A Phase 3, Open-label, Long-term Safety Study of Oral Linaclotide Administered to Pediatric Participants With Functional Constipation (FC) or Irritable Bowel Syndrome With Constipation (IBS-C)
Phase: PHASE3
Conditions: Irritable Bowel Syndrome With Constipation, Functional Constipation
Sponsor: AbbVie

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
1
GRD-CLN-T-01-01 v2.0
Title Page
Protocol Title:
A Long-term Safety Study of Oral Linaclotide Administered to 
Pediatric Participants with Functional Constipation (FC) or Irritable 
Bowel Syndrome with Constipation (IBS-C)
Protocol Number:
LIN-MD-66
Amendment Number:
2
Product:
Linaclotide
Brief Protocol Title:
Long-term Safety of Linaclotide in Pediatric Participants with FC or 
IBS-C
Development Phase:
Extension study
Sponsor Name and Legal Registered Address:
Allergan Sales LLC,
5 Giralda Farms,
Madison, NJ 07940, USA
Allergan Ltd. 
Marlow International, Parkway,
Marlow SL7 1YL, United Kingdom
Regulatory Agency Identifying Number: IND 63,290, EudraCT 2019-001955-38
Emergency Telephone Number
Refer to the study contacts page
SAE Reporting Fax Number/Email:
Business Unit/ Organization
Email
Fax
Allergan Pharmaceuticals
IR-Clinical-SAE@allergan.com
+1.714.796.9504
Backup: +1.714.246.5295
Sponsor Signatory:
 MD
and 
General Medicine and Infectious Diseases
Refer to the final page of this protocol for electronic signature and date of approval.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure
NCT04166058

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
2
GRD-CLN-T-01-01 v2.0
Protocol Amendment Summary of Changes
DOCUMENT HISTORY
Document
Date
Amendment 2
Apr 2021
Amendment 1
Jun 2020
Original Protocol
Jul 2019
Amendment 2 (April 2021)
The purpose of Global Protocol Amendment 2 is to provide LIN-MD-64 completers with IBS-C 
the option to continue on the same blinded dose they received in the LIN-MD-64 lead-in study,
and to provide additional clarification and updates to the LIN-MD-66 protocol (Amendment 1 
dated 10 June 2020).
The following is a summary of changes made in Global Protocol Amendment 2. Strikethrough 
text denotes text removed and bolded text denotes added text. Additional administrative edits 
were also made, but not specifically noted (e.g., corrected spelling, punctuation, grammar, 
abbreviation, and style errors) including global edits required for consistency.
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
3
GRD-CLN-T-01-01 v2.0
Protocol Section(s)
Description of Changes
Rationale for Changes
Title Page

Updated title to remove the words ‘phase 3 open-label’

Revised the Development Phase as follows: 3 Extension study

Updated the sponsor signatory

To account for the blinded 
treatment arm that was added 
to the study and for clarity

For clarification

Updated to reflect the current 
information
Section 1.1 Synopsis

All relevant changes made below in subsequent sections in the body of the 
protocol have been carried up to the synopsis.

The words ‘open-label’ and ‘Phase 3’ were removed from the study description 
throughout the protocol as needed. 

To align with the body of the 
protocol

To account for the blinded 
treatment arm that was added 
to the study and for 
clarification
Section 1.3 Study Schema for 
IBS-C Participants

The label for the 52-week study intervention period was changed as follows: 
‘Open label Intervention Period’ was changed to ‘Study Intervention Period’

To include the blinded 
treatment arm that was added 
to the study
Section 1.4 Schedule of 
Activities (SoA) for FC 
Participants

‘FC’ was added to the titles for Table 1-1 and Table 1-2

For clarification
Section 1.5 Schedule of 
Activities (SoA) for IBS-C 
Participants

‘IBS-C’ was added to the titles for Table 1-3 and Table 1-4

For Table 1-4, the footnote for Study Day 365 was changed from ‘d’ to ‘b’ as 
follows: 365 (+3)d b

For clarification

Updated to reflect the correct 
footnote
Section 2 Introduction

The following text was revised: ‘Linaclotide is approved for the treatment of 
irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic 
constipation (CIC) in the United States, Canada, Japan, Australia, New Zealand, 
Kingdom of Saudi Arabia, and Mexico’

Updated to reflect the current 
information
Section 4.1 Overall Design

The following text was added: ‘For FC participants enrolling from studies 
LIN-MD-62 and LIN-MD-64, and IBS-C participants enrolling from study 
LIN-MD-63, linaclotide treatment will be open-label. For IBS-C participants 
enrolling from study LIN-MD-64, linaclotide treatment will be either blinded
or open-label. Linaclotide treatment will be blinded if participants choose to 

To include the blinded 
treatment arm that was added 
to the study
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
4
GRD-CLN-T-01-01 v2.0
Protocol Section(s)
Description of Changes
Rationale for Changes
remain on the same blinded linaclotide dose they were receiving in the lead-
in LIN-MD-64 study and it will be open-label if participants choose to receive
open-label linaclotide therapy.’

Text was revised as follows: ‘The present study will include a screening period 
and an open labela 24-week (FC participants) or 52-week (IBS-C participants)
study intervention period (Section 1.2 and Section 1.3, respectively).’

The following text was added: ‘Participants who turn 18 years of age during study 
LIN-MD-63 or LIN-MD-64, or after completing the lead-in study, may be eligible 
if they enroll within 28 days (inclusive) of the last day of study intervention in the 
lead-in study (Study LIN-MD-64 [Visit 7] or Study LIN-MD-63 [Visit 5]). Such 
participants will be dosed as 17-year-old participants; refer to the 
Intervention Groups and Study Duration section below for dosing.’

The intervention groups were updated to indicate that LIN-MD-64 completers 
with IBS-C will have the option to either remain on the same blinded linaclotide 
dose they were receiving in the lead-in Phase 3 study LIN-MD-64 or to receive
open-label linaclotide therapy.

Text describing the dose modifications permitted for participants has been deleted 
from this section and the following reference was added: ‘Dose modifications 
permitted for FC and IBS-C participants are described in Section 6.6.’
For clarification

To clarify the dosing for 
participants who turn 18 years 
of age

To allow IBS-C participants 
who responded favorably to 
their dose in the LIN-MD-64
lead-in study to remain on the 
same dose in LIN-MD-66

To streamline this section for 
clarity
Section 4.3 Justification for 
Doses

Text was added referring to the dosing options for LIN-MD-64 IBS-C completers.

Text referring to dose adjustments permitted for a participant who experiences an 
intolerable AE was deleted from this section and the following reference was 
added: ‘Dose modifications permitted for FC and IBS-C participants are 
described in Section 6.6.’

To include the blinded 
treatment arm that was added 
to the study

To streamline this section for 
clarity
Section 6.3 Measures to 
Minimize Bias: Randomization 
and Blinding

The following sentence was deleted: ‘Blinding is not applicable given this is an 
open label study’.

To include the blinded 
treatment arm that was added 
to the study
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
5
GRD-CLN-T-01-01 v2.0
Protocol Section(s)
Description of Changes
Rationale for Changes
Section 6.3.1 Blinding and 
Unblinding

Text was added to include blinding of study intervention for the blinded treatment 
arm and to describe the unblinding process if needed

To include the blinded 
treatment arm that was added 
to the study
Section 6.6 Dose Modification

Text describing the dose adjustments permitted for FC and IBS-C participants was 
streamlined and Table 6-1 Dose Reductions was added which summarizes the 
dose adjustments permitted for all participants.

For clarity and to add the
dose reductions permitted for 
IBS-C participants on 
blinded linaclotide treatment
Section 9.5 Interim Analyses

The following text was deleted: ‘No interim analysis is planned.’ The following 
text was added: ‘An interim analysis to assess long-term safety of linaclotide 
may be performed after at least 120 participants have completed the study. 
Data will be locked after performing data cleaning. Results from the interim 
analysis will be described in an interim clinical study report.’

To evaluate the long-term
safety of linaclotide once at 
least 120 participants have 
completed the study.
Section 10.6 Appendix 6: Study 
Tabular Summary

The following text was revised:
o Trial Phase Classification: Phase 3 Trial Extension Study

The following text was added: 
o ‘Intervention Model: Open-label and blinded’
o ‘Planned Number of Arms: 
2 arms for FC participants: open-label 72 and 145 µg
4 arms for IBS-C participants: 2 arms for open-label (145 and 290 µg) and 
2 arms for blinded (145 and 290 µg)’
o ‘Trial Blinding Schema: Open-label and blinded’

