborside Financial Center, Plaza V
Jersey City, NJ 07311
An Open-label, Long-term Study to Assess the Immunogenicity of Linaclotide 
Administered Orally to Adult Patients With Irritable Bowel Syndrome With 
Constipation or Chronic Idiopathic Constipation
LIN-MD-10
IND #63,290
Original Protocol / Date:
Protocol MCP-103-402, 25 Nov 2013
Amendment #1
09 Apr 2015
Amendment #2
05 Oct 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.
 
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2.0
SYNOPSIS AND SCHEDULE OF EVALUATIONS
CLINICAL STUDY SYNOPSIS: Study LIN-MD-10
Study Number
LIN-MD-10
Title of Study
An Open-label, Long-term Study to Assess the Immunogenicity of Linaclotide 
Administered Orally to Adult Patients With Irritable Bowel Syndrome With 
Constipation or Chronic Idiopathic Constipation
Study Centers (Country)
Approximately 80 (United States)
Development Phase
4
Objectives
The primary objective of this study is to assess the potential of linaclotide 
treatment to induce the development of anti-drug antibodies (ADAs). The 
secondary objectives are to provide additional evidence supporting the long-
term safety and efficacy of linaclotide in adult irritable bowel syndrome with 
constipation (IBS-C) and chronic idiopathic constipation (CIC) patients and to 
evaluate lower doses of linaclotide in patients who consider study withdrawal 
due to intolerable adverse events (AEs).
Methodology
Multicenter, open-label study. Patients who experience intolerable AEs (defined 
as AEs that subjectively would cause a patient to consider study withdrawal),
may have their dosing suspended and, following resolution of the intolerable 
AEs, be randomized to receive the same or lower doses of double-blind 
linaclotide as an optional treatment course. Patients who experience further 
intolerable AEs after the randomization can be transitioned to open-label 72 ug
linaclotide.
Number of Patients
1000 (projected number screened); 800 IBS-C or CIC enrolled. For each patient 
group (IBS-C or CIC), at least 300 patients are expected to be enrolled.
Diagnosis and 
Main Criteria for Inclusion
Male and female adult (≥ 18 years of age) outpatients who meet the Rome III 
criteria for IBS-C or CIC
Test Product, Dosage, and Mode of 
Administration
Patients with CIC: linaclotide 145-ug capsules, orally, once daily 
Patients with IBS-C: linaclotide 290-ug capsules, orally, once daily
Patients with intolerable AEs will be randomized to receive 290 ug, 145 ug, or 
the lower (unapproved) dose of 72 ug linaclotide oral capsules for IBS-C; and 
145 ug or 72 ug for CIC. Patients who experience further intolerable AEs after 
the randomization can be transitioned to open-label 72 ug linaclotide.
Duration of Treatment
Up to a 3-week Screening Period, followed by a 52-week Treatment Period
Reference Therapy, Dosage, and 
Mode of Administration
None
Criteria for Evaluation
Patient-reported assessments
Pharmacokinetic Analysis
Immunogenicity assessments
Primary Outcome Measure
ADA determinations from blood samples
Secondary Outcome Measures
AE reporting of recurrence (including date) of intolerable diarrhea after 
randomization to double-blind treatment following resolution of initial 
intolerable diarrhea.
Assessments of efficacy
 
during open-label 
treatment, and during double-blind treatment.
 
 
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Statistical Methods
Immunogenicity Assessments
For each indication separately and combined, the number and percentage of 
patients meeting treatment-related ADA-positive status will be summarized, 
along with the 1-sided 95% Clopper-Pearson confidence interval, for Safety 
Population patients with at least 1 assessable postbaseline sample, ie, patients 
who are not postbaseline ADA undetermined (sample lost, damaged, or out of 
specifications). A sensitivity analysis will be performed where baseline ADA 
undetermined patients are excluded. 
Efficacy 
The efficacy 
 will be analyzed descriptively based on 
the Intent-to-Treat Population. As this is an open-label study, no inferential 
statistics will be performed.
 
 
 
 
 
 
 
 
 
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3.1 OVERALL TABLE OF CONTENTS 
 
Page
1.0 TITLE PAGE ..............................................................................................
 
2.0 SYNOPSIS AND SCHEDULE OF EVALUATIONS ...............................
 
3.0 OVERALL TABLES OF CONTENTS, TABLES AND FIGURES 
 
3.1 OVERALL TABLE OF CONTENTS .............................................
 
3.2 LIST OF IN-TEXT TABLES ...........................................................
 
3.3  LIST OF IN-TEXT FIGURES ........................................................
 
4.0 IST OF ABBREVIATIONS .......................................................................
 
5.0 ETHICAL CONSIDERATIONS ................................................................
 
5.1 INSTITUTIONAL REVIEW BOARD AND INDEPENDENT 
ETHICS COMMITTEE ................................................................................
 
5.2 ETHICAL CONDUCT OF THE STUDY...............................................
 
5.3 PATIENT INFORMATION AND INFORMED CONSENT.................
 
6.0 INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE ...................................................................................................
 
7.0 INTRODUCTION ......................................................................................
 
7.1 CHRONIC IDIOPATHIC CONSTIPATION .........................................
 
7.2 IRRITABLE BOWEL SYNDROME WITH CONSTIPATION ............
 
7.3 SUMMARY OF LINACLOTIDE PROPERTIES ..................................
 
7.4 CLINICAL EXPERIENCE .....................................................................
 
7.5 RATIONALE FOR THIS STUDY .........................................................
 
8.0 STUDY OBJECTIVES ...............................................................................
 
9.0 INVESTIGATIONAL PLAN .....................................................................
 
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9.1 OVERALL STUDY DESIGN AND PLAN: DESCRIPTION ...............
 
9.2 DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE 
OF CONTROL GROUPS .............................................................................
 
9.3 SELECTION OF STUDY POPULATION .............................................
 
9.3.1 Inclusion Criteria ...............................................................................
 
9.3.2 Exclusion Criteria ..............................................................................
 
9.3.3 Removal of Patients from Therapy or Assessment ...........................
 
9.3.4 Patient Replacement Procedures .......................................................
 
9.4 TREATMENTS .......................................................................................
 
9.4.1 Treatments Administered ..................................................................
 
9.4.2 Identity of Investigational Products ..................................................
 
9.4.3 Method of Assigning Patients to Treatment Groups .........................
 
9.4.4 Selection of Dosages in the Study .....................................................
 
9.4.5 Selection and Timing of Dose for Each Patient ................................
 
9.4.6 Blinding .............................................................................................
 
9.4.7 Unblinding .........................................................................................
 
9.4.8 Prior and Concomitant Therapy ........................................................
 
9.4.9 Monitoring Treatment Compliance ...................................................
 
9.5 EFFICACY AND SAFETY VARIABLES .............................................
 
9.5.1 Primary Outcome Assessment ..........................................................
 
 
9.5.2 Efficacy Assessments ........................................................................
 
 
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9.5.4 Safety Assessments ...........................................................................
 
9.5.4.1 Adverse Events ...........................................................................
 
 
9.5.4.3 Severity Assessment ...................................................................
 
9.5.4.4 Serious Adverse Events ..............................................................
 
9.5.4.5 Reporting Adverse Events and Serious Adverse Events ............
 
9.5.4.6 Immediate Reporting of Serious Adverse Events .......................
 
9.5.4.7 Reporting of Pregnancies That Occur During the Study ............
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.6 DATA QUALITY ASSURANCE ..........................................................
 
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9.6.1 Data Monitoring ................................................................................
 
9.6.2 Data Recording and Documentation .................................................
 
9.7 STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE ..............................................................................................
 
9.7.1 Patient Populations ............................................................................
 
9.7.1.1 Screened Population ....................................................................
 
9.7.1.2 Safety Population ........................................................................
 
9.7.1.3 Intent-to-Treat Population ...........................................................
 
9.7.1.4 Randomized Population ..............................................................
 
9.7.1.5 Double-blind Safety Population ..................................................
 
9.7.1.6 Double-blind ITT Population ......................................................
 
9.7.2 Patient Disposition ............................................................................
 
9.7.3 Demographics and Other Baseline Characteristics ...........................
 
 
 
 
9.7.5 Efficacy Analyses ..............................................................................
 
 
 
 
 
 
 
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9.7.9 Determination of Sample Size ...........................................................
 
9.7.10 Computer Methods ..........................................................................
 
9.8 CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSES ..................................................................................................
 
9.9 PROTOCOL DEVIATIONS ...................................................................
 
10.0 STUDY SPONSORSHIP..........................................................................
 
10.1 STUDY TERMINATION .....................................................................
 
10.2 REPORTING AND PUBLICATION ...................................................
 
11.0 INVESTIGATOR OBLIGATIONS .........................................................
 
11.1 DOCUMENTATION ............................................................................
 
11.2 PERFORMANCE ..................................................................................
 
11.3 USE OF INVESTIGATIONAL MATERIALS ....................................
 
11.4 CASE REPORT FORMS ......................................................................
 
11.5 RETENTION AND REVIEW OF RECORDS .....................................
 
11.6 PATIENT CONFIDENTIALITY .........................................................
 
12.0 INVESTIGATOR’S STATEMENT .........................................................
 
13.0 APPENDICES ..........................................................................................
 
APPENDIX I. ELEMENTS OF INFORMED CONSENT ..............
 
APPENDIX II. CONTACT INFORMATION .................................
 
 
APPENDIX IV. BLOOD SAMPLING AND SHIPPING 
INSTRUCTIONS .............................................................................
 
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APPENDIX V.  SUMMARY ADAPTED FROM 
GUIDELINES OF THE US MULTI-SOCIETY TASK FORCE 
ON COLORECTAL CANCER AND OTHER 
COLONOSCOPY REQUIREMENTS .............................................
 
APPENDIX VI.  BRISTOL STOOL FORM SCALE .....................
 
 
 
 
14.0 LITERATURE CITED .............................................................................
 
 
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3.2 LIST OF IN-TEXT TABLES 
 
Page
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Table 9.7.2–1. Summarization of Patient Disposition ......................................
 
 
 
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3.3 LIST OF IN-TEXT FIGURES 
 
Page
 
 
 
 
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4.0
IST OF ABBREVIATIONS
ADA
anti-drug antibody
AE
adverse event
BM
bowel movement
BP
blood pressure
BSFS
Bristol Stool Form Scale
CIC
chronic idiopathic constipation
CFR
Code of Federal Regulations
ECG
electrocardiogram, electrocardiographic
eCRF
electronic case report form
EDC
electronic data capture
EOS
end of study
ET
early termination
FDA
US Food and Drug Administration
FR
Federal Register
GCP
good clinical practice
GI
gastrointestinal
HIPAA
Health Insurance Portability and Accountability Act
IBS
irritable bowel syndrome
IBS-C
irritable bowel syndrome with constipation
ICF
informed consent form
ICH
International Conference on Harmonisation 
IND
Investigational New Drug (application)
 
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IRB
Institutional Review Board
ITT
intent to treat
IWRS
interactive Web response system
NDA
New Drug Application
NEAE
newly emergent adverse event
PCS
potentially clinically significant
QTc
QT interval corrected for heart rate
RSM
Regional Site Manager
SAE
serious adverse event
SBM
spontaneous bowel movement
TEAE
treatment-emergent adverse event
 
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5.0
ETHICAL CONSIDERATIONS
5.1
INSTITUTIONAL REVIEW BOARD AND INDEPENDENT
ETHICS COMMITTEE
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., 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 study center's IRB in conformance with CFR, Title 21, Part 56.
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 ICH Guidances on General Considerations for 
Clinical Trials (ICH-E8; 62 FR 66113, 17 Dec 1997) and GCP (ICH-E6; 62 FR 25692, 
09 May 1997), as well as Part 312 of the CFR.
5.3
PATIENT INFORMATION AND INFORMED CONSENT
Patients, after being given an explanation of the study, will give voluntary and written 
informed consent and HIPAA authorization (in compliance with 21 CFR, Parts 50 and 
312) or other appropriate forms before participating in any study-related procedures.
Each patient will read, assent to an understanding of, and sign an instrument of informed 
consent or other locally applicable regulation and authorization form, after having had an 
opportunity to discuss the study and the ICF with the study staff; each patient will be 
made aware that he or she may withdraw from the study at any time without impact to 
further treatment.
The informed consent statement contains all the elements of informed consent listed in 
Appendix I of this protocol. Signed copies of the ICF and the HIPAA or other locally 
applicable form will be given to the patient, and both documents will be placed in the 
Investigator’s study files. 
 