For clarification

To include the blinded 
treatment arm that was added 
to the study
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
6
GRD-CLN-T-01-01 v2.0
Table of Contents
Title Page ........................................................................................................................................1
Protocol Amendment Summary of Changes ...............................................................................2
Table of Contents ...........................................................................................................................6
List of Tables...................................................................................................................................9
1.
Protocol Summary ........................................................................................................11
1.1.
Synopsis...................................................................................................................11
1.2.
Study Schema for FC Participants...........................................................................15
1.3.
Study Schema for IBS-C Participants .....................................................................16
1.4.
Schedule of Activities (SoA) for FC Participants ...................................................17
1.5.
Schedule of Activities (SoA) for IBS-C Participants..............................................21
2.
Introduction...................................................................................................................27
2.1.
Study Rationale .......................................................................................................28
2.2.
Background .............................................................................................................29
2.2.1.
Adult Linaclotide Program.............................................................................29
2.2.2.
Pediatric Linaclotide Program........................................................................30
2.2.3.
Other Nonclinical Information .......................................................................33
2.2.3.1.
Non-clinical Toxicology ...................................................................33
2.2.3.2.
GC-C mRNA Expression..................................................................34
2.2.4.
Post-marketing Experience.............................................................................34
2.3.
Benefit/Risk Assessment .........................................................................................34
3.
Objectives and Assessments.........................................................................................35
4.
Study Design..................................................................................................................36
4.1.
Overall Design.........................................................................................................36
4.2.
Scientific Rationale for Study Design.....................................................................38
4.3.
Justification for Doses.............................................................................................38
4.4.
End of Study Definition ..........................................................................................39
5.
Study Population...........................................................................................................39
5.1.
Inclusion Criteria.....................................................................................................40
5.1.1.
General Inclusion Criteria (All Participants)..................................................40
5.1.2.
Inclusion Criteria for Phase 3 LIN-MD-64 Completers 
and Phase 2 LIN-MD-63 Completers Who Enroll in 
LIN-MD-66 Within ≤28 Days From Last Study
Intervention ....................................................................................................40
5.1.3.
Inclusion Criteria for Phase 2 LIN-MD-62 or Phase 2 
LIN-MD-63 and Phase 3 LIN-MD-64 Completers 
Who Enroll in LIN-MD-66 After > 28 Days From Last 
Study Intervention..........................................................................................40
5.2.
Exclusion Criteria....................................................................................................41
5.2.1.
General Exclusion Criteria (All Participants) ................................................41
5.2.2.
Exclusion Criteria for LIN-MD-62, LIN-MD-63 and 
LIN-MD-64 Completers Who Enroll in LIN-MD-66 
> 28 Days From Last Study Intervention .......................................................43
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
7
GRD-CLN-T-01-01 v2.0
5.3.
Lifestyle Considerations..........................................................................................44
5.4.
Screen Failures ........................................................................................................44
6.
Study Intervention........................................................................................................44
6.1.
Study Intervention Administered.............................................................................44
6.2.
Preparation/Handling/Storage/Accountability ........................................................45
6.3.
Measures to Minimize Bias: Randomization and Blinding.....................................46
6.3.1.
Blinding and Unblinding................................................................................46
6.3.1.1.
Blinding.............................................................................................46
6.3.1.2.
Unblinding ........................................................................................46
6.4.
Study Intervention Compliance...............................................................................47
6.5.
Prior and Concomitant Therapy ..............................................................................47
6.6.
Dose Modification...................................................................................................48
6.7.
Intervention after the End of the Study ...................................................................49
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................49
7.1.
Discontinuation of Study Intervention ....................................................................49
7.1.1.
Removal of Individual Participants from Therapy or 
Assessment .....................................................................................................50
7.1.2.
Criteria for Consideration of Study Discontinuation .....................................51
7.2.
Participant Discontinuation/Withdrawal from the Study ........................................51
7.3.
Lost to Follow Up....................................................................................................52
8.
Study Assessments and Procedures.............................................................................52
8.1.
Efficacy Assessments ..............................................................................................53
8.2.
Safety Assessments..................................................................................................54
8.2.1.
Physical Examinations ...................................................................................54
8.2.2.
Vital Signs ......................................................................................................55
8.2.3.
Electrocardiograms.........................................................................................56
8.2.4.
Clinical Safety Laboratory Assessments ........................................................57
8.3.
Adverse Events and Serious Adverse Events..........................................................58
8.3.1.
Adverse Events of Special Interest.................................................................59
8.3.2.
Time Period and Frequency for Collecting Adverse 
Events, Serious Adverse Events, and Adverse Events 
of Special Interest Information.......................................................................59
8.3.3.
Method of Detecting Adverse Events, Serious Adverse 
Events, and Adverse Events of Special Interest .............................................60
8.3.4.
Follow-up of Adverse Events, Serious Adverse Events, 
and Adverse Events of Special Interest ..........................................................60
8.3.5.
Regulatory Reporting Requirements for Serious 
Adverse Events...............................................................................................61
8.3.6.
Pregnancy.......................................................................................................61
8.3.7.
Potential Hy’s Law Cases...............................................................................62
8.3.8.
Medication Errors...........................................................................................62
8.4.
Treatment of Overdose............................................................................................63
8.5.
Pharmacokinetics.....................................................................................................63
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
8
GRD-CLN-T-01-01 v2.0
8.6.
Pharmacodynamics..................................................................................................63
8.7.
Genetics...................................................................................................................63
8.8.
Biomarkers and Other Assessments ........................................................................63
8.9.
Health Economics....................................................................................................63
9.
Statistical Considerations.............................................................................................64
9.1.
Statistical Hypotheses..............................................................................................64
9.2.
Sample Size Determination.....................................................................................64
9.3.
Populations for Analyses.........................................................................................64
9.4.
Statistical Analyses..................................................................................................64
9.4.1.
Adverse Events...............................................................................................65
9.4.2.
Clinical Laboratory Assessments ...................................................................66
9.4.3.
Vital Signs ......................................................................................................66
9.4.4.
Electrocardiograms.........................................................................................66
9.5.
Interim Analyses......................................................................................................67
10.
Supporting Documentation and Operational Considerations..................................68
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations.........................................................................................................68
10.1.1.
Regulatory and Ethical Considerations..........................................................68
10.1.2.
Financial Disclosure.......................................................................................68
10.1.3.
Informed Consent Process..............................................................................69
10.1.4.
Data Protection...............................................................................................70
10.1.5.
Posting Clinical Study Data ...........................................................................71
10.1.6.
Data Quality Assurance..................................................................................71
10.1.6.1.
Data Monitoring................................................................................71
10.1.6.2.
Data Recording and Documentation.................................................72
10.1.6.3.
Data and Safety Monitoring Board...................................................73
10.1.7.
Source Documents..........................................................................................73
10.1.8.
Study and Site Closure ...................................................................................73
10.1.9.
Publication Policy...........................................................................................74
10.1.10. Compliance with Protocol..............................................................................74
10.1.11. Study Documentation.....................................................................................75
10.2.
Appendix 2: Clinical Laboratory Tests....................................................................76
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting..................................................79
10.3.1.
Definition of AE .............................................................................................79
10.3.2.
Definition of SAE...........................................................................................83
10.3.3.
Recording and Follow-Up of AEs or SAEs....................................................84
10.3.4.
Reporting of SAEs..........................................................................................87
10.4.
Appendix 4: Abbreviations......................................................................................88
10.5.
Appendix 5: Standard Discontinuation Criteria......................................................90
10.6.
Appendix 6: Study Tabular Summary.....................................................................92
10.7.
Appendix 7: Contraceptive Guidance and Collection of 
Pregnancy Information............................................................................................94
10.7.1.
Definitions:.....................................................................................................94
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
9
GRD-CLN-T-01-01 v2.0
10.7.2.
Contraception Guidance:................................................................................94
10.7.3.
Pregnancy Testing: .........................................................................................95
10.7.4.
Collection of Pregnancy Information:............................................................96
10.8.
Appendix 8: Instructions for Sprinkled Dose..........................................................98
10.9.
Appendix 9: Liver Safety: Suggested Actions and Follow-up 
Assessments.............................................................................................................99
10.10.
Appendix 10: Study Schedule Supplement...........................................................102
10.10.1. Screening (Visit 1)........................................................................................102
10.10.2. Study Day 1 (Visit 2)....................................................................................104
10.10.3. Week 2 (Visit 3)............................................................................................105
10.10.4. Week 4 (Visit 4)............................................................................................105
10.10.5. Week 8 (Visit 5)............................................................................................105
10.10.6. Week 16 (Visit 6)..........................................................................................106
10.10.7. Week 24/EOT Visit (Visit 7) for FC Participants.........................................106
10.10.8. Week 24 (Visit 7) for IBS-C Participants.....................................................107
10.10.9. Week 32 (Visit 8) for IBS-C Participants.....................................................107
10.10.10.Week 40 (Visit 9) for IBS-C Participants.....................................................108
10.10.11.Week 52/EOT (Visit 10) for IBS-C Participants ..........................................108
10.11.
Appendix 11: Study Conduct During the Novel Coronavirus 
Pandemic ...............................................................................................................110
11.
References....................................................................................................................111
List of Tables
Table 1–1
Schedule of Activities - Phase 3 Study LIN-MD-64 FC Completers Who Enroll in 
Study LIN-MD-66 Within ≤28 Days From Last Study Intervention................... 17
Table 1–2
Schedule of Activities - Phase 2 LIN-MD-62 and Phase 3 LIN-MD-64 FC 
Completers Who Enroll in LIN-MD-66 After > 28 Days From Last Study
Intervention........................................................................................................... 19
Table 1–3
Schedule of Activities - Phase 2 Study LIN-MD-63 and Phase 3 Study
LIN-MD-64 IBS-C Completers Who Enroll in Study LIN-MD-66 Within ≤ 28 
Days From the Last Study Intervention................................................................ 21
Table 1–4
Schedule of Activities – Phase 2 Study LIN-MD-63 and Phase 3 Study
LIN-MD-64 IBS-C Completers Who Enroll in LIN-MD-66 After > 28 Days From 
Last Study Intervention......................................................................................... 24
Table 2–1
Dose Levels (in Micrograms) by Weight in Pediatric Participants Treated with 
Linaclotide in LIN-MD-62 ................................................................................... 31
Table 2-2
Dose Levels (µg) by Weight in Pediatric IBS-C Participants Treated with 
Linaclotide in LIN-MD-63 ................................................................................... 33
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
10
GRD-CLN-T-01-01 v2.0
Table 6-1
Dose Reductions ................................................................................................... 49
Table 10–1
Protocol-Required Safety Laboratory Assessments.............................................. 78
Table 10–2
Highly Effective Contraceptive Methods ............................................................. 95
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
11
GRD-CLN-T-01-01 v2.0
1.
Protocol Summary
1.1.
Synopsis
Protocol Title: A Long-term Safety Study of Oral Linaclotide Administered to Pediatric 
Participants with Functional Constipation (FC) or Irritable Bowel Syndrome with Constipation 
(IBS-C)
Protocol Number: LIN-MD-66
Amendment Number: 2
Brief Title: Long-term Safety of Linaclotide in Pediatric Participants with FC or IBS-C
Study Phase: Extension study
Study Rationale:
Functional constipation (FC) is a common healthcare problem in children of all ages, with a 
worldwide prevalence ranging between 0.7% and 29.6% (Koppen 2018). Symptoms include 
infrequent, hard stools, and painful defecation, and affected children may have abdominal pain 
and fecal incontinence, which is usually the result of fecal impaction leading to overflow 
incontinence. These symptoms can have a severe impact on a child’s quality of life and may lead 
to school absenteeism and substantial costs related to healthcare utilization. Initial non-
pharmacological interventions include education, behavioral modifications, and keeping a bowel 
diary. Despite these interventions, many children require pharmacological interventions. 
Treatment consists of disimpaction (ie, removal of the rectal fecal mass), followed by
maintenance treatment and eventually a weaning phase. Multiple pharmacological agents are 
available for the treatment of FC in children. Despite chronic pharmacological treatment, 
approximately 40% of children with FC referred to a pediatric gastroenterologist remain 
symptomatic after 5 years and 20% of children still have symptoms after 10 years. In some cases, 
symptoms may persist into adolescence or adulthood despite medical treatment. Potential reasons 
for ineffectiveness of treatment include suboptimal dosage regimens, poor compliance with
treatment, or the use of drugs with action mechanisms that do not address the underlying 
pathophysiological etiology. 
Irritable bowel syndrome (IBS) is characterized by symptoms of abdominal discomfort or pain 
associated with altered bowel movement characteristics (Drossman 2006). In adults, Rome III 
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
12
GRD-CLN-T-01-01 v2.0
criteria has classified IBS with constipation (IBS-C), IBS with diarrhea, mixed IBS, and 
unsubtyped IBS, depending on the stool consistency (Longstreth 2006). In children, although 
IBS subtypes are encountered in clinical practice, a classification based on stool consistency had 
not been specified at the time the Phase 2 dose ranging study (LIN-MD-63) was originally
developed.
The overall prevalence of IBS in the pediatric population is low. IBS prevalence in children 
across the United States, based on parental reports, ranges from 1.2% to 2.9%, while school-
based studies in Colombia and Sri Lanka found a prevalence of IBS of 4.9% and 5.4%,
respectively (Hyams 2016). In adults, although not life-threatening, because of its chronic 
relapsing course, IBS is associated with impaired quality of life and high direct and indirect 
medical costs such as absenteeism from work (Thompson 1999). In children and adolescents, 
IBS has been associated with significant impairment as increased rates of school absenteeism, 
health-care utilization and family disruption are common (Chiou and Nurko 2010).
The primary objective of LIN-MD-66 is to assess the long-term safety of linaclotide 
administered to participants with FC (total exposure with linaclotide for 24 weeks) or IBS-C 
(total exposure with linaclotide for 52 weeks) who have completed study intervention in Study
LIN-MD-62, LIN-MD-63, or LIN-MD-64.
Objectives and Assessments:
Objectives
Assessments
Primary
The objective of this study is to assess the long-term
safety of linaclotide in pediatric participants with FC 
(total exposure with linaclotide for 24 weeks) or IBS-C 
(total exposure with linaclotide for 52 weeks) who have 
completed study intervention in Study LIN-MD-62, 
LIN-MD-63, or LIN-MD-64. 
The safety assessments will include monitoring of 
adverse events (AEs), clinical laboratory assessments 
(clinical chemistry, complete blood count [CBC], 
urinalysis), vital sign measurements (including 
postural vital signs), electrocardiograms (ECGs), 
physical examinations, height, and weight.
Overall Study Design:
LIN-MD-66 is a long-term safety study with 24 weeks (FC participants) or 52 weeks (IBS-C 
participants) of linaclotide exposure that will enroll pediatric participants (6-17 years of age) 
with FC or IBS-C who completed study intervention in Phase 2 study LIN-MD-62 or
LIN-MD-63, or Phase 3 study LIN-MD-64, based on the individual study criteria. For FC 
participants enrolling from studies LIN-MD-62 and LIN-MD-64, and IBS-C participants 
enrolling from study LIN-MD-63, linaclotide treatment will be open-label. For IBS-C 
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
13
GRD-CLN-T-01-01 v2.0
participants enrolling from study LIN-MD-64, linaclotide treatment will be either blinded or 
open-label. Linaclotide treatment will be blinded if participants choose to remain on the same 
blinded linaclotide dose they were receiving in the lead-in LIN-MD-64 study and it will be open-
label if participants choose to receive open-label linaclotide therapy.

Phase 2 completers are defined as pediatric participants who completed 4-week 
double-blind study intervention and EOT Visit (Visit 5) in the Phase 2 studies AND
o
Completed the EOS (Visit 6) in Study LIN-MD-62 or
o
Completed the EOS (Visit 6) in Study LIN-MD-63. However, this EOS Visit in LIN-
MD-63 is not required for participants who enroll into LIN-MD-66 prior to that visit.

Phase 3 completers are pediatric participants who completed 12-week double-blind study
intervention in Study LIN-MD-64. Participants must have completed the EOT visit 
(Visit 7) and the EOS visit (Visit 8). However, this EOS visit in LIN-MD-64 is not 
required for participants who enroll into LIN-MD-66 prior to that visit.
The present study will include a screening period and a 24-week (FC participants) or 52-week 
(IBS-C participants) study intervention period (Section 1.2 and Section 1.3, respectively). For 
participants who enroll in LIN-MD-66 on the same day as their EOT Visit or EOS Visit in LIN-
MD-64, the EOT Visit or EOS Visit, respectively, may be combined with the Screening (Visit 1)
and Day 1 Visit (Visit 2) in LIN-MD-66. For participants who enroll within ≤28 days (inclusive) 
from last study intervention in Study LIN-MD-64 (Visit 7), the LIN-MD-66 Screening Visit 
(Visit 1) and Day 1 Visit (Visit 2) procedures may be combined, with the exception of 
participants who are positive for fecal impaction assessment at the Screening Visit (Visit 1).
All participants are required to have a fecal impaction assessment prior to dosing. For those 
participants who do not combine Visit 1 and Visit 2, a fecal impaction assessment will be 
performed at the Screening Visit (Visit 1) and at the Day 1 Visit (Visit 2) prior to dosing. Please 
refer to Section 8.2.1 for further details.
Participants who turn 18 years of age during study LIN-MD-63 or LIN-MD-64, or after 
completing the lead-in study, may be eligible if they enroll within 28 days (inclusive) of the last 
day of study intervention in the lead-in study (Study LIN-MD-64 [Visit 7] or Study LIN-MD-63 
[Visit 5]). Such participants will be dosed as 17-year-old participants; refer to the Intervention 
Groups and Study Duration section below for dosing.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
14
GRD-CLN-T-01-01 v2.0
Number of Participants:
At least 120 participants are planned to be enrolled to receive 24 weeks (FC participants) or 
52 weeks (IBS-C participants) of linaclotide study intervention. However, the actual number of 
participants in this study will depend on the number of participants who have completed study 
intervention in the lead-in study (LIN-MD-62, LIN-MD-64, or LIN-MD-63) and enroll into this 
long-term safety study after fulfilling the eligibility criteria.
Number of Sites:
Up to 120 sites from the United States, Canada, Europe, and the Middle East will have an option 
to participate in the study.
Intervention Groups and Study Duration:
FC participants (LIN-MD-62 and LIN-MD-64 completers) will receive open-label linaclotide 
72 µg or 145 µg once daily for 24 weeks as follows based on their age at the time of enrollment 
into LIN-MD-66:

6 to 11 years of age: 72 µg linaclotide

12 to 17 years of age: will be randomly assigned at 1:1 ratio to 72 µg linaclotide or 145 µg 
linaclotide
IBS-C participants will receive linaclotide for 52 weeks as follows:

LIN-MD-63 completers will receive open-label linaclotide 290 µg once daily except for 
the LIN-MD-63 completers who had received ≤145 µg linaclotide or placebo. These 
participants will have the option to receive open-label linaclotide 145 µg once daily.