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6.0
INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE
This study will be performed at approximately 80 study centers in the United States.
The Investigator is responsible for ensuring that the study is conducted according to the 
signed Investigator statement, the study protocol, 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 used in the study. 
An Investigator shall obtain the informed consent of each 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 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 staff qualified by education, experience, and 
licensure (in accordance with local regulations) and that the Investigator oversight is 
documented and assessment of Investigator capabilities and performance consistent with 
the study protocol. 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
7.1
CHRONIC IDIOPATHIC CONSTIPATION
The symptoms of chronic idiopathic constipation (CIC) are reported in approximately 
15% of the general population (Stewart et al, 1999). The prevalence of CIC is higher in 
women than men and increases with age (Johanson et al, 1989; Lembo and Camilleri, 
2003). Patients with CIC report multiple bowel and abdominal symptoms including 
straining, gas, hard stools, abdominal discomfort, infrequent bowel movements (BMs), 
bloating, a sense of incomplete evacuation, and abdominal pain (Johanson and Kralstein, 
2007).
7.2
IRRITABLE BOWEL SYNDROME WITH CONSTIPATION
Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal (GI) disorder
characterized by recurrent symptoms of abdominal pain and/or discomfort accompanied
by altered bowel function (Longstreth et al, 2006). In moderate to severe cases of IBS, an
overall deterioration in quality of life is often present (Drossman et al, 2002). IBS is one
of the most common GI disorders diagnosed in the United States; data suggest the 
prevalence of IBS is 10% to 15% of the population in North America and Europe
(Muller-Lissner et al, 2001). Based on Rome III guidelines, IBS is subtyped as IBS with 
diarrhea (IBS-D) or IBS with constipation (IBS-C); patients who do not fit IBS-C or 
IBS-D subtypes are classified as having mixed IBS (IBS-M) or untyped IBS (IBS-U) 
(Longstreth et al, 2006). In addition to abdominal pain or discomfort and reduced stool 
frequency, IBS-C patients also report a number of other complaints including bloating, 
hard stools, straining, and a sensation of incomplete evacuation.
7.3
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 and marketed 
as an orally administered therapeutic for the treatment of CIC and IBS-C. By activating
guanylate cyclase subtype C, orally administered linaclotide has been found to increase 
both intestinal fluid secretion and intestinal transit and also to decrease visceral pain in 
animal models (Linaclotide, 2013). Linaclotide has minimal oral bioavailability (≤ 0.2%) 
in several animal species (Bryant et al, 2010; Eutamene et al, 2009). 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 patients with IBS-C and CIC (Linaclotide, 2013).
 
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7.4
CLINICAL EXPERIENCE
Linaclotide has been developed by the Sponsor (Forest Research Institute, Inc.) 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 approvals included the following 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 safety studies (LIN-MD-02 and MCP-103-305), each with 78-week 
treatment periods
In addition, a randomized, double-blind, placebo-controlled, parallel-group Phase 3b 
study (LIN-MD-04) in patients with CIC was recently 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 an 
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. 
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 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 was diarrhea occurring in 13.1% to 17.2% of CIC 
patients in both studies. 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.
 
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The systemic exposure to linaclotide was also evaluated in the Phase 3 IBS-C and CIC 
studies in adults. Analysis of plasma indicated that linaclotide and its only active 
metabolite (des tyrosine linaclotide) MM-419447, plasma concentrations are generally 
not detectable. Linaclotide was detectable at concentrations just above the limit of 
detection (0.2 ng/mL) in the plasma of only 2 out of the 465 patients whose plasma 
samples were analyzed (both were IBS-C patients). MM-419447 was not detectable in 
any patient plasma samples.
Because of linaclotide’s limited systemic availability, a thorough QT study was not 
performed. However, triplicate electrocardiograms (ECGs) were part of the safety data 
obtained during the Phase 3 studies in adults. There were no clinically meaningful 
differences between placebo and linaclotide groups in the mean or change from baseline 
QT interval (corrected by either the Bazett or Fridericia formula). Overall the data 
indicated that linaclotide does not adversely affect the ECG of adult linaclotide-treated 
patients.
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. Study MCP-103-305 had a 
single case of aplastic anemia reported; the clinical presentation of the patient suggested 
that the disease process culminating in aplastic anemia began prior to linaclotide 
exposure and was most likely idiopathic. Post-hoc analyses of the linaclotide Phase 3 
clinical studies and long-term safety studies were undertaken to determine whether there 
was any evidence of a linaclotide effect on blood cell counts. There was no evidence of 
such an effect and based on linaclotide’s pharmacologic properties and minimal systemic 
bioavailability, linaclotide is unlikely to cause aplastic anemia. 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.
The recently 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 
chronic constipation 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.
 
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Safety data from these studies in adults showed that, except for diarrhea, the proportion 
of patients reporting a TEAE was similar between placebo and each linaclotide dose 
group, and the incidence of TEAEs was not dose-related. With the exception of the 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.
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. 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 in young juvenile mice.
7.5
RATIONALE FOR THIS STUDY
The possibility of an immune response to linaclotide, in the form of anti-drug antibody 
(ADA), was not evaluated in the linaclotide clinical development program. Upon 
approval of the NDA, the FDA Division of Gastroenterology and Inborn Errors Products 
required the Sponsors to evaluate this possibility by performing “a clinical trial in adults 
receiving Linzess (linaclotide) to assess development of ADA responses in patient 
samples.” The Division also prescribed that in this trial “adverse events will be 
collected.”
Evaluation of the immunogenicity of therapeutic proteins and peptides remains an 
important part of product development. Antibody-related clinical sequelae that can occur 
in humans range from no apparent or mild side effects to altered efficacy, 
immune-complex-mediated symptoms, and allergic reactions. Thus, it is necessary to 
collect appropriate data regarding the possibility of the appearance of and, if they appear, 
the characteristics of antibodies induced over time and assess how these findings may be 
associated with clinical outcomes. (Koren et al, 2008; Parenky et al, 2014; Shankar et al, 
2014)
 
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This open-label study is designed to fulfill a post-marketing requirement and in doing so 
determine if ADAs develop in patients treated with linaclotide. Secondarily, the study 
will provide additional evidence to support the long-term safety of linaclotide in adult 
IBS-C and CIC patients and evaluate lower doses of linaclotide in patients who develop 
intolerable AEs that prompt consideration of study withdrawal.
 
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8.0
STUDY OBJECTIVES
The primary objective of this study is to assess the potential of linaclotide treatment to 
induce the development of ADAs. The secondary objectives are to provide additional 
evidence supporting the long-term safety and efficacy of linaclotide in adult irritable 
bowel syndrome with constipation (IBS-C) and CIC patients and to evaluate lower doses 
of linaclotide in patients who consider study withdrawal due to intolerable AEs.
 
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9.0
INVESTIGATIONAL PLAN
9.1
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION
This will be a multicenter, open-label, long-term clinical study to assess the 
immunogenicity and long-term safety of linaclotide administered orally to adult patients 
with IBS-C or CIC, and to evaluate lower doses of linaclotide in patients who consider 
study withdrawal due to intolerable AEs that may be related to the use of linaclotide.
Approximately 800 IBS-C or CIC patients (a minimum of 300 each) will be enrolled.
The study will consist of up to a 3-week Screening Period, followed by a 52-week 
Treatment Period (Figure 9.1–1). Patients who meet the entry criteria will receive once 
daily, open-label doses of 290 ug linaclotide for patients with IBS-C; those with CIC will 
receive once daily, open-label doses of 145 ug linaclotide.
In order to limit patient withdrawals from the study due to AEs and to gain information 
about the effect of lowering the dose in patients who experience intolerable AEs (defined 
as AEs that subjectively would cause a patient to consider study withdrawal), in 
particular diarrhea and other GI AEs that may be related to the use of linaclotide, the 
following intervention (Figure 9.1–2) will be offered as an optional treatment course to 
such patients, unless deemed clinically inappropriate by the Investigator:
1. A temporary suspension of dosing of up to 7 days. If the dose suspension needs to last 
longer than 7 days because the intolerable AE has not resolved, then the Investigator 
should contact the Study Physician to discuss the duration of the dose suspension or 
withdrawal of the patient from the study. All AEs resulting in the temporary 
suspension will be recorded on the eCRF.
2. After the intolerable AE has resolved, the patient will be randomized into a 
Double-blind Treatment Period via an interactive Web response system (IWRS) and 
will receive dose regimens specific to each indication as follows. If the randomized 
dose regimen is tolerated, the patient will remain on this dose for the duration of the 
study (total duration of linaclotide exposure [whether open-label or double-blind] is 
not to exceed 52 weeks).
IBS-C patients will be randomized in a 1:1:1 ratio to 1 of the following regimens:
○
Linaclotide 290 ug every day
○
Linaclotide 145 ug every day
○
Linaclotide 72 ug every day
 
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CIC patients will be randomized in a 1:1 ratio to 1 of the following regimens:
○
Linaclotide 145 ug every day
○
Linaclotide 72 ug every day
3. If, after randomization, patients experience intolerable AEs, in particular diarrhea or 
other GI AEs, the dosing should be temporarily suspended for up to 7 days. If the 
dose suspension needs to last longer than 7 days because the intolerable AE has not 
resolved, then the Investigator should inform the Study Physician about the duration 
of dose suspensions or withdrawal of the patient from the study. 
After the intolerable AE has resolved, irrespective of the IBS-C or CIC status, 
patients should be dispensed open-label linaclotide (72 ug) and may continue on this 
dose in a Dose-Reduced Open-label Treatment Period for the duration of the study.
4. If patients experience an intolerable AE while receiving the adjusted dose of 72 ug in 
the Dose-Reduced Open-label Treatment Period, study participation should be 
terminated.
5. In the event of a planned procedure or an AE during which a patient requires dose 
suspension longer than 7 days, the Investigator should inform the Study Physician 
about the duration of dose suspensions. Upon event completion or AE resolution, the 
patient should be resumed on the assigned dose.
 
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Screening Period
The Screening Period starts with signing of the ICF and lasts for up to 21 calendar days. 
During this period, patient eligibility for entry into the Treatment Period will be 
determined, based on results of physical examination, medication history, 
medical/surgical history, all laboratory tests, ECG, and colonoscopy (if applicable). The 
end of the Screening Period coincides with the start of the Treatment Period. 
Treatment Period
The Treatment Period lasts for 52 weeks, including open-label treatment (all patients) and 
double-blind treatment (patients with intolerable AEs). Patients will attend study visits to 
complete all assessments. A list of assessments to be completed for all patients, for IBS-C 
patients, and for CIC patients, as well as the visits at which they are performed is 
provided in the Schedule of Evaluations (Section 2.0). 
 
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Follow-up Period
The follow-up period consists of a 1-month telephone visit for all patients (Visit 9). A 
4-Month Follow-Up Visit (Visit 10) is required only for patients with treatment-related 
ADAs at the time of study completion (52 weeks, Visit 8) or early termination [ET]. If 
treatment-related ADAs are still present in the patient’s serum at the 4-Month 
Follow-up Visit, an 8-Month Follow-up Visit will be required for ADA testing. Patients 
completing the 4-Month Follow-up Visit will also have a subsequent 1-month 
telephone call to review ADA status and determine if continuation to an 8-Month 
Follow-up Visit (Visit 11) is necessary.
If an ADA-positive patient becomes ADA negative or a baseline ADA-positive patient’s 
titer returns to less than 4-fold the baseline titer at the end the treatment period 
(52 weeks or early termination) or 4-Month Follow-up Visit (Visit 10), no further 
follow-up or visits are required. A list of assessments and the visits at which they are 
performed is provided in the Schedule of Evaluations (Section 2.0).
9.2
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE 
OF CONTROL GROUPS
An open-label study design with up to 52 weeks (12 months) of investigational-product 
exposure was chosen in accordance with the concepts in the ICH-E1 guideline for the 
safety evaluation of drugs intended for the long-term treatment (chronic or repeated 
intermittent use for longer than 6 months) of non-life-threatening diseases. The 12-month 
duration of the study will allow for assessment of the potential for ADAs to develop in 
response to long-term linaclotide treatment.
Two of the linaclotide doses selected for use in this study for CIC and IBS-C patients 
(145- and 290-ug, respectively) have been approved, and are currently marketed, in North 
America (ie, United States, Canada, and Mexico for both indications) and the European 
Union (IBS-C only). Patients with intolerable AEs that occur during open-label dosing 
will be randomized to receive double-blind treatments of 290 ug, 145 ug, or the lower 
(unapproved) dose of 72 ug linaclotide oral capsules for IBS-C; and 145 ug or 72 ug for 
CIC. Patients who experience further intolerable AEs after the randomization can be 
transitioned to open-label 72 ug linaclotide.
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. Provide written informed consent obtained from the patient before the initiation of 
any study-specific procedures
 
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2. Be an ambulatory, community-dwelling male or non-pregnant female 18 years or 
older at the Screening Visit
 
 
 