LIN-MD-64 completers will have the option to either remain on the same blinded
linaclotide dose they were receiving in lead-in study LIN-MD-64 or to receive open-label
290 µg linaclotide. Study intervention in LIN-MD-66 is assigned via IWRS; treatment 
assignments for LIN-MD-64 completers who choose to remain on the same blinded
linaclotide dose in long-term safety study LIN-MD-66 will remain blinded to participants, 
investigators, and all site personnel during the study.
o
LIN-MD-64 completers who choose to remain on the same blinded linaclotide dose 
received in the lead-in study LIN-MD-64 will continue to receive blinded linaclotide 
145 or 290 µg once daily.
o
LIN-MD-64 completers who choose to receive open-label linaclotide therapy will 
receive linaclotide 290 µg once daily.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
16
GRD-CLN-T-01-01 v2.0
1.3.
Study Schema for IBS-C Participants
*
For participants who enroll in LIN-MD-66 on the same day as their EOT Visit or EOS Visit in LIN-MD-63 or 
LIN-MD-64, the EOT Visit or EOS Visit, respectively, may be combined with the Screening Visit (Visit 1). For 
participants who enroll within ≤ 28 days (inclusive) from last study intervention in LIN-MD-63 (Visit 5) or 
LIN-MD-64 (Visit 7), the Screening Visit (Visit 1) and Day 1 (Visit 2) procedures may be combined, with the 
exception of participants who are positive for fecal impaction assessment at Screening Visit.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
17
GRD-CLN-T-01-01 v2.0
1.4.
Schedule of Activities (SoA) for FC Participants
Table 1–1
Schedule of Activities - Phase 3 Study LIN-MD-64 FC Completers Who Enroll in Study LIN-MD-66 Within 
≤28 Days From Last Study Intervention
Study Periods (Duration)
Screening (Up 
to 14 days)
Study Intervention Period
(24 weeks)
Study Visito
Screening
Day 1
Week 2
Week 4
Week 8
Week 16
Week 24 Visit/ 
EOT
Visit Number
1
2
3
4
5
6
7
Study Day
-14 to -1a,b
1b
15 (± 3)c
(Phone Visit)
29 (± 3)
57 (± 3)
113 (± 3)
169 (+ 3)d
Study Procedure
Parent/caregiver consent/assent 
X
Inclusion and exclusion criteria 
X
X
Rome III assessment
X
IWRS 
X
X
X
X
X
Medical history
X
Physical examinatione
X
Fecal Impaction assessmentf
X
Xg
Vital signs, and postural vital 
signsh
X
X
X
X
X
Height
X
Electrocardiogram
X
Prior and concomitant medication
X
X
X
X
X
X
X
Clinical laboratory testsi
X
Urine pregnancy testj
X
X
X
X
X
X
Study intervention administration 
in the clinicl
Xm
Adverse event evaluationk
X
X
X
X
X
X
X
Study intervention dispensedn
X
X
X
X
Study intervention compliance and 
accountability
X
X
X
X
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
18
GRD-CLN-T-01-01 v2.0
a
Study procedures for screening may be combined with LIN-MD-64 EOT Visit.
b
Provided there is no fecal impaction at Screening (Visit 1), study procedures for Screening (Visit 1) and Day 1 Visit (Visit 2) may be combined.
c
Week 2 visit will be a phone visit for all participants.
d
All enrolled participants who prematurely discontinue from the study, regardless of cause, are required to return for the EOT study assessments.
e
Physical examinations will be performed by medically qualified site personnel at Visit 7 and may be done at the investigator’s discretion at any time.
f
Fecal impaction is defined as a hard mass in the lower abdomen identified on physical examination or a dilated rectum filled with a large amount of stool on 
rectal examination. If fecal impaction is documented during an optional repeat physical examination, the sponsor must be notified. If a rectal examination is 
performed, the medically qualified site personnel should assess for and document the presence of anal wink and normal anal tone.
g
A fecal impaction assessment is performed at the study Day 1 Visit (Visit 2) prior to study intervention administration. If the participant is impacted at Visit 2, 
the participant would not be eligible for the study.
h
Vital signs include weight, temperature (oral, rectal, or tympanic), and respiratory rate. Postural vital signs (supine and standing) include pulse rate and 
systolic and diastolic blood pressure. At all visits, postural vital signs must be obtained after participants have been in a supine position for at least 2 to 
3 minutes, followed by a standing position for at least 1 minute.
i
Clinical laboratory tests consist of clinical chemistry, hematology, and urinalysis. All laboratory tests requiring blood draws should be collected at the same 
time.
j
Urine pregnancy test will be performed in female participants of childbearing potential at Visit 1 and Visit 2 prior to dosing and at Visits 4 to 7 during study 
intervention. To continue in this study, a negative urine tests must be documented at Day 1 Visit (Visit 2) to start study intervention and at Visits 4 to 6 to 
continue study intervention. LIN-MD-64 completers who enroll in this study on the same day do not need to repeat the urine pregnancy test (Section 10.7).
k
The ongoing AEs from LIN-MD-64 study will be transferred to LIN-MD-66 in the auto-rollover function in EDC.
l
Study intervention will be administered in the clinic at the Day 1 Visit (Visit 2). On the day of this visit, all participants must fast for at least 2 hours before 
arriving at the clinic for their visit, where they will receive their initial dose of study intervention. Participants may eat 30 minutes after dosing (the 
requirement for linaclotide to be administered 30 minutes prior to any meal at the same time each day will not apply for the first dose). On all other days, it is 
recommended that participants take linaclotide at approximately the same time each day, 30 minutes before any meal.
m
Participants who took their last dose of study intervention in LIN-MD-64 on the day of the EOT Visit and enroll into LIN-MD-66 on that same day will take 
their first dose of LIN-MD-66 study intervention outside of the clinic at a designated time the following day. Qualified site personnel will complete a follow-
up phone call to participants within 48 hours following initial study intervention administration to assess safety.
n
The number of bottles of study intervention that should be dispensed at each visit is as follows: V2 (1 bottle), V4 (1 bottle), V5 (2 bottles), and V6 (2 bottles)
The bottles will be assigned via IWRS.
o
Additional unscheduled visits may be allowed at the discretion of the investigator with approval from the sponsor.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
19
GRD-CLN-T-01-01 v2.0
Table 1–2
Schedule of Activities - Phase 2 LIN-MD-62 and Phase 3 LIN-MD-64 FC Completers Who Enroll in LIN-MD-66 
After > 28 Days From Last Study Intervention
Study Periods (Duration)
Screening (Up 
to 14 days
Study Intervention Period (24 weeks)
Study Visitm
Screening
Day 1
Week 2
Week 4
Week 8
Week 16
Week 24 Visit/
EOT
Visit Number
1
2
3
4
5
6
7
Study Day
-14 to -1
1
Day 15 (± 3)a
(Phone Visit)
Day 29 (± 3)
Day 57 (± 3)
Day 113 (± 3)
Day (169+ 3)b
Study Procedure
Parent/caregiver consent/assent 
X
Inclusion and exclusion criteria 
X
X
Rome III assessment
Xn
X
IWRS 
X
X
X
X
X
Medical history 
X
Lifestyle modifications review
X
Physical examinationc
X
X
Fecal impaction assessmentd
X
Xe
Vital signs, and postural vital 
signsf
X
X
X
X
X
X
Height
X
X
ECG
X
X
Prior and concomitant medication
X
X
X
X
X
X
X
Clinical laboratory testsg
X
X
Urine drug screenh
X
Serum pregnancy testi
X
Urine pregnancy testi
X
X
X
X
X
Study intervention administration 
in the clinicj
X
AE evaluationk
X
X
X
X
X
X
X
Study intervention dispensedl
X
X
X
X
Study intervention compliance 
and accountability
X
X
X
X
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
20
GRD-CLN-T-01-01 v2.0
a
Week 2 visit (Visit 3) will be a phone visit for all participants.
b
All enrolled participants who prematurely discontinue from the study, regardless of cause, are required to return for the EOT study assessments.
c
Physical examinations performed by medically qualified site personnel at Visits 1 and 7 may be repeated at the investigator’s discretion at any time.
d
Fecal impaction is defined as a hard mass in the lower abdomen identified on physical examination or a dilated rectum filled with a large amount of stool on 
rectal examination. If fecal impaction is documented during an optional repeat physical examination, the sponsor must be notified. If a rectal examination is 
performed, the medically qualified site personnel should assess for and document the presence of anal wink and normal anal tone.
e
A fecal impaction assessment is performed at the study Day 1 Visit (Visit 2) prior to study intervention administration. If the participant is impacted at Visit 2, 
the participant would not be eligible for the study.
f
Vital signs include weight, temperature (oral, rectal, or tympanic), and respiratory rate. Postural vital signs (supine and standing) include pulse rate and 
systolic and diastolic blood pressure. At all visits, postural vital signs must be obtained after participants have been in a supine position for at least 2 to 
3 minutes, followed by a standing position for at least 1 minute.
g
Clinical laboratory tests consist of clinical chemistry, hematology, and urinalysis. All laboratory tests requiring blood draws should be collected at the same 
time.
h
The urine drug screen will be obtained at Screening (Visit 1) for all participants 12 to 17 years of age and, only if deemed necessary by the investigator, for 
participants 6 to 11 years of age.
i
A pregnancy test will be obtained for female participants of childbearing potential. Serum β-hCG will be performed at Screening (Visit 1), while urine 
pregnancy test will be performed at Visits 2 and 4 to 7 during study intervention. To continue in this study, a negative serum test must be documented at the 
Screening Visit (Visit 1) and negative urine tests must be documented at Day 1 Visit (Visit 2) to start study intervention and at Visits 4 to 6 to continue study 
intervention.
j
Study intervention will be administered in the clinic at the Day 1 Visit (Visit 2). On the day of this visit, all participants must fast for at least 2 hours before 
arriving at the clinic for their visit, where they will receive their initial dose of study intervention. Participants may eat 30 minutes after dosing (the 
requirement for study intervention to be administered 30 minutes prior to any meal at the same time each day will not apply for the first dose). On all other 
days, it is recommended that participants take linaclotide at approximately the same time each day, 30 minutes before any meal.
k
The ongoing AEs from LIN-MD-62 will be entered in the eCRF. The ongoing AEs from LIN-MD-64 will be transferred to LIN-MD-66 in the auto-rollover 
function in EDC.
l
The number of bottles of study intervention that should be dispensed at each visit is as follows: V2 (1 bottle), V4 (1 bottle), V5 (2 bottles), and V6 (2 bottles).
m
Additional unscheduled visits may be allowed at the discretion of the investigator with approval from the sponsor.
n
Rome III assessment at Screening will be assessed over the 2 month period immediately prior to the LIN-MD-66 Screening Visit (Visit 1), or over the 
1 month period immediately prior to the LIN-MD-66 Screening Visit if 2 months have not elapsed.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
21
GRD-CLN-T-01-01 v2.0
1.5.
Schedule of Activities (SoA) for IBS-C Participants
Table 1–3
Schedule of Activities - Phase 2 Study LIN-MD-63 and Phase 3 Study LIN-MD-64 IBS-C Completers Who 
Enroll in Study LIN-MD-66 Within ≤ 28 Days From the Last Study Intervention
Study Periods 
(Duration)
Screening 
(Up to 14 
days)
Study Intervention Period
(52 weeks)
Study Visito
Screening
Day 1
Week 2
Week 4
Week 8
Week 16
Week 24
Week 32
Week 40
Week 52 Visit/ 
EOT
Visit Number
1
2
3
4
5
6
7
8
9
10
Study Day
-14 to -1a,b
1b
15 (± 3)c
(Phone Visit)
29 (± 3)
57 (± 3)
113 
(± 3)
169 (±3)
225 (±3)
281 (±3)
365 (+3)d
Study Procedure
Parent/caregiver 
consent/assent 
X
Inclusion and exclusion 
criteria 
X
X
Rome III assessment
X
IWRS 
X
X
X
X
X
X
X
X
Medical history           
X
Physical examinatione  
X
Fecal Impaction 
assessmentf
X
Xg
Vital signs, and postural 
vital signsh
X
X
X
X
X
X
X
X
Height
X
Electrocardiogram
X
Prior and concomitant 
medication
X
X
X
X
X
X
X
X
X
X
Clinical laboratory testsi
X
Urine pregnancy testj
X
X
X
X
X
X
X
X
X
Study intervention 
administration in the 
clinicl
Xm
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
22
GRD-CLN-T-01-01 v2.0
Study Periods 
(Duration)
Screening 
(Up to 14 
days)
Study Intervention Period
(52 weeks)
Study Visito
Screening
Day 1
Week 2
Week 4
Week 8
Week 16
Week 24
Week 32
Week 40
Week 52 Visit/ 
EOT
Visit Number
1
2
3
4
5
6
7
8
9
10
Study Day
-14 to -1a,b
1b
15 (± 3)c
(Phone Visit)
29 (± 3)
57 (± 3)
113 
(± 3)
169 (±3)
225 (±3)
281 (±3)
365 (+3)d
Adverse event 
evaluationk
X
X
X
X
X
X
X
X
X
X
Study intervention 
dispensedn  
X
X
X
X
X
X
X
Study intervention 
compliance and 
accountability
X
X
X
X
X
X
X
a
Study procedures for screening may be combined with EOT Visit in study LIN-MD-63 or LIN-MD-64.
b
Provided there is no fecal impaction at Screening (Visit 1), study procedures for Screening (Visit 1) and Day 1 Visit (Visit 2) may be combined.
c
Week 2 visit will be a phone visit for all participants.
d
All enrolled participants who prematurely discontinue from the study, regardless of cause, are required to return for the EOT study assessments.
e
Physical examinations will be performed by medically qualified site personnel at Visit 10 and may be done at the investigator’s discretion at any time. 
f
Fecal impaction is defined as a hard mass in the lower abdomen identified on physical examination or a dilated rectum filled with a large amount of stool on 
rectal examination. If fecal impaction is documented during an optional repeat physical examination, the sponsor must be notified. If a rectal examination is 
performed, the medically qualified site personnel should assess for and document the presence of anal wink and normal anal tone.
g
A fecal impaction assessment is performed at the study Day 1 Visit (Visit 2) prior to study intervention administration. If the participant is impacted at Visit 2, 
the participant would not be eligible for the study. 
h
Vital signs include weight, temperature (oral, rectal, or tympanic), and respiratory rate. Postural vital signs (supine and standing) include pulse rate and 
systolic and diastolic blood pressure. At all visits, postural vital signs must be obtained after participants have been in a supine position for at least 2 to 
3 minutes, followed by a standing position for at least 1 minute.
i
Clinical laboratory tests consist of clinical chemistry, hematology, and urinalysis. All laboratory tests requiring blood draws should be collected at the same 
time.
j
Urine pregnancy test will be performed in female participants of childbearing potential at Visit 1 and Visit 2 prior to dosing and at Visits 4 to 10 during study 
intervention. To continue in this study, a negative urine tests must be documented at Day 1 Visit (Visit 2) to start study intervention and at Visits 4 to 9 to 
continue study intervention. LIN-MD-63 and LIN-MD-64 completers who enroll in this study on the same day do not need to repeat the urine pregnancy test 
(Section 10.7).
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
23
GRD-CLN-T-01-01 v2.0
k
The ongoing AEs from LIN-MD-63 will be entered in the eCRF. The ongoing AEs from LIN-MD-64 study will be transferred to LIN-MD-66 in the auto-
rollover function in EDC.
l
Study intervention will be administered in the clinic at the Day 1 Visit (Visit 2). On the day of this visit, all participants must fast for at least 2 hours before 
arriving at the clinic for their visit, where they will receive their initial dose of study intervention. Participants may eat 30 minutes after dosing (the 
requirement for linaclotide to be administered 30 minutes prior to any meal at the same time each day will not apply for the first dose). On all other days, it is 
recommended that participants take linaclotide at approximately the same time each day, 30 minutes before any meal.
m
Participants who took their last dose of lead-in study intervention in LIN-MD-63 or LIN-MD-64 on the day of the EOT Visit and enroll into LIN-MD-66 on 
that same day will take their first dose of LIN-MD-66 study intervention outside of the clinic at a designated time the following day. Qualified site personnel 
will complete a follow-up phone call to participants within 48 hours following initial study intervention administration to assess safety.
n
The number of bottles of study intervention that should be dispensed at each visit is as follows: V2 (1 bottle), V4 (1 bottle), V5 (2 bottles), V6 (2 bottles), V7 
(2 bottles), V8 (2 bottles), and V9 (3 bottles). The bottles will be assigned via IWRS.
o
Additional unscheduled visits may be allowed at the discretion of the investigator with approval from the sponsor.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
24
GRD-CLN-T-01-01 v2.0
Table 1–4
Schedule of Activities – Phase 2 Study LIN-MD-63 and Phase 3 Study LIN-MD-64 IBS-C Completers Who 
Enroll in LIN-MD-66 After > 28 Days From Last Study Intervention
Study Periods 
(Duration)
Screening 
(Up to 14 
days
Study Intervention Period (52 weeks)
Study Visitm
Screening
Day 1
Week 2
Week 4
Week 8
Week 16
Week 24
Week 
32
Week 
40
Week 52 
Visit/ 
EOT
Visit Number
1
2
3
4
5
6
7
8
9
10
Study Day
-14 to -1
1
Day 15 (± 3)a
(Phone Visit)
Day 29 
(± 3)
Day 57 (± 
3)
Day 113 
(± 3)
Day 169 
(± 3)
225 (±3)
281 (±3)
365 (+3)b
Study Procedure
Parent/caregiver 
consent/assent 
X
Inclusion and exclusion 
criteria 
X
X
Rome III assessment
Xn
X
IWRS 
X
X
X
X
X
X
X
X
Medical history 
X
Lifestyle modifications 
review
X
Physical examinationc
X
X
Fecal impaction 
assessmentd
X
Xe
Vital signs, and postural 
vital signsf
X
X
X
X
X
X
X
X
X
Height
X
X
ECG
X
X
Prior and concomitant 
medication
X
X
X
X
X
X
X
X
X
X
Clinical laboratory testsg
X
X
Urine drug screenh
X
Serum pregnancy testi
X
Urine pregnancy testi
X
X
X
X
X
X
X
X
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
25
GRD-CLN-T-01-01 v2.0
Study Periods 
(Duration)
Screening 
(Up to 14 
days
Study Intervention Period (52 weeks)
Study Visitm
Screening
Day 1
Week 2
Week 4
Week 8
Week 16
Week 24
Week 
32
Week 
40
Week 52 
Visit/ 
EOT
Visit Number
1
2
3
4
5
6
7
8
9
10
Study Day
-14 to -1
1
Day 15 (± 3)a
(Phone Visit)
Day 29 
(± 3)
Day 57 
(± 3)
Day 113 
(± 3)
Day 169 
(± 3) 
225 (±3)
281 (±3)
365 (+3)b
Study Procedure
Study intervention 
administration in the 
clinicj
X
AE evaluationk
X
X
X
X
X
X
X
X
X
X
Study intervention 
dispensedl
X
X
X
X
X
X
X
Study intervention 
compliance and 
accountability
X
X
X
X
X
X
X
a
Week 2 visit (Visit 3) will be a phone visit for all participants.
b
All enrolled participants who prematurely discontinue from the study, regardless of cause, are required to return for the EOT study assessments.
c
Physical examinations performed by medically qualified site personnel at Visits 1 and 10 may be repeated at the investigator’s discretion.
d
Fecal impaction is defined as a hard mass in the lower abdomen identified on physical examination or a dilated rectum filled with a large amount of stool on 
rectal examination. If fecal impaction is documented during an optional repeat physical examination, the sponsor must be notified. If a rectal examination is 
performed, the medically qualified site personnel should assess for and document the presence of anal wink and normal anal tone.
e
A fecal impaction assessment is performed at the study Day 1 Visit (Visit 2) prior to study intervention administration. If the participant is impacted at Visit 2, 
the participant would not be eligible for the study. 
f
Vital signs include weight, temperature (oral, rectal, or tympanic), and respiratory rate. Postural vital signs (supine and standing) include pulse rate and 
systolic and diastolic blood pressure. At all visits, postural vital signs must be obtained after participants have been in a supine position for at least 2 to 
3 minutes, followed by a standing position for at least 1 minute.
g
Clinical laboratory tests consist of clinical chemistry, hematology, and urinalysis. All laboratory tests requiring blood draws should be collected at the same 
time.
h
The urine drug screen will be obtained at Screening (Visit 1) for all participants 12 to 17 years of age and, only if deemed necessary by the investigator, for 
participants 7 to 11 years of age.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
26
GRD-CLN-T-01-01 v2.0
i
A pregnancy test will be obtained for female participants of childbearing potential. Serum β-hCG will be performed at Screening (Visit 1), while urine 
pregnancy test will be performed at Visits 2 and 4 to 10 during study intervention. To continue in this study, a negative serum test must be documented at the 
Screening Visit (Visit 1) and negative urine tests must be documented at Day 1 Visit (Visit 2) to start study intervention and at Visits 4 to 9 to continue study 
intervention. 
j
Study intervention will be administered in the clinic at the Day 1 Visit (Visit 2). On the day of this visit, all participants must fast for at least 2 hours before 
arriving at the clinic for their visit, where they will receive their initial dose of study intervention. Participants may eat 30 minutes after dosing (the 
requirement for study intervention to be administered 30 minutes prior to any meal at the same time each day will not apply for the first dose). On all other 
days, it is recommended that participants take linaclotide at approximately the same time each day, 30 minutes before any meal.
k
The ongoing AEs from LIN-MD-63 will be entered in the eCRF. The ongoing AEs from LIN-MD-64 study will be transferred to LIN-MD-66 in the auto-
rollover function in EDC.
l
The number of bottles of study intervention that should be dispensed at each visit is as follows: V2 (1 bottle), V4 (1 bottle), V5 (2 bottles), V6 (2 bottles), V7 
(2 bottles), V8 (2 bottles), and V9 (3 bottles). The bottles will be assigned via IWRS.
m
Additional unscheduled visits may be allowed at the discretion of the investigator with approval from the sponsor.
n
Rome III assessment at Screening will be assessed over the 2 month period immediately prior to the LIN-MD-66 Screening Visit (Visit 1), or over the 
1 month period immediately prior to the LIN-MD-66 Screening Visit if 2 months have not elapsed.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
27
GRD-CLN-T-01-01 v2.0
2.
Introduction
Linaclotide is a 14-amino acid peptide that acts on the apical surface of epithelial cells 
surrounding the intestinal lumen to stimulate the guanylate cyclase subtype C (GC-C) receptor. 
Linaclotide is approved for the treatment of irritable bowel syndrome with constipation (IBS-C) 
and chronic idiopathic constipation (CIC) in the United States, Canada, Japan, Australia, New 
Zealand, Kingdom of Saudi Arabia, and Mexico; for the treatment of IBS-C in China, the 
European Union (EU), Hong Kong, Macau, and Switzerland; and is being studied in other 
regions. By activating GC-C, orally administered linaclotide has been found to increase intestinal 
fluid secretion and intestinal transit, and to decrease visceral (abdominal) pain. Linaclotide has 
minimal oral bioavailability (≤ 0.2%) in several animal species (Bryant 2010; Eutamene 2010)
and is minimally absorbed with low systemic availability in adults. Refer to the Investigator’s 
Brochure (IB) for a more detailed description of the chemistry, pharmacology, efficacy, and 
safety of linaclotide, based on studies conducted in animals, healthy volunteers, and in 
participants with IBS-C and CIC (linaclotide IB).
Two Phase 2 dose-ranging studies have been conducted with linaclotide in pediatric participants; 
one in FC, 6 to 17 years of age (LIN-MD-62), and one in IBS-C, 7 to 17 years of age 
(LIN-MD-63). Results from these two studies are summarized in Section 2.2.2. 
This study will assess the long-term safety of linaclotide administered to pediatric participants 
with FC (total exposure with linaclotide for 24 weeks) or IBS-C (total exposure with linaclotide 
for 52 weeks) who have completed Study LIN-MD-62, LIN-MD-63, or LIN-MD-64: 

LIN-MD-62 (Phase 2): A Multicenter, Randomized, Double-blind, Placebo-controlled, 
Parallel-group, Safety and Efficacy Study of a Range of Linaclotide Doses Administered 
Orally to Children, Ages 6 to 17 Years, Who Fulfill Modified Rome III Criteria for 
Child/Adolescent FC

LIN-MD-63 (Phase 2): A Multicenter, Randomized, Double-blind, Placebo-controlled, 
Parallel-group, Safety and Efficacy Study of a Linaclotide Dose Administered Orally to 
Children, Ages 7 to 17 Years, With Irritable Bowel Syndrome With Constipation (IBS-C) 
(ie, Fulfill Rome III Criteria for Child/Adolescent IBS and Fulfill Modified Rome III 
Criteria for Child/Adolescent Functional Constipation)

LIN-MD-64 (Phase 3): A Phase 3, Multicenter, Randomized, Double-blind, 
Parallel-group, Safety and Efficacy Study of Linaclotide in Pediatric Participants, Ages 6 
to 17 Years, With Irritable Bowel Syndrome with Constipation (IBS-C) and of Linaclotide 
versus Placebo in Pediatric Participants with Functional Constipation (FC) 
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
28
GRD-CLN-T-01-01 v2.0
2.1.
Study Rationale
Functional constipation (FC) is a common healthcare problem in children of all ages, with a 
worldwide prevalence ranging between 0.7% and 29.6% (Koppen 2018). Symptoms include 
infrequent, hard stools, and painful defecation, and affected children may have abdominal pain 
and fecal incontinence, which is usually the result of fecal impaction leading to overflow 
incontinence. These symptoms can have a severe impact on a child’s quality of life and may lead 
to school absenteeism and substantial costs related to healthcare utilization. Initial 
nonpharmacological interventions include education, behavioral modifications, and keeping a 
bowel diary. Despite these interventions, many children require pharmacological interventions. 
Treatment consists of disimpaction (ie, removal of the rectal fecal mass), followed by
maintenance treatment and eventually a weaning phase. Multiple pharmacological agents are 
available for the treatment of FC in children. Despite chronic pharmacological treatment, 
approximately 40% of children with FC referred to a pediatric gastroenterologist remain 
symptomatic after 5 years and 20% of children still have symptoms after 10 years. In some cases, 
symptoms may persist into adolescence or adulthood despite medical treatment. Potential reasons 
for ineffectiveness of treatment include suboptimal dosage regimens, poor compliance with 
treatment, or the use of drugs with action mechanisms that do not address the underlying 
pathophysiological etiology. 
Irritable bowel syndrome (IBS) is characterized by symptoms of abdominal discomfort or pain 
associated with altered bowel movement characteristics (Drossman 2006). In adults, Rome III 
criteria has classified IBS with constipation (IBS-C), IBS with diarrhea, mixed IBS, and 
unsubtyped IBS, depending on the stool consistency (Longstreth 2006). In children, although 
IBS subtypes are encountered in clinical practice, a classification based on stool consistency had 
not been specified at the time the Phase 2 dose ranging study (LIN-MD-63) was originally
developed.
The overall prevalence of IBS in the pediatric population is low. IBS prevalence in children 
across the United States, based on parental reports, ranges from 1.2% to 2.9%, while school-
based studies in Colombia and Sri Lanka found a prevalence of IBS of 4.9% and 5.4%, 
respectively (Hyams 2016). In adults, although not life-threatening, because of its chronic 
relapsing course, IBS is associated with impaired quality of life and high direct and indirect 
medical costs such as absenteeism from work (Thompson 1999). In children and adolescents, 
IBS has been associated with significant impairment as increased rates of school absenteeism, 
health-care utilization and family disruption are common (Chiou and Nurko 2010).
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
29
GRD-CLN-T-01-01 v2.0
The primary objective of this study (LIN-MD-66) is to assess the long-term safety of linaclotide 
administered to participants with FC (total exposure with linaclotide for 24 weeks) or IBS-C 
(total exposure with linaclotide for 52 weeks) who have completed Study LIN-MD-62, 
LIN-MD-63, or LIN-MD-64.
2.2.
Background
2.2.1.
Adult Linaclotide Program
Linaclotide has been developed by the sponsors, Allergan Sales, LLC and Ironwood 
Pharmaceuticals Inc., and is approved at 72 µg and 145 µg doses for the treatment of CIC and 
290 µg dose for the treatment of IBS-C in adults. The adult clinical development program for 
linaclotide that culminated in FDA and EMA approvals included the following studies conducted 
in North America.