 
6. Patient meets the colonoscopy requirements defined in Appendix V, which are 
modified from the Summary of the US-Multi-Society Task Force on Colorectal 
Cancer and other Colonoscopy Requirements
7. Patient has no clinically significant findings on a physical examination, 12-lead ECG, 
and clinical laboratory tests (clinical chemistry panel, complete blood count, urine 
drug screen, urinalysis) after signing the ICF but before receiving the first dose of 
investigational product. (Note: The Investigator will determine if a particular finding 
is clinically significant. In making this determination, the Investigator will consider 
whether the particular finding could prevent the patient from performing any of the 
protocol-specified assessments, could represent a condition that would exclude the 
patient from the study, could represent a safety concern if the patient participates in 
the study, or could confound the study-specified assessments of safety or efficacy)
8. Patient meets the Rome III criteria for IBS-C or CIC as described below:
IBS-C Criteria: the patient must meet the following 2 criteria (A and B): 
A. IBS Criteria: The patient must have abdominal pain or discomfort at least 
3 days per month in the 3 months before diagnosis (with symptom onset at 
least 6 months before diagnosis) associated with 2 or more of the following:
 
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1. Improvement with defecation
2. Onset associated with a change in frequency of stool
3. Onset associated with a change in form (appearance) of stool
B
Stool Consistency Requirement: During the 3 months before diagnosis in the 
absence of laxative or enema use, the patient has hard or lumpy stools 
(Bristol Stool Form Scale [BSFS] score 1 or 2) with at least 25% of BMs and 
has loose or mushy stools (BSFS 5 or 6) with < 25% of BMs
CIC Criteria: the patient must meet the following 3 criteria (A, B, and C): 
A. Patient meets 2 or more of the following criteria for 3 months before the 
diagnosis with symptom onset at least 6 months before diagnosis:
1. Straining during at least 25% of defecations
2. Lumpy or hard stools in at least 25% of defecations
3. Sensation of incomplete evacuation for at least 25% of defecations
4. Sensation of anorectal obstruction/blockage for at least 25% of 
defecations
5. Manual maneuvers to facilitate at least 25% of defecations (eg, digital 
evacuation, support of the pelvic floor)
6. Fewer than 3 defecations per week
B. Loose stools are rarely present without the use of laxatives
C. Insufficient criteria for irritable bowel syndrome. (The criteria for IBS are 
provided in Point A under IBS Criteria, above)
 
9.3.2
Exclusion Criteria
Patients who meet any of the following criteria will not be eligible to participate in the 
study:
1. At the Day 1 Visit, the patient reports having 6 or more spontaneous bowel 
movements (SBMs) when asked about the number of SBMs that they had during the 
week before the visit. (Note: An SBM is a bowel movement that occurred in the 
absence of laxative, enema, or suppository use on either the day of the BM or the day 
before the BM)
2. At the Day 1 Visit, patient reports having any SBMs that were watery (BSFS = 7) or 
more than 1 SBM that was mushy (BSFS = 6) when asked about the number of SBMs 
that were watery or mushy during the week before the visit
 
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3. Patients who have any of the following: 
 
 
 
○
Structural abnormality of the GI tract or a disease or history of a condition that 
can affect GI motility (eg, gastroparesis, celiac disease)
 
 
 
 
 
 
 
 
 
 
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9. Patient has ever received linaclotide as a treatment (including commercially-available 
product) or has been randomized into any clinical study in which linaclotide was a 
treatment. (Patients who enrolled into linaclotide clinical studies conducted prior to or 
during this study but failed to be randomized are eligible for the current study)
10. Patient has ever received plecanatide, SP-333, or has participated in a plecanatide 
clinical study
 
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9.3.3
Removal of Patients from Therapy or Assessment
A premature discontinuation will occur when a patient who signed the ICF ceases 
participation in the study, regardless of circumstances, before the completion of the 
study. Patients can be prematurely discontinued from the study for one of the following 
reasons:
○
Screen failure (failure to meet inclusion/exclusion criteria)
○
Withdrawal of consent
○
AE
○
Lack of efficacy
○
Protocol violation
○
Noncompliance with investigational product
○
Lost to follow-up
○
Study terminated by Sponsor
○
Site terminated by Sponsor
○
Other 
All enrolled patients who prematurely discontinue from the study, unless the cause is 
screen failure, must be seen for a final assessment at ET, and follow-up blood samples as 
described in the Schedule of Evaluations (Section 2.0) should be obtained for patients 
who are ADA positive at the last visit. A final assessment will be defined as completion 
of the evaluations scheduled for the Final Visit at the end of Week 52 End of Study 
(EOS)/ET Visit (Visit 8). 
 
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Any patient who withdraws because of an AE will be followed until the AE resolves, 
stabilizes, or can be explained as being unrelated to investigational product. The study
centers must make a reasonable effort to follow pregnant patients until delivery or end of 
the pregnancy.
Patients who do not complete all required scheduled visits/procedures must be requested 
in writing to come in for an ET Visit and to return any unused investigational product. A 
clear description of premature discontinuation must be documented. A copy of the letter, 
together with the source documentation, will be kept by the Investigator. The reasons for 
premature discontinuation from the study will be reflected on the eCRF.
9.3.4
Patient Replacement Procedures
Patients in this study who prematurely discontinue treatment will not be replaced.
9.4
TREATMENTS
9.4.1
Treatments Administered
Investigational product in the form of capsules will be provided by the Sponsor. Patients 
will be supplied capsules with identical appearance containing either 72 ug linaclotide, 
145 ug linaclotide, or 290 ug linaclotide.
Rescue medication will not be provided; however, patients may use any laxative, 
suppository, or enema that they choose when at least 72 hours have passed since their 
previous BM or when their symptoms become intolerable. Laxative, suppository or 
enema use must be documented with all other concomitant medication use in the eCRF.
9.4.2
Identity of Investigational Products
All investigational product will be supplied in bottles containing 35 capsules and will be 
labeled with the following content: protocol number, storage information, warning 
language (“Caution: New Drug-Limited by Federal Law to Investigational Use. Keep Out 
of Reach of Children”), and instructions to take as directed. The label will also include 
the kit number. All 3 strengths of linaclotide (72 ug, 145 ug, and 290 ug) will be listed on 
the bottle label. IWRS will be used to dispense kits in Open-label and Double-blind 
treatment periods.
Immediately before dispensing investigational product, the Investigator or designee will 
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Investigational product must be stored at the study center in an appropriate secure area 
(eg, a locked cabinet in a locked room) 
 excursions permitted between 
 Keep product in the original container. Do not subdivide 
or repackage. Protect from moisture. Do not remove desiccant from the container. Keep 
bottles tightly closed in a dry place.
Formulation information for the investigational products is provided below. 
 
 
 
 
 
 
 
 
 
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 must be returned, and 
whenever investigational products are returned, unit counts must be performed. All 
investigational products must be accounted for. At the end of the study, all unused 
investigational products and empty investigational product bottles 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 signs the ICF at the first screening visit, study personnel will register the 
patient in the IWRS, and the system will assign the patient a sequential patient 
identification number. The first patient to sign the ICF at each site will be assigned the 
first number in the sequence by the system.
 
 
 
 
The study center must contact the IWRS at the Screening Visit and at investigational 
product dispensing visits; the IWRS will assign the kit number for the investigational 
product to be dispensed to the patient at the first Treatment Period visit (Visit 2) and at 
other visits as designated on the Schedule of Evaluations (Section 2.0). 
This is an open-label (unblinded) study, with IBS-C patients initially assigned to receive 
290 ug linaclotide and CIC patients assigned to receive 145 ug. Patients who experience 
intolerable AEs during open-label phase will be randomized into a Double-blind 
Treatment Period via the IWRS and will receive dose regimens specific to each 
indication as described in Section 9.4.4.
9.4.4
Selection of Dosages in the Study
The linaclotide dosages chosen for the open-label phase of this study (145 ug and 290 ug)
have been shown to be safe and effective in adults for treatment of IBS-C (290 ug) and 
CIC (145 ug) and are approved in North America at those doses for those indications. 
Data from the pivotal clinical studies showed that for patients in both patient populations 
treated with linaclotide, diarrhea was the most frequent AE, reported in 20% for 
IBS-C patients treated with 290 ug linaclotide and in 16% for CIC patients treated with 
145 ug linaclotide, and was the most common reason for discontinuation (5%). In the 
majority of cases, onset of the diarrhea occurred within the first 2 weeks of treatment, and 
the diarrhea was generally mild to moderate (being assessed as severe in only 2% of 
linaclotide-treated patients in each patient population). 
Patients with intolerable AEs that may be related to the use of linaclotide will be 
randomized to receive double-blind 290 ug, 145 ug, or 72 ug linaclotide oral capsules for 
IBS-C; and 145 ug or 72 ug for CIC. Patients who experience further intolerable AEs 
after the randomization can be transitioned to open-label 72 ug linaclotide.
 
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The 72 ug dose was selected as part of the dose regimen during the double-blind phase 
for patients with intolerable AEs as it demonstrated efficacy in Phase 2b IBS-C and CIC 
studies, particularly related to improvement of bowel symptoms, with an improved safety 
profile compared to higher doses. 
9.4.5
Selection and Timing of Dose for Each Patient
All investigational product will be administered orally as a single daily dose in the 
morning at least 30 minutes before the first meal of the day.
Patients who meet all eligibility criteria at Day 1 (Visit 2) will be dispensed 1 bottle 
(assigned by IWRS) containing 35 capsules of investigational product. Additional bottles 
of investigational product will be dispensed at subsequent visits per the Schedule of 
Evaluations (Section 2.0). Patients will be instructed to return any unused investigational 
product at the next study visit.
Patients must have fasted for at least 2 hours before arriving at the site for Day 1 
(Visit 2). Patients will take their initial dose of investigational product (1 capsule) at the 
study center during Day 1 (Visit 2) after all study eligibility criteria have been confirmed. 
On all subsequent days, the patient will take 1 capsule of investigational product in the 
morning at least 30 minutes before breakfast. If, for any reason, it is inconvenient for a 
patient to take linaclotide in the morning, the dose may be taken at another time during 
the day with the Investigator’s prior approval and documentation, as long as linaclotide is 
taken on an empty stomach or at least 2 hours after a meal.
Should an intolerable AE occur and, in the Investigator’s judgment, the patient is unable 
to resume investigational product dosing after 7 days, the Investigator must contact the 
Study Physician to discuss the patient’s continued participation in the study 
9.4.6
Blinding
Randomization only occurs for those patients who experience intolerable AEs that may 
be related to the use of linaclotide and undergo intervention (Section 9.1). For those 
patients, a list of patient randomization codes will be generated by Statistical 
Programming at the Sponsor or designee, 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. 
 
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9.4.7
Unblinding
In the open-label and double-blind treatment phases, bottles of linaclotide will be 
dispensed that include on the label: contains either 72 ug linaclotide, 145 ug linaclotide, 
or 290 ug linaclotide. During the open-label treatment phase both the Investigator and 
patient will be made aware of the dose contained in the IWRS-assigned bottle.
Unblinding procedures are applicable to the double-blind treatment phase only.
Any unblinding (performed only via IWRS) at a study center should be done only in an 
emergency that requires the investigational product to be identified for the medical 
management of the patient. The Investigator must notify the Study Physician immediately 
(see 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 center will immediately 
disqualify the patient from further participation in the study.
Treatment codes may be broken by the Patient Safety Department at Forest Research 
Institute, Inc., 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.
In an emergency, the Investigator can obtain the treatment assignment of any patient at 
his or her study site through the IWRS.
9.4.8
Prior and Concomitant Therapy
All ongoing medicines taken by the patient at the time of screening and prior to first dose 
of investigational product will be recorded as prior medications. Any changes in 
concomitant medicines or new medicines added will be recorded in the eCRF. 
Concomitant medicines will be recorded at study visits throughout the entire study 
(beginning at Visit 1) including the Follow-up Period (Visits 9 - 11).
The concomitant medicines listed below are prohibited from the Screening Visit until the 
end of the Treatment Period (Appendix III):
 
 
 
 
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During the Follow-up Period there are no concomitant medication restrictions.
9.4.9
Monitoring Treatment Compliance
Investigational-product compliance during the Treatment Period will be monitored by 
counting the number of capsules dispensed and returned. Patients will be instructed to 
return all investigational product and bottles at specified visits defined in the Schedule of 
Evaluations (Section 2.0). Before new investigational product is dispensed at the 
specified visits, every effort will be made to collect all unused investigational product.
9.5
EFFICACY AND SAFETY VARIABLES
9.5.1
Primary Outcome Assessment
Assessments of total anti-linaclotide antibodies will be used to determine the primary 
outcome parameter, the presence of ADAs. The presence of anti-linaclotide antibodies 
will be determined by a validated assay.   
9.5.1.1
Immunogenicity Assessments 
Blood will be collected for determination of ADAs to linaclotide at the Day 1 Visit 
(Visit 2) prior to the patient receiving investigational product (to acquire a baseline), and 
at all scheduled study visits during the Treatment Period. For patients who prematurely 
discontinue, blood samples should be obtained within 7 days of the last dose of 
linaclotide, and follow-up blood samples as described in the Schedule of Evaluations 
(Section 2.0) should be obtained for patients who are ADA positive at the last visit.
Blood samples collected for ADA determinations will be analyzed in batches; therefore 
real-time reports of ADA results will not be available.   
Investigators and patients will remain blinded throughout the study as to ADA status. 
Patients who develop positive or increased ADA titers will not be withdrawn from 
treatment; investigators will continue such patients on therapy as they would any patient 
in the study. Clinical symptoms of hypersensitivity such as anaphylactic shock, 
angioedema, skin rash, and urticaria require treatment withdrawal even without ADA 
results available at the time of occurrence. 
Each individual sample will be assayed and categorized as one of the following:
○
ADA positive
○
ADA negative
○
ADA undetermined (sample lost, damaged, or out of specifications)
 
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A sample is only considered ADA positive if the screening and confirmatory assay both 
indicate the presence of ADAs. A sample indicating the presence of ADAs by the 
screening assay that cannot be confirmed (eg, insufficient sample, laboratory error) will 
be considered ADA undetermined.
ADA-positive patients will be split into two groups at the end of the study; treatment-
related ADA and non–treatment-related ADA. A treatment-related ADA is any patient 
who is ADA negative at baseline and becomes ADA positive at one or more time points 
in the study (treatment induced ADA), or who is ADA positive at baseline and has a 
titer increase greater than or equal to 4-times the baseline titer at one or more time 
points in the study (treatment boosted ADA). A non–treatment-related ADA positive 
patient is any patient who is ADA positive at baseline and is either ADA negative or 
has a titer less than 4-fold the baseline titer at any time point in the study.
Patients with treatment-related ADAs detected at the end of the Treatment Period 
(52 weeks visit or early termination visit) will be followed at 4 months (Visit 10) and, if 
needed, up to a maximum of 8 months (Visit 11), or until they are ADA negative or 
their titers revert to baseline. Any patient who is ADA negative or has non–treatment-
related ADA at the end of the treatment period (52 weeks or ET) does not require 
follow up regardless of ADA status at any other time during the study. In order to 
minimize the number of ADA-undetermined results, patients whose serum samples 
from the Week 52 EOS/ET Visit (Visit 8) are lost, damaged, or out of specification may 
be called for an unscheduled visit to obtain another sample.
In order to show reversion to baseline for treatment-related ADA-positive patients who 
require follow up, 1 negative sample or 1 sample showing a return to an ADA titer less 
than 4-fold the baseline titer is required. Patients with treatment-related ADAs who 
complete the study or terminate early will be requested to return for additional follow-
up visits to provide blood samples for ADA assessments at 4 and 8 months to document 
persistence of positivity or reversion to baseline. No further visits will be required after 
the 8-Month Follow-up Visit (Visit 11). Patients previously ADA positive who have 
become ADA negative or have reverted back to within 4-fold their baseline titer at the 
4-Month Follow-up Visit will not be required to complete the 8-Month Follow-up Visit. 
Investigators will be notified of the ADA status following patient completion or ET and 
before the 1-month follow-up phone call to the patient.
Samples will be banked for up to 10 years in case further testing for isoform, subform,
and/or linaclotide concentration is requested. Consent for storage and further testing will 
be obtained from patients. 
In cases of SAEs, ADA status can be reported to both patients and investigators if
requested and felt to be necessary for the medical care of the patient. If the blind is 
broken, the patient must be withdrawn from treatment.
 
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The study Sponsor will contract with Q-Squared Solutions BioSciences LLC for ADA 
testing.
The testing methods will be the following: 

Screening assay for the presence of anti-linaclotide antibodies: custom bridging 
ELISA with electrochemiluminescence detection. Positive results in the screening 
assay will be confirmed by competitive displacement of the anti-linaclotide antibodies 
with free linaclotide using the same assay. A sample is considered ADA negative if it 
is negative in either the screening or confirmatory assays. A sample is considered 
ADA positive if it is positive in the confirmatory assay  

ADA positive serum will be titered and assayed for neutralizing antibodies and cross 
reactivity with the endogenous hormones, guanylin and uroguanylin 
9.5.2
Efficacy Assessments
The following information will be captured at the specified study visits (Section 2.0). All 
assessments required on Day 1 Visit (Visit 2) should be performed before first dose of 
linaclotide.
For all patients:

Patient Assessment of Constipation Severity (captured at all study visits except 
the Screening Visit [Visit 1]): 
o
Rating of the constipation severity during the previous 7 days on a 5-point 
ordinal scale will be provided by the patient answering the following question:
“On average, how would you rate your constipation during the past 7 days?”
o
1=None
o
2=Mild
o
3=Moderate
o
4=Severe
o
5=Very Severe
For IBS-C patients:

Patient Assessment of IBS Symptom Severity (captured at all study visits except 
the Screening Visit [Visit 1]): 
o
Rating of IBS symptoms severity during the previous 7 days on a 5-point 
ordinal scale will be provided by the patient answering the following question:
“On average, how would you rate your IBS symptoms during the past 7 days?”
o
1=None
o
2=Mild
o
3=Moderate
 
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o
4=Severe
o
5=Very severe 

Degree of Relief of IBS Symptoms (captured at all study visits except the 
Screening Visit [Visit 1]):
o
Rating of degree of relief of IBS symptoms during previous 7 days on a 
7-point balanced ordinal scale will be provided by the patient answering the 
following question: 
“Compared to before you started this study, how would you rate your IBS 
symptoms during the past 7 days?”
o
1 = completely relieved, 
o
2 = considerably relieved
o
3 = somewhat relieved
o
4 = unchanged
o
5 = somewhat worse
o
6 = considerably worse 
o
7 = as bad as I can imagine

IBS Treatment Satisfaction Assessment (captured at all study visits except the 
Screening [Visit 1] and Day 1 Visits [Visit 2]): 
o
Rating of degree of satisfaction with the investigational product’s ability to 
relieve IBS symptoms on a 5-point ordinal scale will be provided by the 
patient answering the following question:
“Overall, how satisfied are you with the study medication’s ability to relieve your 
IBS symptoms?”
o
1=Not at all satisfied
o
2=A little satisfied
o
3=Moderately satisfied
o
4=Quite satisfied
o
5=Very satisfied
For CIC patients:

Constipation Treatment Satisfaction Assessment (captured at all study visits 
except the Screening [Visit 1] and Day 1 Visits [Visit 2]):
o
Rating of degree of satisfaction with the investigational product’s ability to 
relieve constipation symptoms on a 5-point ordinal scale will be provided by 
the patient answering the following question:
“Overall, how satisfied are you with the study medication’s ability to relieve your
constipation symptoms?”
o
1=Not at all satisfied
o
2=A little satisfied
 
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o
3=Moderately satisfied
o
4=Quite satisfied
o
5=Very satisfied
 
 
 
 
 
 
 
 
 
 
9.5.4
Safety Assessments
9.5.4.1
Adverse Events
An AE is any untoward medical occurrence in a patient or clinical investigation subject
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).
 
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For the purpose of the site’s data collection responsibilities, any untoward event that was 
reported from the time the patient signed the ICF until 30 days after the last known dose 
of investigational product, until ADA positive status for antibody positive patients has 
reverted to ADA negative, or until the end of the Follow-up Period (whichever is later), 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 inform consent, including any change in severity 
or frequency of pre-existing disease

All clinically relevant abnormalities in laboratory values or clinically relevant 
physical findings that occur during the study schedule
Please note that 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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9.5.4.3
Severity Assessment
The Investigator will provide an assessment of the severity of each AE by recording a 
severity rating on the appropriate AE reporting page of the patient’s eCRF. Severity,
which is a description of the intensity of manifestation of the AE, is distinct from 
seriousness, which implies a patient outcome or AE-required treatment measure 
associated with a threat to life or functionality (Section 9.5.4.4). Severity will be assessed 
according to the following scale:
Mild:
The AE was an annoyance to the patient but did not further hinder 
baseline functioning; the AE may have been intermittent or continuous.
Moderate:
The AE caused the patient to experience some discomfort or some 
interference with normal activities but was not hazardous to health; 
prescription drug therapy may have been employed to treat the AE.
Severe:
The AE caused the patient to experience severe discomfort or severely 
limited or prevented normal activities and represented a definite hazard to 
health; prescription drug therapy and/or hospitalization may have been 
employed to treat the AE.
9.5.4.4
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.
 
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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 (eg, elective procedures for pre-existing conditions that did 
not worsen, such as cosmetic surgery and hysterectomy) are excluded from SAE 
reporting.
9.5.4.5
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 9.5.4.1, to notify site personnel of any AEs occurring up to 30 days after the last 
known dose of linaclotide, or for ADA positive patients, until the end of the 8-month 
Follow-up Period. Any AEs reported by the patient (or patient representative) during this 
period are to be recorded in original source documents. AEs are also to be recorded in the 
eCRF if at least 1 of the following conditions is met: 1) the event meets the criteria for an 
SAE (see Sections 9.5.4.4 and 9.5.4.6), and/or 2) the event is considered by the 
Investigator to be potentially causally related to investigational product.
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 stabilized, or can 
be explained as being unrelated to the investigational product. 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.  
 
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9.5.4.6
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 Patient Safety on the SAE Form for
Clinical Studies. The Sponsor’s Study Physician may also be notified by telephone.
If, during follow-up, any nonserious AE worsens and eventually meets the criteria for an 
SAE, that AE should be recorded as a new SAE. 
The site must transmit the SAE Form for Clinical Studies to the SAE fax number shown 
below. Even if an initial report is made by telephone, the SAE Form for Clinical Studies
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 Studies to Forest Research Institute, Inc.
SAE fax number: 
Sponsor's Study Physician Medical Emergency phone number: 
9.5.4.7
Reporting of Pregnancies That Occur During the Study
Study site personnel must report a pregnancy from the time the patient signs the ICF until 
30 days after the last dose of investigational product. Within 24 hours of learning of the 
pregnancy, the study site personnel must report the event to Forest Patient Safety on the 
Clinical Study Pregnancy Form and fax it to the SAE/Pregnancy fax number stated in 
Section 9.5.4.6, even if no AE has occurred. Pregnancies in female partners of male 
patients occurring during the time frame described above must also be reported.
 
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The pregnancy must be followed to term and the outcome reported by completing a 
follow-up Clinical Study Pregnancy Form. If the pregnancy is associated with an SAE 
(eg, if the mother is hospitalized for hemorrhage), a separate SAE Form for Clinical 
Studies must be filed as described in Section 9.5.4.6 with the appropriate serious criterion 
(eg, hospitalization) indicated in addition to the Pregnancy Form.
9
8
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9
9
 
 
 
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9
1
 
 
 
 
 
 
9
2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9
4
 
 
 
 
 
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9
5
 
 
 
9
6
 
 
 
   
 
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9
7
 
9.6
DATA QUALITY ASSURANCE
9.6.1
Data Monitoring
Before any patient enters the study, a representative of Forest Research Institute, Inc., 
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 electronic data capture EDC system. After the 
first patient is enrolled, the Forest representative, a Regional Site Manager (RSM) or 
designee, will periodically monitor the progress of the study by conducting on-site visits. 
This RSM 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 RSM 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.
 
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9.6.2
Data Recording and Documentation
Data collection will involve the use of the Forest 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 Forest 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, etc.) 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 Forest Research Institute, Inc., its 
authorized representatives, and the FDA or other health authorities.
9.7
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
9.7.1
Patient Populations
The following populations will be considered in the statistical analysis of the study.
9.7.1.1
Screened Population
The Screened Population will consist of all patients who sign an ICF for the study and 
receive a patient identification number.
9.7.1.2
Safety Population
The Safety Population will consist of all patients in the Screened Population who receive 
at least 1 dose of investigational product during the Treatment Period.
 
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9.7.1.3
Intent-to-Treat Population
The Intent-to-Treat (ITT) Population will consist of all patients in the Safety Population 
who have at least 1 postbaseline assessment for any efficacy or health 
outcomes parameter.
9.7.1.4
Randomized Population
The Randomized Population will consist of all patients in the Safety Population who are 
randomized to double-blind investigational product following resolution of an 
intolerable AE.
9.7.1.5
Double-blind Safety Population
The Double-blind Safety Population will consist of all patients in the Randomized 
Population who receive at least 1 dose of investigational product during the Double-blind 
Treatment Period.
9.7.1.6
Double-blind ITT Population
The Double-blind ITT Population will consist of all patients in the Double-blind Safety 
Population who have at least 1 post-randomization assessment for any parameter during 
the Double-blind Treatment Period.
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 indication (IBS-C or CIC), and study center.
The number of screen failures (ie, patients who enter the Screening Period but not the 
Treatment Period) along with the associated reasons for failure will be tabulated overall. 
The number and percentage of patients in the categories described in Table 9.7.2–1 will 
be summarized overall and by treatment group, if specified, for each indication in the 
Safety Population.
 