4 large double-blind, placebo-controlled Phase 3 registration studies (2 IBS-C studies 
[LIN-MD-31 and MCP-103-302] and 2 CIC studies [LIN-MD-01 and MCP-103-303])

2 long-term adult safety studies (LIN-MD-02 and MCP-103-305), each with 78-week 
study intervention periods

3 randomized, double-blind, placebo-controlled, parallel-group studies (1 IBS-C study
[Phase 3b study MCP-103-312] and 2 CIC studies [Phase 3b study LIN-MD-04 and 
Phase 3 study MCP-103-309]) have been completed.
Safety data from these adult studies showed that, except for diarrhea, the proportion of 
participants reporting a TEAE was similar between placebo and each linaclotide dose group in 
the IBS-C and CIC studies, and the incidence of TEAEs was not dose-related. 
With the exception of the gastrointestinal (GI) System Organ Class (SOC), (due to, as previously
stated, the disproportionately high reporting of diarrhea in patients taking linaclotide), the 
occurrence of TEAEs in the CIC and IBS-C participants was balanced across study intervention 
groups in each SOC for the adult Phase 3, placebo-controlled studies. Diarrhea was the most 
frequently reported TEAE in linaclotide-treated CIC and IBS-C participants, 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 study intervention groups within each indication, and 
there were no SAEs of diarrhea reported. An analysis of the SAEs across the entire clinical 
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
30
GRD-CLN-T-01-01 v2.0
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 study
intervention groups for any of these parameters in the Phase 3 placebo-controlled studies in 
adults.
Additional registration studies were conducted outside of North America, which supported the 
approval of linaclotide for the treatment of IBS-C and CC in Japan and IBS-C only in China.
Results from these studies were consistent with those reported for the studies conducted in 
North America (linaclotide IB). 
2.2.2.
Pediatric Linaclotide Program
A total of 214 pediatric participants were treated with linaclotide in two Phase 2 dose-ranging 
studies in the FC and IBS-C pediatric populations (LIN-MD-62 and LIN-MD-63, respectively).
LIN-MD-62 was a Phase 2, double-blind, placebo-controlled, parallel-group, safety and efficacy
study of a range of linaclotide doses administered to participants 6 to 17 years of age who 
fulfilled modified Rome III criteria for FC (refer to Table 2–1 for dosing information). The 
objective of Study LIN-MD-62 was to evaluate the dose response, safety, and efficacy of 
4 weeks of study intervention with 1 of 3 linaclotide doses (Dose A, B, and C) or 145 µg (as an 
exploratory objective in the adolescent participants 12 to 17 years of age using the approved 
adult dose) compared with placebo in pediatric participants, who fulfilled modified Rome III 
criteria for child/adolescent FC with the goal of selecting an optimal dose of linaclotide to 
evaluate in a confirmatory study.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
31
GRD-CLN-T-01-01 v2.0
Table 2–1
Dose Levels (in Micrograms) by Weight in Pediatric Participants Treated 
with Linaclotide in LIN-MD-62
Age Group
(Dose, µg)
Linaclotide 
Dose A 
N=36
Linaclotide Dose 
B 
N=41
Linaclotide Dose 
C 
N=39
Approved Adult 
Dose
(exploratory)
N=16
Participants 6 to 11 years
18 to < 35 kg
9
18
36
-
≥ 35 kg
18
36
72
-
Participants 12 to 17 years
18
36
72
145
A total of 173 participants were randomized to receive 1 of 3 proposed linaclotide doses
(Dose A, B, or C in 116 participants), the approved adult linaclotide dose (145 µg in 
16 participants), or placebo (41 participants) for 4 weeks of study intervention followed by a 
1-week Postintervention Period. For the primary and key secondary endpoints of the study, none 
of the 3 linaclotide doses (A [low dose], B [medium dose], and C [high dose]) indicated clear 
improvement over placebo (p-value ≥ 0.1502) based on analysis of the ITT Population. However, 
a numerical trend toward efficacy at the higher doses was observed for the primary endpoint of 
change from baseline in 4-week overall SBM frequency rate (SBMs/week). Overall, linaclotide 
was well tolerated across all doses and both age groups. The safety profile was consistent with 
prior adult linaclotide studies for CIC. The most frequently reported TEAE was diarrhea, which 
occurred in 7.6% of linaclotide-treated participants versus 0% in the placebo group. The majority
of the TEAEs of diarrhea reported were mild; none were severe. In the 12 to 17 years of age 
group, one participant experienced moderate diarrhea (related) leading to discontinuation in the 
linaclotide Dose C group.
There were no reported AESIs (ie, significant volume depletion and/or significant electrolyte 
abnormalities and/or ECG abnormalities that are considered by the investigator or sponsor to be 
related to diarrhea) or deaths. There were 2 SAEs, neither of which were diarrhea, in participants 
in the 12-17 years of age group, neither were considered related to study intervention. In the 
younger pediatric participants, 6 to 11 years of age, no SAEs or AEs leading to discontinuation 
were reported.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
32
GRD-CLN-T-01-01 v2.0
As with adults, linaclotide is minimally absorbed with low systemic availability in this pediatric 
population.
LIN-MD-63 was a Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-
group, safety and efficacy dose-ranging study of linaclotide in children ages 7 to 17 years with 
IBS-C. The objectives of LIN-MD-63 were to evaluate the dose response, safety, and efficacy of 
4 weeks of treatment with 1 of 3 linaclotide doses (Dose A, B, or C; refer to Table 2-2 for dosing 
information) or 290 g (as an exploratory objective in the adolescent participants, 12 to 17 years 
of age, using the approved adult dose) compared with placebo in pediatric participants 7 to 
17 years of age who fulfill the Rome III criteria for child/adolescent IBS and modified Rome III 
criteria for child/adolescent FC.
According to the original study design, approximately 260 participants with IBS-C were planned 
to be randomized in this study. However, due to slow participant enrollment, this study was 
terminated early based on FDA’s feedback (Type C Meeting for pediatric IBS-C, June 2019). 
The actual sample size achieved was 101 randomized participants, which is approximately 39% 
of the original planned sample size. These 101 IBS-C participants were randomized to receive 1 
of 3 proposed linaclotide doses (Dose A, B, and C) for pediatrics (n = 74 participants), the 
approved adult linaclotide dose (290 µg, n = 8 participants), or placebo (n = 19 participants) for 
4 weeks of study intervention. For the primary efficacy endpoint of change from baseline in 
4-week overall SBM frequency rate, numerical improvement was observed with each increasing 
linaclotide dose compared with placebo based on analysis of the ITT population. For the key
secondary efficacy endpoint of change from baseline in 4-week abdominal pain daytime 
symptoms, numerical improvement was observed with linaclotide 290 µg compared with 
placebo, while results were similar in the other linaclotide groups (Dose A, B, and C) compared 
with placebo.
Overall, linaclotide was safe and well tolerated across all doses and both age groups. The safety 
profile was consistent with prior adult linaclotide studies for IBS-C. The most commonly
reported TEAE was diarrhea. The majority of the TEAEs of diarrhea reported were mild; none 
were severe. In participants 12 to 17 years of age, AEs leading to discontinuation were reported 
in 1 participant in the linaclotide Dose B group (diarrhea [related]) and 1 participant in the 
placebo group (abdominal pain, anaphylactic reaction [SAE], and hematemesis; all considered 
not related to study treatment). There were no AESIs (ie, significant volume depletion and/or 
significant electrolyte abnormalities and/or ECG abnormalities that are considered by the 
investigator or sponsor to be related to diarrhea) or deaths reported. There were 2 SAEs reported 
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
33
GRD-CLN-T-01-01 v2.0
in participants 12-17 years of age (1 each in the placebo and linaclotide Dose A [36 µg] groups), 
neither of which were diarrhea, and neither were considered related to study intervention. 
Moreover, in pediatric participants 7 to 11 years of age, no SAEs or AEs leading to 
discontinuation were reported.
As with adults, linaclotide is minimally absorbed with low systemic availability in this pediatric 
population.
Table 2-2
Dose Levels (µg) by Weight in Pediatric IBS-C Participants Treated with 
Linaclotide in LIN-MD-63
Age Group
(years)
Weight
(kg)
Linaclotide 
Dose A (µg) 
N = 29
Linaclotide 
Dose B (µg)
N = 21
Linaclotide 
Dose C (µg) 
N = 24
Approved Adult 
Dose (µg)
N = 8
7–11
18 to <35
18
36
72
–
≥35
36
72
145
–
12–17
N/A
36
72
145
290
Additional information from studies conducted with linaclotide can be found in the 
linaclotide IB.
2.2.3.
Other Nonclinical Information
2.2.3.1.
Non-clinical Toxicology
In nonclinical studies, oral administration of linaclotide at 10 µg/kg/day caused deaths in young 
neonatal mice (human age equivalent of approximately 0 to 28 days old). These deaths were due 
to rapid and severe dehydration produced by significant fluid shifts into the intestinal lumen 
resulting from GC-C agonism in neonatal mice. Supplemental subcutaneous fluid administration 
prevented death after linaclotide administration in neonatal mice. Tolerability to linaclotide 
increases with age in juvenile mice. In 2-week-old mice, linaclotide was well tolerated at a dose 
of 50 µg/kg/day, but deaths occurred after a single oral dose of 100 µg/kg. In 3-week-old mice, 
linaclotide was well tolerated at 100 µg/kg/day, but deaths occurred after a single oral dose of 
600 µg/kg. Significantly higher doses (≥ 200 times the clinically relevant adult dose) were 
tolerated in 4-week-old juvenile mice, human age equivalent of approximately > 2 to 7 years of 
age without supplemental fluid administration. Based on these nonclinical results, the Linzess PI
has a contraindication in pediatric patients less than 6 years of age and a boxed warning 
regarding its use in pediatric patients.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
34
GRD-CLN-T-01-01 v2.0
2.2.3.2.
GC-C mRNA Expression
Prior research suggested GC-C receptors may be present in younger children at a greater density
than in adults (Guarino 1987; Cohen 1988). Greater GC-C receptor density in childhood could 
result in amplification of the pharmacological effects of GC-C activation, with important clinical 
implications for treating children with a GC-C agonist. Study MCP-103-311 was conducted to 
measure GC-C mRNA levels in duodenal and colonic mucosal tissue samples obtained from 
children 0 to < 18 years of age who underwent endoscopy or colonoscopy. Four different age 
groups were evaluated (ie, birth to < 24 months, 24 months to < 6 years, 6 years to < 12 years, 
and 12 years to < 18 years). 
The results showed that there was no trend toward an increase or decrease in GC-C mRNA
expression based on age in either duodenal or colonic tissues. Along with results in LIN-MD-62 
(Section 2.2.2), these results from study MCP-103-311 support a flat dosing approach for 
pediatric participants in the Phase 3 pediatric studies and not a body weight-based approach.
2.2.4.
Post-marketing Experience
In post-marketing experience, severe diarrhea AEs associated with dizziness, syncope, 
hypotension, and electrolyte abnormalities (hypokalemia and hyponatremia) requiring 
hospitalization or IV fluid administration have been reported in adult patients treated with 
linaclotide.
2.3.
Benefit/Risk Assessment
Although not life threatening, FC is a common healthcare problem in children of all ages, with a 
worldwide prevalence ranging between 0.7% and 29.6% (Koppen 2018). Symptoms include 
infrequent, hard stools, and painful defecation, and affected children may have abdominal pain 
and fecal incontinence, which is usually the result of fecal impaction leading to overflow 
incontinence. These symptoms can have a severe impact on a child’s quality of life and may lead 
to school absenteeism and substantial costs related to healthcare utilization. 
The overall prevalence of IBS in the pediatric population is low. IBS prevalence in children 
across the United States, based on parental reports, ranges from 1.2% to 2.9%, while school-
based studies in Colombia and Sri Lanka found a prevalence of IBS of 4.9% and 5.4%, 
respectively (Hyams 2016). In adults, although not life-threatening, because of its chronic 
relapsing course, IBS is associated with impaired quality of life and high direct and indirect 
medical costs such as absenteeism from work (Thompson 1999). In children and adolescents, 
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
35
GRD-CLN-T-01-01 v2.0
IBS has been associated with significant impairment as increased rates of school absenteeism, 
health-care utilization and family disruption are common (Chiou and Nurko 2010).
Linaclotide has a safety profile that has been well established in adults with IBS-C and CIC. 
Moreover, the safety profiles in the first completed pediatric linaclotide studies in FC, 
LIN-MD-62, and IBS-C, LIN-MD-63, were consistent with prior adult linaclotide studies in 
CIC and IBS-C, respectively. There were no new safety signals observed in the pediatric 
participants and linaclotide was well tolerated across all doses and age groups. Refer to the IB
for a more detailed description of the chemistry, pharmacology, efficacy, and safety of 
linaclotide, based on studies conducted in animals, healthy volunteers, and in participants with 
IBS-C and CIC (linaclotide IB).
There are no pharmacologic therapies approved in the pediatric population specifically for the 
treatment of FC or IBS-C. Thus, there is a need for new agents with favorable safety and 
tolerability profiles that are effective in providing relief at the same time for the symptoms 
associated with FC and IBS-C in pediatric patients. 
Linaclotide provides an important treatment option for adult patients with CIC and IBS-C and 
may offer a therapeutic option to treat the symptoms in the pediatric population with FC and 
IBS-C. The sponsors consider the benefit-risk balance to be favorable and supports further 
clinical development of linaclotide as a treatment for FC or IBS-C in the pediatric population.
See Section 4, Study Design for details of study procedures, dose, and study design justification.
3.
Objectives and Assessments
Objectives
Assessments
Primary
The objective of this study is to assess the long-term
safety of linaclotide in pediatric participants with FC 
(total exposure with linaclotide for 24 weeks) or IBS-C 
(total exposure with linaclotide for 52 weeks) who have 
completed Study LIN-MD-62, LIN-MD-63, or 
LIN-MD-64. 
The safety assessments will include monitoring of 
adverse events (AEs), clinical laboratory assessments 
(clinical chemistry, complete blood count [CBC], 
urinalysis), vital sign measurements (including 
postural vital signs), electrocardiograms (ECGs), 
physical examinations, height, and weight.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
36
GRD-CLN-T-01-01 v2.0
4.
Study Design
4.1.
Overall Design
LIN-MD-66 is a long-term safety study with 24 weeks (FC participants) or 52 weeks (IBS-C 
participants) of linaclotide exposure that will enroll pediatric participants (6-17 years of age) 
with FC or IBS-C who completed study intervention in Phase 2 study LIN-MD-62 or LIN-MD-
63, or Phase 3 study LIN-MD-64, based on the individual study criteria. For FC participants 
enrolling from studies LIN-MD-62 and LIN-MD-64, and IBS-C participants enrolling from 
study LIN-MD-63, linaclotide treatment will be open-label. For IBS-C participants enrolling 
from study LIN-MD-64, linaclotide treatment will be either blinded or open-label. Linaclotide 
treatment will be blinded if participants choose to remain on the same blinded linaclotide dose 
they were receiving in the lead-in LIN-MD-64 study and it will be open-label if participants 
choose to receive open-label linaclotide therapy.