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Table 9.7.2–1.
Summarization of Patient Disposition
Category
By Treatment 
Group
Patients who complete the Open-label Treatment Period
No
Patients who prematurely discontinue during the Open-label Treatment Period
No
Reasons for premature discontinuation of open-label treatment as recorded on the 
eCRF
No
Patients who prematurely discontinue open-label treatment due to AE who do not 
randomize to double-blind treatment
No
Patients who prematurely discontinue open-label treatment due to AE who do 
randomize to double-blind treatment (Randomized Population)
Yes
Patients who complete the Double-blind Treatment Period
Yes
Patients who prematurely discontinue during the Double-blind Treatment Period
Yes
Reasons for premature discontinuation of double-blind treatment as recorded on the 
eCRF
Yes
Patients who prematurely discontinue double-blind treatment due to AE who do not 
reduce dose to open-label 72 ug dose
Yes
Patients who prematurely discontinue double-blind treatment due to AE who do reduce 
dose to open-label 72 ug dose
Yes
Patients who complete the Dose-Reduced Open-label Treatment Period
Yes
Patients who prematurely discontinue during the Dose-Reduced Open-label Treatment 
Period
Yes
Reasons for premature discontinuation of dose-reduced open-label treatment as 
recorded on the eCRF
Yes
9.7.3
Demographics and Other Baseline Characteristics
Demographic parameters (ie, age, race, ethnicity, sex, weight, height, and body mass 
index) and other baseline characteristics will be summarized by indication for the Safety 
Population, and for each indication by randomized treatment group for the Double-blind 
ITT Population.
Prior medicines are defined as any medicines taken prior to date of first dose of 
investigational product. Concomitant medicines are defined as any medicines taken 
during the Treatment Period (ie, between the date of the first dose of investigational 
product in the Treatment Period and the date of the last dose of investigational product in 
the Treatment Period, inclusive). Any medicines started after the date of last dose of 
investigational product will not be considered concomitant medicines for summary 
purposes, but will be included in the patient data listings.
 
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Both prior and concomitant medicine use will be summarized by the number and 
proportion of patients in each patient group receiving each medicine within each 
therapeutic class. Concomitant medicine use will be presented for the Treatment Period 
as a whole by indication (IBS-C and CIC) for the Safety Population. Multiple medicines 
used by a patient in the same category (based on Anatomical-Therapeutic-Chemical 
classification) will only be counted once.
The WHO Drug Dictionary, Version September 2013 or newer, will be used to classify 
prior and concomitant medications by therapeutic class and drug name.
 
 
 
 
 
 
 
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9.7.5
Efficacy Analyses
The efficacy analyses will be based on the ITT Population. As this is an open-label study, 
no inferential statistics will be performed on these endpoints.
Descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) 
will be presented for continuous variables, and frequency distributions will be presented 
for categorical variables. These summaries will be presented by indication (IBS-C and 
CIC) and, where the endpoint is measured for both IBS-C and CIC, pooled across both 
indications at each scheduled visit the parameter is assessed. 
The following parameters will be summarized: 

Constipation severity

IBS symptom severity (IBS-C only)

Degree of relief of IBS symptoms (IBS-C only)

IBS treatment satisfaction (IBS-C only)

Constipation treatment satisfaction (CIC only)
 
 
 
 
 
 
 
For recurrence of diarrhea parameters, tables based on the Double-blind ITT Population 
will specifically refer to recurrence of diarrhea. Listings based on the Randomized 
Population will identify the patient-specific AEs.
 
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Parameter
Description
 
Recurrence of 
(intolerable) diarrhea
Frequency summary; Fisher exact test, comparing treatment groups.
Time to first recurrence 
of (intolerable) diarrhea
Parameter = First recurrence of (intolerable) diarrhea date – first randomized dose 
date + 1; censored at date of last randomized dose for patients who do not have 
recurrence of (intolerable) diarrhea.
Summary statistics for patients who have recurrence of (intolerable) diarrhea; 
Kaplan-Meier summary statistics, log-rank test, and figure, and hazard ratio per 
Cox proportional hazards regression model, for all patients, comparing treatment 
groups, controlling for geographic region.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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.
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9.7.8.2.1
Immunogenicity Assessments
A patient’s baseline ADA status (ADA positive, ADA negative, or ADA undetermined)
will be the assay result of the Treatment Period Day 1 (Visit 2) sample. A patient’s 
overall postbaseline ADA status will be derived from all postbaseline samples during the 
Treatment Period and within 7 days after the last dose of investigational product. The 
possible categories, dependent on baseline ADA status, are described in
Table 9.7.8.2.1–1.
Table 9.7.8.2.1–1.
Patient Postbaseline ADA Categorization
Baseline ADA Negative and ADA Undetermined 
Patients
Baseline ADA Positive Patients
Treatment-induced ADA positive
Treatment-boosted ADA positive
Non-treatment-boosted ADA positive
ADA negative
ADA negative
ADA undetermined
ADA undetermined
Postbaseline ADA category derived for each patient based all postbaseline samples after Visit 2 through 7 days after 
last dose of investigational product.
Treatment-induced ADA positive: Baseline ADA negative or ADA undetermined patient with ≥1 ADA positive 
sample
Treatment-boosted ADA positive: Baseline ADA positive patient with ≥1 ADA positive sample and with titer ≥4-fold 
the baseline titer
Non-treatment-boosted ADA positive: Baseline ADA positive patient with subsequent ADA positive samples that 
have titer values < 4-fold increase from the baseline
ADA negative:
Patient with ≥1 ADA negative sample with no ADA positive samples
ADA undetermined:
Patient with no assessable samples (sample lost, damaged, or out of specifications
 
A patient will meet treatment-related ADA positive status if the patient meets either of 
the following criteria: 
○
Treatment-induced ADA positive for baseline ADA negative or ADA 
undetermined patients
○
Treatment-boosted ADA positive for baseline ADA positive patients
 
 
A sensitivity analysis will be performed where baseline ADA 
undetermined patients are excluded.
 
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9
4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.7.8.5.2
Interim Analysis
No interim analysis is planned for this study.
9.7.9
Determination of Sample Size
The objective of this study is to assess the long-term safety of linaclotide administered to 
patients with IBS-C or CIC and to determine the potential of linaclotide to induce ADAs.
If 0 of 800 patients develop ADAs, the 1-sided 95% upper confidence interval for this
rate (0/800 [0%]) is 0.374%.
9.7.10
Computer Methods
Statistical analyses will be performed using version 9.3 (or newer) of SAS on a Linux 
operating system.
 
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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 Forest 
Research Institute, Inc. No protocol amendment may be implemented (with the 
exceptions noted below) before it has been approved by the IRB and the signature page, 
signed by the Investigator, has been received by Forest Research Institute, Inc. If the 
protocol is amended to eliminate or reduce the risk to patients, the amendment may be 
implemented before IRB review and approval. However, the IRB must be informed in 
writing of such an amendment, and approval must be obtained within reasonable 
time limits. 
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 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 Forest Research
Institute, Inc. Protocol deviations should be reported to the Sponsor (either verbally or
electronically) in a timely manner from the date 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 must be notified according to the criteria and time period dictated by the IRB 
associated with this study.
 
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10.0
STUDY SPONSORSHIP
This study is sponsored Forest Research Institute, Inc.
10.1
STUDY TERMINATION
Forest Research Institute, Inc., reserves the right to terminate the study in its entirety or at 
a specific study center before study completion. 
10.2
REPORTING AND PUBLICATION
All data generated in this study are the property of Forest Research Institute, Inc. and 
Ironwood Pharmaceuticals, Inc. 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, Forest Research Institute Inc., and Ironwood Pharmaceuticals Inc.
 
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11.0
INVESTIGATOR OBLIGATIONS
11.1
DOCUMENTATION
The Investigator must provide the following to Forest Research Institute, Inc., 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 Forest Research Institute, Inc., for submission to 
the FDA

A fully executed contract

The curricula vitae for the Investigator and all Sub-Investigators listed on Form FDA 
1572, including a copy of each physician’s license

A copy of the original IRB 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, as stated in Section 5.1

A copy of the IRB-approved ICF

A copy of the HIPAA authorization form, or other local privacy applicable forms

A list of the IRB members or the 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 
Sub Investigators listed on Form FDA 1572. The Investigator and all 
Sub Investigators 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 Sub-Investigators 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 Forest Research Institute, Inc., will inventory the 
investigational products at the site. The Investigator must maintain adequate records 
documenting the receipt and disposition of all study supplies. Forest Research Institute, 
Inc., 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 and empty investigational product bottles should be returned to 
the Sponsor or the local distributor at the address provided in the Study Reference 
Binder. 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 Forest 
Research Institute, Inc., 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 Forest. 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 case report 
forms, 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 Principal Investigator must permit access to any documentation relating to the study 
upon request of the Sponsor or applicable regulatory authorities. If the Principal 
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.
11.6
PATIENT CONFIDENTIALITY
All patient records will only be identified by initials and patient identification number. 
Patients’ names are not to be transmitted to Forest Research Institute, Inc. The 
Investigator will keep a master patient list on which the patient identification 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 (LIN-MD-10, dated 
05 Oct 2015), and with all applicable government regulations and good clinical practice
guidance.
_______________________________________
_____/_____/______
Principal Investigator’s Signature
Date
_______________________________________
Principal 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 
legally authorized representative. 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; 
Forest Research Institute, Inc.; 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 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 participate . . .”)

A place for the patient’s 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 should be given to the patient.
 
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APPENDIX II.
CONTACT INFORMATION
Contact information for Forest Research Institute, Inc., personnel is as follows:
Medical Emergency contact number:
 
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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 center to the central laboratory on the day of 
collection or as specified in the laboratory manual. The central laboratory will provide 
packaging, labeling, and shipping instructions.
 
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APPENDIX V.
SUMMARY ADAPTED FROM GUIDELINES OF THE US
MULTI-SOCIETY TASK FORCE ON COLORECTAL 
CANCER AND OTHER COLONOSCOPY 
REQUIREMENTS
Note: Patient may be enrolled if no follow-up colonoscopy after polyp removal is due while 
participating in the study.
1.
Patients age 50 years (40 years if African American) and older must have had a 
colonoscopy with negative findings within the 10 years prior to the Screening Visit 
(Visit 1).
2.
If the most recent colonoscopy revealed hyperplastic polyps that were entirely 
removed, the patient may be enrolled, provided the colonoscopy was performed 
within 10 years prior to the Screening Visit (Visit 1).
3.
If the most recent colonoscopy revealed 2 or fewer small (< 1 cm) adenomatous 
polyps with tubular structure with low grade dysplasia and without appreciable 
villous tissue, the patient may be enrolled, provided the colonoscopy was 
performed within 5 years prior to the Screening Visit (Visit 1). 
4.
Patients who have 1 first-degree relative with colorectal cancer or adenomatous 
polyps diagnosed before age 60 or 2 first-degree relatives with colorectal cancer 
diagnosed at any age must have had a colonoscopy with negative findings 5 years 
before the Screening Visit (Visit 1). This applies to patients who are 40 years or 
older and to patients younger than 40 years, who are 10 or fewer years from the 
age at which their youngest relative was found to have 1 of the aforementioned 
conditions.
5.
Patients who have 1 first-degree relative with colorectal cancer or adenomatous 
polyps diagnosed at age 60 or older or 2 second-degree relatives with colorectal 
cancer diagnosed at any age must have had a colonoscopy with negative findings 
within 10 years prior to the Screening Visit (Visit 1). This applies to patients who 
are 40 years or older and to patients younger than 40 years, who are 10 years or 
fewer years from the age at which their youngest relative was found to have 1 of 
the aforementioned conditions. 
Other Colonoscopy Requirements:
Patients of any age who have alarm symptoms must have had a colonoscopy with
negative findings after the onset of the alarm symptoms and within 5 years prior to the 
Screening Visit (Visit 1). Alarm symptoms include lower GI bleeding (rectal bleeding or 
heme-positive stool), iron-deficiency anemia, and weight loss. (Note: Current 
unexplained or clinically significant alarm symptoms are exclusionary.)
These requirements are adapted based on recent Guidance on Colorectal Cancer Screening 
(Levin et al, 2008; Lieberman et al, 2012; Quaseem et al, 2012).
 
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APPENDIX VI. 
BRISTOL STOOL FORM SCALE
Type 1 - Separate hard lumps like nuts (difficult to pass) 
Type 2 - Sausage shaped but lumpy 
Type 3 - Like a sausage but with cracks on surface 
Type 4 - Like a sausage or snake, smooth and soft 
Type 5 - Soft blobs with clear-cut edges (passed easily) 
Type 6 - Fluffy pieces with ragged edges, a mushy stool 
Type 7 - Watery, no solid pieces (entirely liquid) 
 
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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 Sciences 2010;86:760-5. 
Drossman DA, Camilleri M, Mayer EA, et al. AGA technical review on irritable bowel 
syndrome. Gastroenterology 2002;123:2108-31. 
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.
Johanson JF, Sonnenberg A, Koch TR. Clinical epidemiology of chronic constipation. 
J Clin Gastroenterol 1989;11:525-36.
Johanson JF, Kralstein J. Chronic constipation: a survey of the patient perspective. 
Aliment Pharmacol Ther 2007;25:599-608. 
Koren E, Smith HW, Shores, E, et al. Recommendations on risk-based strategies for 
detection and characterization of antibodies against biotechnology products. J Immunol 
Methods 2008;333:1-9.
Lembo A, Camilleri M. Chronic constipation. N Engl J Med 2003;349:1360-8. 
Levin B, Lieberman DA, McFarland B, et al. Screening and surveillance for the early 
detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the 
American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and 
the American College of Radiology. Gastroenterology 2008;134:1570-95.
Lieberman DA, Rex DK, Winawer SJ, et al. Guidelines for colonoscopy surveillance 
after screening and polypectomy: a consensus update by the US Multi-Society Task 
Force on Colorectal Cancer. Gastroenterology 2012;143:844-57.
Linaclotide: Investigator’s brochure. Edition 8. Cambridge, MA: Ironwood 
Pharmaceuticals, Inc; 2013 Mar 12. 
Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders. 
Gastroenterology 2006;130:1480-91. 
Muller-Lissner SA, Bollani S, Brummer RJ, et al. Epidemiological aspects of irritable 
bowel syndrome in Europe and North America. Digestion 2001;64:200-4.
Parenky A, Myler H, Lakshmi A, et al. New FDA Draft Guidance on Immunogenicity. 
Am Assoc Pharm Sci J 2014;16: 3.
 
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Quaseem A, Denberg TD, Hopkins RH, et al. Screening for colorectal cancer: a guidance 
statement from the American College of Physicians. Ann Intern Med 2012;156:378-86. 
Shankar G, Devanarayan V, Amaravadi L, et al. Recommendations for the validation of 
immunoassays used for detection of host antibodies against biotechnology products. 
J Pharm Biomed Anal 2008;48:1267-81.
Stewart WF, Liberman JN, Sandler RS, et al. Epidemiology of constipation (EPOC) 
study in the United States: relation of clinical subtypes to sociodemographic features. 
Am J Gastroenterol 1999;94:3530-40.
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 May 10.
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-103-302: 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.
 
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US Department of Health and Human Services, Food and Drug Administration. Guidance 
for industry, drug-induced liver injury: premarketing clinical evaluation. 2009 Jul. 
Available from: http://www.fda.gov/downloads/Drugs/Guidances/UCM174090.pdf. 
Accessed 2015 Jan 7.
 
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Forest Research Institute, Inc., an affiliate of Actavis Inc.
Harborside Financial Center, Plaza V
Jersey City, NJ 07311
SUMMARY OF CHANGES TO PROTOCOL 
An Open-label, Long-term Study to Assess the Immunogenicity of Linaclotide 
Administered Orally to Adult Patients With Irritable Bowel Syndrome With 
Constipation or Chronic Idiopathic Constipation
LIN-MD-10
IND #63,290
Original Protocol / Date:
Ironwood Protocol MCP-103-402, 25 Nov 2013
Amendment #1: 
09 Apr 2015
Amendment #2: 
05 Oct 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.
 
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1.0
INTRODUCTION
Amendment #2 specifies the following changes to the original, FDA-approved protocol
Ironwood Pharmaceuticals, Inc., Protocol MCP-103-402, dated 25 Nov 2013 and 
previously amended 09 Apr 2015:
 
 
3. Updating of contact information
4. Correction of minor typographic errors
This summary of changes presents all new content as green underlined text. Deleted 
material is shown as strikeout text. The page numbers shown in the headings of this 
document are those of the last published version of the protocol (Amendment #1).
 
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2.0
GLOBAL CHANGES
The following changes have been made globally to the protocol:

 
 
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3.0
SECTIONS DELETED
The following sections have been removed from the protocol, and subsequent sections 
and appendices have been renumbered:
 
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4.0
SECTIONS ADDED
Rationale: A new section has been added to introduce the possibility that some patients’ 
ADAs may not have reverted to baseline at the 4-Month Follow-up Visit; an additional 
visit (Visit 11) will be required for those patients.
The new section will read as follows:
 
 
 
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5.0
REVISIONS
5.1
SECTION 2.0 SYNOPSIS AND SCHEDULE OF 
EVALUATIONS (PAGE 2)
 
 
 
 
 
 
 
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5.3
SECTION 9.3.1, INCLUSION CRITERIA (PAGE 25)
Rationale: Inclusion criterion 9 that addresses language fluency had previously been 
attached in error to the end of inclusion criterion 8.
The last sentence of inclusion criterion 8 becomes inclusion criterion 9 as follow:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5.6
SECTION 9.5.4.6, IMMEDIATE REPORTING OF SERIOUS 
ADVERSE EVENTS (PAGE 44)
Rational: This section has been amended to update the Sponsor's Study Physician 
Medical Emergency phone number.
The last paragraph of this section now reads as follow:
Sponsor's Study Physician Medical Emergency phone number: 
 
 
 
 
 
 
 
 
 
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Bullet 3 of this section now reads as follows:

Review and record AEs
○
Patients who report an AE of diarrhea or who report a symptom that could be 
considered diarrhea (eg, loose stools or BMs, soft stools, watery stools, liquid 
stools, mushy stools) will also complete the diarrhea questionnaire during the 
study visit (Appendix VII)
 
 
 
 
 
 
 
 
 
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5.12
APPENDIX II, CONTACT INFORMATION (PAGE 79)
Rationale: This appendix was updated to reflect changes of staff for the study team.
The revised appendix will read as follows:
Contact information for Forest Research Institute, Inc., personnel is as follows:
Medical Emergency contact number:
 
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6.0
INVESTIGATOR’S STATEMENT
I agree to conduct the study in accordance with this protocol (LIN-MD-10, 
Amendment #2, dated 05 Oct 2015) and with all applicable government regulations and 
good clinical practice guidance.
_______________________________________     _____/_____/______
Principal Investigator’s Signature                                             Date
_______________________________________
Principal Investigator’s Name
 
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SAP_001.pdf: 
NCT02590432 
 
Study ID: LIN‐MD‐10 
 
Title: An Open‐label, Long‐term Study to Assess the Immunogenicity of Linaclotide Administered Orally 
to Adult Patients With Irritable Bowel Syndrome With Constipation or Chronic Idiopathic Constipation 
 
 
Statistical Analysis Plan Date: 23‐May‐2018 
 
 
 


Allergan Sales, LLC Confidential
SAP LIN-MD-10
Linaclotide
1
1.
Title Page
STATISTICAL ANALYSIS PLAN
An Open-label, Long-term Study to Assess the Immunogenicity of Linaclotide 
Administered Orally to Adult Patients With Irritable Bowel Syndrome With Constipation 
or Chronic Idiopathic Constipation
Final 2.0: 2018-05-23
Protocol Number:
LIN-MD-10
Development Phase:
4
Product Name:
Linaclotide
Study Statistician:
Sponsor:
Allergan Sales, LLC
5 Giralda Farms
Madison, NJ 07940
This document is the property of Allergan Sales, LLC 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 Sales, LLC.


Allergan Sales, LLC Confidential
SAP LIN-MD-10
Linaclotide
2
2.
Table of Contents
1.
Title Page ................................................................................................................................. 1
2.
Table of Contents..................................................................................................................... 2
2.1
List of Tables.................................................................................................................. 3
2.2
List of Figures ................................................................................................................ 5
3.
List of Abbreviations and Definition of Terms........................................................................ 6
4.
Introduction.............................................................................................................................. 7
4.1
Study Design Summary ................................................................................................. 7
4.2
Study Objectives and Endpoints .................................................................................. 10
4.3
Schedule of Activities .................................................................................................. 12
5.
Statistical Methodology and Study Endpoints....................................................................... 16
5.1
Statistical Methods Planned in the Protocol and Determination of Sample Size ........ 16
5.1.1
Statistical and Analytical Plans........................................................................ 16
5.1.1.1
Common Conventions....................................................................... 16
5.1.1.2
Demographics.................................................................................... 20
5.1.1.5
Subgroup Analyses............................................................................ 33
5.1.1.6
Interim Analyses................................................................................ 33
5.1.2
Determination of Sample Size ......................................................................... 33


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6.4
Efficacy Endpoint Conventions ................................................................................... 38
7.
References.............................................................................................................................. 44
8.
History of Change.................................................................................................................. 45
2.1
List of Tables
Table 3–1
Abbreviations and Definitions of Terms................................................................. 6
Table 5–1
Analysis Populations............................................................................................. 16
Table 5–2
Treatment Groups by Indication and Treatment Period........................................ 17
Table 5–3
Statistical Methodology ........................................................................................ 17
Table 5–4
Missing Data Handling by Endpoint Type............................................................ 19
Table 5–5
Treatment Period Definitions................................................................................ 19


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Table 5–6
Analysis Population Summaries ........................................................................... 20
Table 5–7
Participant Disposition Summaries....................................................................... 20
Table 5–8
Protocol Deviation Summary................................................................................ 21
Table 5–9
Demographic Summaries...................................................................................... 21
Table 5–10
Baseline Characteristics Summaries..................................................................... 22
Table 5–11
Medical History Summary.................................................................................... 22
Table 5–12
Medication Summaries ......................................................................................... 22
Table 5–13
Efficacy Endpoints................................................................................................ 23


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2.2
List of Figures


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3.
List of Abbreviations and Definition of Terms
Table 3–1
Abbreviations and Definitions of Terms
Abbreviation/Term
Definition
ADA
anti-drug antibody
AE
adverse event
ANCOVA
analysis of covariance
ATC
Anatomical Therapeutic Chemical
BM
bowel movement
CIC
chronic idiopathic constipation
CFB
change from baseline
eCRF
electronic case report form
ECG
electrocardiogram, electrocardiographic
eDISH
evaluation of drug-induced serious hepatotoxicity.
GCP
Good Clinical Practice
GI
gastrointestinal
HR
hazard ratio
IBS
irritable bowel syndrome
IBS-C
irritable bowel syndrome with constipation
ICF
informed consent form
ITT
intent-to-treat
LIN
linaclotide
LLN
lower limit of normal
LS
least squares
MedDRA
Medication Dictionary for Regulatory Activities
NEAE
newly emergent adverse event
OR
odds ratio
PID
participant identification
SAP
statistical analysis plan
SBM
spontaneous bowel movement
TEAE
treatment-emergent adverse event
WHO
World Health Organization


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4.
Introduction
This statistical analysis plan (SAP) details comprehensive, technical specifications of the 
statistical analyses of the efficacy and safety data outlined and/or specified in the final protocol 
of Study LIN-MD-10 and the most recent amendment (version 2). Specifications of tables, 
figures, and data listings are contained in a separate document.
4.1
Study Design Summary
This will be a multicenter, open-label, long-term clinical study to assess the immunogenicity and 
long-term safety of linaclotide administered orally to adult participants with irritable bowel 
syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC), and to evaluate 
lower doses of linaclotide in participants who consider study withdrawal due to intolerable 
adverse events (AEs) that may be related to the use of linaclotide. Approximately 800 IBS-C or 
CIC participants (a minimum of 300 each) will be enrolled.
The study will consist of up to a 3-week Screening Period, followed by a 52-week Treatment 
Period (Figure 4–1). Participants who meet the entry criteria will receive once daily, open-label
doses of 290 μg linaclotide for participants with IBS-C; those with CIC will receive once daily, 
open-label doses of 145 μg linaclotide.
In order to limit participant withdrawals from the study due to AEs and to gain information about 
the effect of lowering the dose in participants who experience intolerable AEs (defined as AEs 
that subjectively would cause a participant to consider study withdrawal), in particular diarrhea 
and other gastrointestinal (GI) AEs that may be related to the use of linaclotide, the following 
intervention (Figure 4-2) will be offered as an optional treatment course to such participants, 
unless deemed clinically inappropriate by the Investigator:
1. A temporary suspension of dosing of up to 7 days. If the dose suspension needs to last 
longer than 7 days because the intolerable AE has not resolved, then the Investigator 
should contact the Study Physician to discuss the duration of the dose suspension or 
withdrawal of the participant from the study. All AEs resulting in the temporary 
suspension will be recorded on the electronic case report form (eCRF).