Phase 2 completers are defined as pediatric participants who completed 4-week 
double-blind study intervention and EOT Visit (Visit 5) in the Phase 2 studies AND:
o
Completed the EOS (Visit 6) in Study LIN-MD-62 or
o
Completed the EOS (Visit 6) in Study LIN-MD-63. However, the EOS Visit is not 
required for participants who enroll prior to that visit.

Phase 3 completers are pediatric participants who completed 12-week double-blind study
intervention in Study LIN-MD-64. Participants must have completed the EOT Visit 
(Visit 7) and the EOS Visit (Visit 8). However, the EOS visit is not required for 
participants who enroll prior to that visit. 
The present study will include a screening period and a 24-week (FC participants) or 52-week 
(IBS-C participants) study intervention period (Section 1.2 and Section 1.3, respectively). For 
participants who enroll in LIN-MD-66 on the same day as their EOT Visit or EOS Visit in LIN-
MD-63 or LIN-MD-64, the EOT Visit or EOS Visit, respectively, may be combined with the 
Screening Visit (Visit 1) and Day 1 Visit (Visit 2) in LIN-MD-66. For participants who enroll 
within ≤ 28 days (inclusive) from last study intervention in Study LIN-MD-64 (Visit 7) or Study
LIN-MD-63 (Visit 5), the LIN-MD-66 Screening Visit (Visit 1) and Day 1 Visit (Visit 2) 
procedures may be combined, with the exception of participants who are positive for fecal 
impaction assessment at the Screening Visit (Visit 1).
All participants are required to have a fecal impaction assessment prior to dosing. For those 
participants who do not combine Visit 1 and Visit 2, a fecal impaction assessment will be 
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
37
GRD-CLN-T-01-01 v2.0
performed at the Screening Visit (Visit 1) and at the Day 1 Visit (Visit 2) prior to dosing. Please 
refer to Section 8.2.1 for further details.
Participants who turn 18 years of age during study LIN-MD-63 or LIN-MD-64, or after 
completing the lead-in study, may be eligible if they enroll within 28 days (inclusive) of the last 
day of study intervention in the lead-in study (Study LIN-MD-64 [Visit 7] or Study LIN-MD-63 
[Visit 5]). Such participants will be dosed as 17-year-old participants; refer to the Intervention 
Groups and Study Duration section below for dosing.
Number of Participants:
At least 120 participants are planned to be enrolled to receive 24 weeks (FC participants) or 
52 weeks (IBS-C participants) of linaclotide study intervention. However, the actual number of 
participants in this study will depend on the number of participants who have completed study 
intervention in the lead-in study (LIN-MD-62, LIN-MD-64, and LIN-MD-63) and enroll into this 
long-term safety study after fulfilling the eligibility criteria.
Number of Sites:
Up to 120 sites from the United States, Canada, Europe, and the Middle East will have an option 
to participate in the study.
Intervention Groups and Study Duration:
FC participants (LIN-MD-62 and LIN-MD-64 completers) will receive open-label linaclotide 
72 µg or 145 µg once daily for 24 weeks as follows based on their age at the time of enrollment 
into LIN-MD-66:

6 to 11 years of age: 72 µg linaclotide

12 to 17 years of age: will be randomly assigned at 1:1 ratio to 72 µg linaclotide or 145 µg 
linaclotide
IBS-C participants will receive linaclotide for 52 weeks as follows: 

LIN-MD-63 completers will receive open-label linaclotide 290 µg once daily except for 
the LIN-MD-63 completers who had received ≤145 µg linaclotide or placebo. These 
participants will have the option to receive open-label linaclotide 145 µg once daily.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
38
GRD-CLN-T-01-01 v2.0