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2. After the intolerable AE has resolved, the participant will be randomized into a 
Double-blind Treatment Period via an interactive Web response system (IWRS) and will 
receive dose regimens specific to each indication as follows. If the randomized dose 
regimen is tolerated, the participant will remain on this dose for the duration of the study 
(total duration of linaclotide exposure [whether open-label or double-blind] is not to 
exceed 52 weeks).
IBS-C participants will be randomized in a 1:1:1 ratio to 1 of the following regimens:

Linaclotide 290 μg every day

Linaclotide 145 μg every day

Linaclotide 72 μg every day
CIC participants will be randomized in a 1:1 ratio to 1 of the following regimens:

Linaclotide 145 μg every day

Linaclotide 72 μg every day
3. If, after randomization, participants experience intolerable AEs, in particular diarrhea or 
other GI AEs, the dosing should be temporarily suspended for up to 7 days. If the dose 
suspension needs to last longer than 7 days because the intolerable AE has not resolved, 
then the Investigator should inform the Study Physician about the duration of dose 
suspensions or withdrawal of the participant from the study. 
After the intolerable AE has resolved, irrespective of the IBS-C or CIC status, participants 
should be dispensed open-label linaclotide (72 μg) and may continue on this dose in a 
Dose-reduced Open-label Treatment Period for the duration of the study.
4. If participants experience an intolerable AE while receiving the adjusted dose of 72 μg in 
the Dose-reduced Open-label Treatment Period, study participation should be terminated.
5. In the event of a planned procedure or an AE during which a participant requires dose 
suspension longer than 7 days, the Investigator should inform the Study Physician about 
the duration of dose suspensions. Upon event completion or AE resolution, the participant
should be resumed on the assigned dose.


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4.2
Study Objectives and Endpoints
Each study objective is presented with corresponding endpoint(s) below:


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Table 4–1
Study Objectives
Objectives
Endpoints
Primary

To assess the potential of linaclotide treatment to 
induce the development of anti-drug antibodies 
(ADAs)

Treatment-related ADA positive responder
Secondary

To provide additional evidence supporting the long-
term safety of linaclotide in adult IBS-C and CIC 
participants

Adverse Events

Clinical Laboratory Assessments

Vital Signs

Electrocardiograms

Immunogenicity

To provide additional evidence supporting the long-
term efficacy of linaclotide in adult IBS-C and CIC 
participants

Patient assessment of constipation severity

Patient assessment of IBS symptom severity (IBS-C 
only)

Degree of relief of IBS symptoms (IBS-C only)

IBS treatment satisfaction assessment (IBS-C only)

Constipation treatment satisfaction assessment (CIC 
only)

To evaluate lower doses of linaclotide in 
participants who consider study withdrawal due to 
intolerable AEs

Recurrence of diarrhea

Recurrence of intolerable diarrhea

Time to first recurrence of diarrhea

Time to first recurrence of intolerable diarrhea


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5.
Statistical Methodology and Study Endpoints
5.1
Statistical Methods Planned in the Protocol and Determination of 
Sample Size
This statistical analysis plan (SAP) expands the statistical section of the protocol and contains a 
detailed description of methods to analyze data collected in the study. The text portion of the 
SAP will be included in the CSR report as Appendix 16.1.9.
5.1.1
Statistical and Analytical Plans
Statistical analyses will be conducted using SAS Version 9.3 or newer.
5.1.1.1
Common Conventions
5.1.1.1.1
Analysis Populations
The analysis populations will consist of participants as defined below:
Table 5–1
Analysis Populations
Population
Definition
Study Treatment
Screened
All screened participants who sign an ICF for the study and 
receive a participant identification number (PID)

Rescreened participants considered separately for each 
unique PID
—
All enrolled 
participants
All Screened Population participants who continue into the 
Open-label Treatment Period per the screening disposition eCRF

This population will be used for selected listings only 
and is not considered a formal analysis population
Indication
Safety
All Screened Population participants who receive ≥ 1 
administration of study treatment
Indication
Intent-to-Treat (ITT)
All Safety Population participants with ≥ 1 postbaseline 
assessment for any efficacy or health outcomes parameter during 
the Treatment Period, fully described in Section 5.1.1.3

Patient assessment of constipation severity

Patient assessment of IBS symptom severity (IBS-C 
only)

Degree of relief of IBS symptoms (IBS-C only)

IBS treatment satisfaction assessment (IBS-C only)

Constipation treatment satisfaction assessment (CIC 
only)
 
Indication
Randomized
All Safety Population participants who are randomized to double-
blind study treatment following resolution of an intolerable AE
Randomized assignment
Double-blind Safety
All Randomized Population participants who receive ≥ 1 
administration of study treatment during the Double-blind 
Treatment Period
Randomized assignment


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Population
Definition
Study Treatment
Double-blind ITT
All Double-blind Safety Population participants with ≥ 1 post-
randomization assessment for any efficacy or health outcomes
parameter during the Double-blind Treatment Period, fully 
described in Section 5.1.1.3

Patient assessment of constipation severity

Patient assessment of IBS symptom severity (IBS-C 
only)

Degree of relief of IBS symptoms (IBS-C only)

IBS treatment satisfaction assessment (IBS-C only)

Constipation treatment satisfaction assessment (CIC 
only)
 
Randomized assignment
5.1.1.1.2
Study Treatments
The following linaclotide (LIN) treatment groups are defined for this study:
Table 5–2
Treatment Groups by Indication and Treatment Period
Treatment Period
Indication
IBS-C
CIC
Open-label
LIN 290 μg
LIN 145 μg
Double-blind
LIN 290 μg
LIN 145 μg
LIN 145 μg
LIN 72 μg
LIN 72 μg
Dose-reduced Open-label
LIN 72 μg
LIN 72 μg
5.1.1.1.3
Statistical Methodology
The methodologies defined below apply as specified to individual endpoints defined in this SAP. 
When indicated, 95% 2-sided confidence intervals (CIs) and 2-sided p-values will be presented
unless otherwise specified. 
Table 5–3
Statistical Methodology
Methodology
Description
Categorical counts

Number of participants in individual categories
o
Participants with ≥ 1 qualifying event counted once per individual category
Categorical 
descriptives

Number and percentage of participants in individual categories
o
Participants with ≥ 1 qualifying event counted once per individual category

(Optional if specified) N1 if percentage denominator ≠ number of participants in the 
population (standard percentage denominator)
o
N1 = participants with non-missing baseline value
 
 


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Methodology
Description
o
Unevaluable assessments considered missing
o
If specified, participants with baseline PCS values will be excluded
 
Continuous 
descriptives

N1, mean, SD, median, minimum, maximum

N1 = participants with non-missing value
CFB descriptives

Continuous descriptives for baseline, postbaseline, and change from baseline (CFB) 
values

N1 = participants with non-missing values at both baseline and the specified 
postbaseline analysis visit
 
CFB ANCOVA

Continuous descriptives and SE for baseline, postbaseline, and CFB values

Estimates derived from ANCOVA model for CFB value controlling for fixed factors 
(treatment group) and fixed covariates (baseline value)
o
Least squares (LS) means and standard errors
o
LS mean differences, standard errors, and CIs vs highest LIN dose1
o
P-values from contrast t-test comparing lower LIN doses2 vs highest LIN 
dose1

N1 = participants with non-missing values at both baseline and the specified 
postbaseline analysis visit
Responder

Categorical descriptives for responders and nonresponders
o
Nonresponders include:

Participants who do not meet responder criteria

Participants with no postbaseline values 

Risk differences and Wald CIs vs highest LIN dose1

Unadjusted risk ratios (RRs), odds ratios (ORs), and CIs vs highest LIN dose1

P-values from Fisher’s exact test comparing lower LIN doses2 vs highest LIN dose1
Immunogenicity 
responder

Categorical descriptives for responders and nonresponders
o
Nonresponders include:

Participants who do not meet responder criteria

Participants with no postbaseline values 

Responder rate 1-sided 95% Clopper-Pearson CIs

N1 = all participants unless otherwise specified
Time-to-event

Categorical descriptives for participants with events and censoring
o
Censoring includes:

Participants who do not meet event criteria

Participants with no postbaseline values

Quartiles and CIs derived from Kaplan-Meier (KM) nonparametric model using log-
log transformation of survivor function

Estimates derived from Cox proportional hazards model controlling for factor 
(treatment group)
o
Hazard ratios (HRs) and CIs vs highest LIN dose1

Estimates derived from log-rank model controlling for factor (treatment group)
o
P-values comparing lower LIN doses2 vs highest LIN dose1

N1 = all participants unless otherwise specified
KM figure

Step-function figure of cumulative distribution function (1 – survivor function) 
estimates with censoring indicators, derived from KM nonparametric model
CFB = change from baseline; ANCOVA = analysis of covariance; TTE = time-to-event.


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Methodology
Description
1 Highest LIN dose by indication: IBS-C: LIN 290 μg; CIC: LIN 145 μg.
2 Lower LIN doses by indication: IBS-C: LIN 72 μg, LIN 145 μg; CIC: LIN 72 μg.
Raw and derived data listings will be provided, and will be fully defined in the table, figure, and 
data listing specification document.
5.1.1.1.4
Missing Data
General missing data handling conventions are specified for methodologies in Section 5.1.1.1.3
and summarized as follows:
Table 5–4
Missing Data Handling by Endpoint Type
Parameter type
Timing
Missing Data Handling
Responder
Double-blind 
Treatment Period

All participants included unless otherwise specified

Participants with no postbaseline values = nonresponders
Immunogenicity 
responder
Treatment Period

Participants with no postbaseline assessable values excluded
Time-to-event
Double-blind 
Treatment Period

Participants not reporting specified event (intolerable 
diarrhea) during the Open-label Treatment Period excluded

Participants with no postbaseline values = censored
CFB ANCOVA
Treatment Period

If missing covariates (including baseline if applicable) 
o
Participant excluded

If missing derived value at the specified postbaseline analysis 
visit:
o
Participant excluded
5.1.1.1.5
Treatment Periods
The non-overlapping Open-label, Double-blind, and Dose-reduced Open-label treatment periods
are defined by their respective treatment start and end dates. These 3 treatment periods are 
subsets of the overall Treatment Period. The start and end dates for each period are defined as 
follows:
Table 5–5
Treatment Period Definitions
Parameter 
Start
End
Treatment Period
Treatment start date =  first dose date of any 
LIN treatment
Treatment end date = last dose date of any 
LIN treatment
Open-label 
Treatment Period
Open-label start date = first dose date of open-
label LIN treatment

Identical to treatment start date
Open-label end date = last dose date of open-
label LIN treatment

Identical to treatment end date for 
participants who do not enter the 
Double-blind Treatment Period
Double-blind 
Treatment Period
Double-blind start date = first dose date of 
double-blind LIN treatment
Double-blind end date = last dose date of 
double-blind LIN treatment

Identical to treatment end date for 
participants who do not enter the 
Dose-reduced Open-label Treatment 
Period


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Dose-reduced 
Open-label 
Treatment Period
Dose-reduced open-label start date = first dose 
date of dose-reduced open-label LIN 
treatment
Dose-reduced open-label end date = last dose 
date of open-label LIN treatment

Identical to treatment end date
5.1.1.2
Demographics
5.1.1.2.1
Analysis Populations
The distribution of participants within the analysis populations will be summarized as follows:
Table 5–6
Analysis Population Summaries
Parameter
Description
Timing
Methodology
Screened, Safety, and 
Intent-to-Treat (ITT)
populations
Distribution overall and within sites in 
total and by indication
—
Categorical counts
Randomized, Double-
blind Safety, and 
Double-blind ITT 
populations
Distribution overall and within sites in 
total and by treatment group within each 
indication
—
Categorical counts
5.1.1.2.2
Participant Disposition
Participant disposition encompasses the distribution of participants who enter, complete, and 
discontinue each specified period (epoch) as defined by study design, along with eCRF-reported 
discontinuation reasons from each respective period. Participant disposition will be summarized 
as follows:
Table 5–7
Participant Disposition Summaries
Parameter
Description
Timing
Methodology
Screening Period 
Disposition
Distribution in total for the Screened 
Population
Screening Period
Categorical 
descriptives
Treatment Period 
Disposition
Distribution in total and by indication for 
the Safety Population

Participants categorized based on 
latest available eCRF from the 
Open-label, Double-blind, and 
Dose-reduced Open-label 
treatment periods
Treatment Period
Categorical 
descriptives
Open-label Treatment 
Period Disposition
Distribution in total and by indication for 
the Safety Population
Include distribution of participants who 
discontinue who:

do continue to Double-blind 
Treatment Period 

do not continue to Double-blind 
Treatment Period
Open-label 
Treatment Period
Categorical 
descriptives
Double-blind Treatment 
Period Disposition
Distribution in total and by treatment 
group within each indication for the 
Randomized Population 
Include distribution of participants who 
Double-blind
Treatment Period
Categorical 
descriptives


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Parameter
Description
Timing
Methodology
discontinue who:

do continue to Dose-Reduced 
Open-label Treatment Period 

do not continue to Dose-Reduced 
Open-label Treatment Period
Dose-reduced Open-
label Treatment Period 
Disposition
Distribution in total and by treatment 
group within each indication for the 
Randomized Population 
Dose-reduced Open-
label Treatment 
Period
Categorical 
descriptives
5.1.1.2.3
Significant Protocol Deviations
Protocol deviations and significance classification will be defined in the protocol deviation 
requirements specification document. Unique participants reporting significant protocol 
deviations will be summarized in total and by indication as follows:
Table 5–8
Protocol Deviation Summary
Parameter
Description
Timing
Methodology
Significant protocol 
deviations
Overall summary and by protocol 
deviation term
—
Categorical 
descriptives
5.1.1.2.4
Demographics
Demographics will be summarized in treated and non-treated groups for the Screened 
Population, in total and by indication for the Safety and ITT populations, and in total and by 
treatment group within each indication for the Double-blind ITT Population as follows:
Table 5–9
Demographic Summaries
Parameter
Description
Timing
Methodology
Age
Age (years) relative to informed consent 
date
Informed consent
Continuous 
descriptives
Age group

< 40 years

≥ 40 – < 65 years

≥ 65 years
Informed consent
Categorical 
descriptives
Sex, race, race group, 
and ethnicity

eCRF categories

Race group
o
White
o
Non-white
Screening Period
Categorical 
descriptives
5.1.1.2.5
Baseline Characteristics
Baseline characteristics will be summarized in total and by indication for the Safety and ITT 
populations, and in total and by treatment group within each indication for the Double-blind ITT 
Population as follows:


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Table 5–10
Baseline Characteristics Summaries
Parameter
Description
Timing
Methodology
Baseline characteristics

Height (cm)

Weight (kg)

Body mass index (BMI)
o
Weight (kg) / height (m)2
Latest assessment
on or before 
Treatment Day 1
Continuous 
descriptives
Baseline efficacy
Endpoints fully described in Section 
5.1.1.3

Patient assessment of constipation 
severity

Patient assessment of IBS 
symptom severity (IBS-C only)

Degree of relief of IBS symptoms 
(IBS-C only)
 
 
 
Summarize only for the ITT population
Latest assessment
on or before 
Treatment Day 1
Continuous 
descriptives
5.1.1.2.6
Medical History
Medical history, encompassing abnormalities and surgeries reported as occurring before the 
Screening Visit, will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), version 19.0 or newer. Unique participants who report medical history events will be 
summarized by MedDRA system organ class and preferred term in total and by indication for the 
Safety Population as follows:
Table 5–11
Medical History Summary
Parameter
Description
Timing
Methodology
Medical history
Abnormalities and surgeries occurring 
before the Screening Visit
Screening Period
Categorical 
descriptives
5.1.1.2.7
Prior and Concomitant Medications
Medications will be coded using the World Health Organization (WHO) Drug Dictionary, 
version March 2016 or newer. Unique participants who reported medications will be summarized 
by Anatomical Therapeutic Chemical (ATC) 4 class and preferred term in total and by indication
for the Safety Population as follows:
Table 5–12
Medication Summaries
Parameter
Description
Timing
Methodology
Prior medications
Medications taken ≥ 1 time before the 
treatment start date, regardless of 
Screening Period
Categorical 
descriptives


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Parameter
Description
Timing
Methodology
medication end date
Concomitant 
medications
Medications taken ≥ 1 time on or after the 
treatment start date, regardless of 
medication start date

Medications starting 1 day after 
treatment end date will be listed 
but excluded from analysis
Treatment Period
Categorical 
descriptives
5.1.1.3
Efficacy
Efficacy 
 will be based on the ITT Population unless otherwise 
specified.
Baseline values for efficacy 
endpoints are defined as the latest assessment 
on or before Treatment Day 1. There are no baseline values for treatment satisfaction endpoints.
5.1.1.3.1
Efficacy Analyses
Efficacy endpoints will be summarized in total and by indication (if applicable) as follows:
Table 5–13
Efficacy Endpoints
Endpoint
Description
Timing
Methodology
Patient assessment of 
constipation severity
Rating of constipation severity during the 
previous 7 days on a 5-point ordinal scale

Higher scores indicate greater 
severity
Weeks 2, 4, 12, 26, 
40, 521
CFB descriptives
Patient assessment of 
IBS symptom severity 
(IBS-C only)
Rating of IBS symptoms severity during 
the previous 7 days on a 5-point ordinal 
scale

Higher scores indicate greater 
severity
Weeks 2, 4, 12, 26, 
40, 521
CFB descriptives
Degree of relief of IBS 
symptoms (IBS-C only)
Rating of degree of relief of IBS symptoms 
during previous 7 days on a 7-point 
balanced ordinal scale

Lower scores indicate greater 
relief
Weeks 2, 4, 12, 26, 
40, 521
CFB descriptives
IBS treatment 
satisfaction assessment 
(IBS-C only)
Rating of degree of satisfaction with the 
study treatment’s ability to relieve IBS 
symptoms on a 5-point ordinal scale

Higher scores indicate greater 
satisfaction
Weeks 2, 4, 12, 26, 
40, 521
Continuous 
descriptives
Constipation treatment 
satisfaction assessment 
(CIC only)
Rating of degree of satisfaction with the 
study treatment’s ability to relieve 
constipation symptoms on a 5-point 
ordinal scale

Higher scores indicate greater 
satisfaction
Weeks 2, 4, 12, 26, 
40, 521
Continuous 
descriptives
1 Analysis visits defined in Section 6.2.


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5.1.1.3.3
Double-blind Treatment Period Analyses
A set of exploratory analyses will be conducted for Double-blind Safety Population participants, 
unless otherwise specified, for the subset of participants who experience an intolerable AE 
during the initial Open-label Treatment Period. Data from the Dose-reduced Open-label 
Treatment Period following discontinuation of double-blind treatment will be excluded from 
these analyses.


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Pre-randomization (Double-blind Treatment Period baseline) values for efficacy
 
endpoints are defined as the latest available assessment during the Treatment Period on 
or before the Double-blind start date.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.1.1.4
Safety Analyses
Safety analyses will be based on the Safety Population unless otherwise specified.
Baseline values for applicable safety endpoints are defined as the latest non-missing assessment 
on or before the treatment start date.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.1.1.4.2
Adverse Events
The following adverse event (AE) terms are defined:
Table 5–20
AE Terms
Term
Description
Treatment-
emergent 
An event that meets the following condition:

Treatment start date ≤ event start date ≤ treatment end date + 1
and meets either of the following conditions:

The same term is never reported before the treatment start date

The same term is reported before the treatment start date and the term increases in 
severity on or after the treatment start date
o
Event severity > maximum severity of same term reported before the treatment 
start date
 
 
On-therapy
An event where:

Treatment start date ≤ event start date ≤ treatment end date + 30
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.1.1.4.6
Immunogenicity
Individual immunogenicity samples will be assayed and categorized as 1 of the following:

ADA positive
o
Screening result = positive AND confirmatory result for anti-linaclotide 
antibodies = positive

ADA negative
o
Any of the following:

Screening result = negative 

Screening result = positive AND confirmatory result for anti-linaclotide 
antibodies = negative


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
ADA undetermined (sample lost, damaged, out of specifications, insufficient volume)
o
Any of the following:

Screening result = missing

Screening result = positive AND confirmatory result for anti-linaclotide 
antibodies = missing
Baseline ADA status is defined as the assay result of the Treatment Day 1 (Visit 2) pre-treatment
sample.
Overall postbaseline ADA status will be derived using all postbaseline samples during the 
Treatment Period and within 7 days after the treatment end date, and are defined as follows:
Table 5-27
Overall Postbaseline ADA Status Categories
Assessment/Term
Description
Treatment-induced ADA 
positive1
≥1 postbaseline ADA positive sample
Treatment-boosted ADA 
positive2
≥1 postbaseline ADA positive sample with titer values ≥ 4 × baseline titer value
Non-treatment-boosted ADA 
positive2
All postbaseline ADA positive samples with titer values < 4 × baseline titer value
and not qualifying as ADA negative
ADA negative
≥ 1 postbaseline ADA negative sample and no postbaseline ADA positive samples
ADA undetermined
Participant with no assessable samples (sample lost, damaged, out of specifications, 
insufficient volume)

Missing data considered ADA undetermined
1 Only applicable to baseline ADA negative or ADA undetermined participants
2 Only applicable to baseline ADA positive participants
Immunogenicity endpoints will be summarized in total and by indication as follows:
Table 5–28
Immunogenicity Endpoints
Endpoint
Description
Timing
Methodology
Treatment-related ADA 
positive responder
Meets either of the following criteria:

Treatment-induced ADA positive 
for baseline ADA negative or 
ADA undetermined participants

Treatment-boosted ADA positive 
for baseline ADA positive 
participants
Non-responder otherwise
Only includes participants with ≥ 1 
assessable postbaseline sample (ADA 
undetermined excluded)
Treatment Period + 
7 days after 
treatment end date
Immunogenicity 
responder
 
 
 
 
 
 
 
 
 
 
 
 


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5.1.1.5
Subgroup Analyses
Not applicable.
5.1.1.6
Interim Analyses
Not applicable.
5.1.2
Determination of Sample Size
The objective of this study is to assess the long-term safety of linaclotide administered to 
participants with IBS-C or CIC and to determine the potential of linaclotide to induce ADAs. If 0 
of 800 participants develop ADAs, the 1-sided 95% upper CI for this rate (0/800 [0%]) is
0.374%.
 


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Complete
 
 
 


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6.4
Efficacy Endpoint Conventions
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Bicarbonate
Glucose


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7.
References
EuroQol – a new facility for the measurement of health-related quality of life. The EuroQol 
Group. Health Policy 1990 Dec 16;3:199-208.
Marquis P, De La Loge C, Dubois D, McDermott A, Chassany O. Development and Validation of 
the Patient Assessment of Constipation Quality of Life Questionnaire. Scandinavian Journal of 
Gastroenterology 2005;40:540-551.
Patrick DL, Drossman DA, Frederick IO. A quality of life measure for persons with irritable 
bowel syndrome (IBS-QOL). user’s manual and scoring diskette. U.S. version. Seattle, WA: 
University of Washington; 1997 Jun.
Patrick DL, Drossman DA, Frederick IO, et al. Quality of life in persons with irritable bowel 
syndrome: development and validation of a new measure. Dig Dis Sci 1998;43:400-11.
Shaw JW, Johnson JA, Coons SJ. U.S. valuation of the EQ-5D health states: development and 
testing of the D1 valuation model. Med Care 2005;43:203-20.


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8.
History of Change
Amendment 1: 2018-05-23
Section(s)
Description
Rationale
Global
Corrected case for selected hyphenated words:

Dose-reduced

Double-blind
Alignment with MW style guidelines
1
Changed sponsor from Forest to Allergan on cover page 
and headers, and changed sponsor address
Updated NDA holder
3
Global
Removed selected abbreviations and expansion of 
 
; Removed instances 
of removed abbreviations from SAP body; inclusion of 
selected references in table footnotes
Alignment with MW style guidelines; 
abbreviations not required
5.1.1.1.1
Added All enrolled participants population
Handling of participants who entered 
OL with exposure records not 
indicating treatment was actually taken
5.1.1.2.2
Specified participant disposition based on study design 
epochs, not analysis periods
Clarification
5.1.1.2.2
For participants who continued to next period, removed 
“due to AE” clause
Simplification/elimination of confusion
5.1.1.2.3
Specified “significant” protocol deviations
Accuracy
5.1.1.2.5
Changed height unit to cm
Accuracy
5.1.1.3.1
5.1.1.3.2
Changed continuous descriptives to CFB descriptives for 
endpoints with baseline values
Incorrect analysis references
5.1.1.3.3
Changed population to DB Safety for selected analyses
Incorrectly specified in protocol
5.1.1.3.3
Changed assignment of values on same date as DB start 
date from post-rand to pre-rand
Value from DB start date assumed to 
be before first DB administration
 
Clarification
5.1.1.4.6
Revised details of ADA classification rules; Revised 
listing specification
Clarification
Correction