LIN-MD-64 completers will have the option to either remain on the same blinded
linaclotide dose they were receiving in lead-in study LIN-MD-64 or to receive open-label
290 µg linaclotide. Study intervention in LIN-MD-66 is assigned via IWRS; treatment 
assignments for LIN-MD-64 completers who choose to remain on the same blinded 
linaclotide dose in long-term safety study LIN-MD-66 will remain blinded to participants, 
investigators, and all site personnel during the study.
o
LIN-MD-64 completers who choose to remain on the same blinded linaclotide dose 
received in the lead-in study LIN-MD-64 will continue to receive blinded linaclotide 
145 or 290 µg once daily.
o
LIN-MD-64 completers who choose to receive open-label linaclotide therapy will 
receive linaclotide 290 µg once daily.
Participants will be instructed to take their assigned dose orally as a single daily dose at 
approximately the same time each day, 30 minutes prior to any meal, except for the Day 1 Visit, 
at which the linaclotide dose will be administered in the clinic.
Participants who took their last dose of lead-in study intervention on the day of the EOT Visit 
and enroll into LIN-MD-66 on that same day will take their first dose of LIN-MD-66 study
intervention outside of the clinic the following day, at approximately the same time as the last 
dose in the lead-in study. Qualified site personnel will complete a follow-up phone call to 
participants within 48 hours following initial study intervention administration to assess safety.
Dose modifications permitted for FC and IBS-C participants are described in Section 6.6.
Detailed descriptions of each study visit can be found in the SoA (Section 1.4 for FC 
participants, Section 1.5 for IBS-C participants) and Section 10.10.
4.2.
Scientific Rationale for Study Design
The Phase 2 studies LIN-MD-62, LIN-MD-63, and the Phase 3 study, LIN-MD-64 will provide 
placebo-controlled information on the safety and efficacy of linaclotide for the treatment of 
pediatric participants with FC and IBS-C. This study, LIN-MD-66, will provide additional 
information on the long-term safety of linaclotide in the 6 to 17-year-old pediatric population.
4.3.
Justification for Doses
The linaclotide dosages chosen for FC participants in this long-term safety study (72 and 145 µg) 
were well tolerated among participants 6 to 17 years of age with FC in LIN-MD-62. The safety 
profile was consistent with prior adult linaclotide studies for CIC. FC participants 6 to 17 years of 
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
39
GRD-CLN-T-01-01 v2.0
age who complete either LIN-MD-62 or LIN-MD-64, will have the option to enroll into this 
study. FC participants, 6 to 11 years of age, will receive open-label 72 µg linaclotide. FC 
participants, 12 to 17 years of age, will be randomly assigned open-label linaclotide at a 1:1 ratio 
to 72 µg linaclotide or 145 µg linaclotide. 
The linaclotide doses of 290 µg or 145 µg once daily chosen for IBS-C participants in this long-
term safety study were well tolerated among participants 12 to 17 years of age (290 µg dose) and 
6 to 17 years of age (145 µg dose) with IBS-C in LIN-MD-63. The safety profile was consistent 
with prior adult linaclotide studies for IBS-C. While the 290 µg linaclotide dose is the highest dose 
being evaluated in IBS-C participants 6 to 17 years of age in the lead-in Phase 3 study LIN-MD-
64, LIN-MD-63 completers who received ≤145 µg linaclotide or placebo in LIN-MD-63 will 
have the option to receive open-label linaclotide 145 µg once daily for 52 weeks. LIN-MD-64 
completers with IBS-C will have the option to either remain on the same blinded linaclotide dose 
they were receiving in lead-in study LIN-MD-64 (blinded linaclotide 290 µg or 145 µg once
daily) or to receive open-label linaclotide 290 µg once daily. 
Dose modifications permitted for FC and IBS-C participants are described in Section 6.6. 
4.4.
End of Study Definition
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the SoA for the last participant in the study globally.
A participant is considered to have completed the study if he/she has completed all visits in the 
study including the last visit.
5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers, is not permitted.
Participants who have completed the lead-in Phase 2 (LIN-MD-62 or LIN-MD-63) or Phase 3 
(LIN-MD-64) studies must meet all the inclusion and exclusion criteria as described in the 
following sections.
Where applicable for this pediatric population, the term “participant” refers to the participant, 
parent, guardian, legally authorized representative (LAR), and/or caregiver.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
40
GRD-CLN-T-01-01 v2.0
5.1.
Inclusion Criteria
Specific inclusion and exclusion criteria are presented individually for the following participant 
populations who completed the following studies per the individual protocols. 
5.1.1.
General Inclusion Criteria (All Participants)
1.01
Participant weighs ≥18 kg at the time the parent/guardian/LAR and/or caregiver has 
provided signed consent.
1.02
Female participants who have had their first menstrual period and are sexually active 
must agree to use a reliable form of contraception. Reliable contraception is defined 
in Appendix 7.
1.03
Male or female participants must be 6 to 17 years of age (inclusive), at the time the 
parent/guardian/LAR and/or caregiver provides written informed consent and the 
participant must provide assent before the initiation of any study-specific procedures.
1.04
Participants must have completed study intervention in their lead-in study as defined 
in Section 4.1.
1.05
Female participants of childbearing potential must have a negative pregnancy test at 
both Screening (Visit 1) and at Study Day 1 (Visit 2) (Section 1.4 [SoA] and 
Section 10.7).
5.1.2.
Inclusion Criteria for Phase 3 LIN-MD-64 Completers and Phase 2 LIN-MD-63 
Completers Who Enroll in LIN-MD-66 Within ≤28 Days From Last Study 
Intervention
2.01
Participants who turn 18 years of age prior to enrollment must provide consent for the 
study.
5.1.3.
Inclusion Criteria for Phase 2 LIN-MD-62 or Phase 2 LIN-MD-63 and Phase 3 
LIN-MD-64 Completers Who Enroll in LIN-MD-66 After > 28 Days From Last 
Study Intervention
3.01
Female participants of childbearing potential must have a negative serum pregnancy
test at the Screening Visit (Visit 1) and negative urine pregnancy test prior to the first 
dose on the Day 1 Visit (Visit 2).
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
41
GRD-CLN-T-01-01 v2.0
3.02
This criterion has been removed.
3.03
This criterion has been removed.
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
5.2.1.
General Exclusion Criteria (All Participants)
1.01
Participant has an unresolved AE or a clinically significant finding on a physical 
examination or vital sign assessment along with ECG or clinical laboratory tests (if 
results are available by the time of enrollment) that; in the opinion of the investigator, 
could represent a safety concern or a condition that would be exclusionary, could 
prevent the participant from performing any protocol assessments, or could confound 
study assessments.
1.02
Participant has a known allergy or sensitivity to the study intervention or its 
components or other medications in the same drug class.
1.03
Participant is not willing or able to abide by the restrictions regarding concomitant 
medicine use defined in Section 6.5.
1.04
Participant received an investigational drug, other than linaclotide, during the 30 days 
before the Screening Visit (Visit 1) or is planning to receive an investigational drug 
(other than that administered during this study) or use an investigational device at any 
time during the study.
1.05
Female participants who are currently pregnant or nursing, or plan to become 
pregnant or nurse during the clinical study.
1.06
Participant has fecal impaction at the Day 1 Visit (Visit 2).
1.07
Participant has required manual disimpaction any time prior to study intervention.
1.08
Participant has any of the following conditions:
a) Down's syndrome or any other chromosomal disorder
b) Anatomic malformations (eg, imperforate anus, anal stenosis, anterior displaced 
anus) 
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
42
GRD-CLN-T-01-01 v2.0
c) Intestinal nerve or muscle disorders (eg, Hirschprung disease, visceral 
myopathies, visceral neuropathies)
d) Neuropathic conditions (eg, spinal cord abnormalities, neurofibromatosis, tethered 
cord, spinal cord trauma)
e) Neurodevelopmental disabilities (early-onset, chronic disorders that share the 
essential feature of a predominant disturbance in the acquisition of cognitive, 
motor, language, or social skills, which has a significant and continuing impact on 
the developmental progress of an individual) producing a cognitive delay that 
precludes comprehension by the participant
1.09
Participant has an acute or chronic condition that, in the investigator's opinion, would 
limit the participants’ ability to complete or participate in this clinical study.
1.10
The participant has a condition or is in a situation which, in the investigator’s opinion, 
may put the participant at significant risk, may confound the study results, or may
interfere significantly with the participant’s participation in the study.
1.11
Participant has a known or suspected mechanical bowel obstruction or pseudo-
obstruction.
1.12
Participant currently has both unexplained and clinically significant alarm symptoms
(lower GI bleeding [rectal bleeding or heme-positive stool], iron-deficiency anemia, 
or any unexplained anemia, or weight loss) and systemic signs of infection or colitis, 
or any neoplastic process.
1.13
Participant has an active anal fissure (Note: history of anal fissure is not an 
exclusion).
1.14
Participant has had surgery that meets any of the following criteria:
a) Bariatric surgery for treatment of obesity, or surgery to remove a segment of the 
GI tract at any time before the Screening Visit (Visit 1).
b) Surgery of the abdomen, pelvis, or retroperitoneal structures during the 6 months 
before the Screening Visit (Visit 1)
c) An appendectomy or cholecystectomy during the 60 days before the Screening 
Visit
d) Other major surgery during the 30 days before the Screening Visit (Visit 1)
1.15
This criterion has been removed.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
43
GRD-CLN-T-01-01 v2.0
1.16
This criterion has been removed.
5.2.2.
Exclusion Criteria for LIN-MD-62, LIN-MD-63 and LIN-MD-64 Completers
Who Enroll in LIN-MD-66 > 28 Days From Last Study Intervention
2.01
Participant has a history of nonretentive fecal incontinence.
2.02
This criterion has been removed.
2.03
Participant has a history of drug or alcohol abuse.
2.04
Participant has any of the following conditions:
a) Celiac disease, or positive serological test for celiac disease and the condition has 
not been ruled out by endoscopic biopsy 
b) Cystic fibrosis
c) Hypothyroidism that is untreated or treated with thyroid hormone at a dose that 
has not been stable for at least 3 months prior to the Screening (Visit 1) 
d) Lead toxicity, hypercalcemia
e) Inflammatory bowel disease
f)
Childhood functional abdominal pain syndrome
g) Childhood functional abdominal pain 
h) Poorly treated or poorly controlled psychiatric disorders that might influence his 
or her ability to participate in the study
i)
Lactose intolerance that is associated with abdominal pain or discomfort and 
could confound the assessments in this study
j)
History of cancer other than treated basal cell carcinoma of the skin. (Note: 
Participants with a history of cancer are allowed provided that the malignancy has 
been in a complete remission for at least 5 years before the Randomization Visit. 
A complete remission is defined as the disappearance of all signs of cancer in 
response to treatment.)
k) History of diabetic neuropathy
2.05
Participants who have positive urine drug screen results for cocaine, barbiturates, 
opiates, or cannabinoids.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
44
GRD-CLN-T-01-01 v2.0
Rationale for Inclusion and Exclusion Criteria
The inclusion and exclusion criteria are meant to identify a population of participants that is well 
characterized as having FC or IBS-C symptoms as defined by Rome III criteria. This population
has been previously studied in studies LIN-MD-62, LIN-MD-63, or LIN-MD-64 during which 
the safety and efficacy of study intervention was assessed.
5.3.
Lifestyle Considerations
Not applicable.
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered into the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any
SAE.
Individuals who do not meet the criteria for participation in this study (screen failures) may be 
rescreened under special circumstances (eg, failure to meet prohibited medication requirements). 
All requests for rescreening must be sent to the sponsor for approval.
6.
Study Intervention
Study intervention is defined as any study intervention(s), marketed product(s), or placebo 
intended to be administered to a study participant according to the study protocol.
The study intervention in this study does not have marketing authorization in the EU for the 
pediatric indication.
6.1.
Study Intervention Administered
Linaclotide in the form of capsules will be packaged in bottles and provided by the sponsor. 
Participants will be instructed to take their assigned dose orally as a single daily dose at 
approximately the same time each day, 30 minutes prior to any meal, except for the Day 1 Visit, 
at which the linaclotide dose will be administered in the clinic. Confirmation will be recorded in 
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
45
GRD-CLN-T-01-01 v2.0
the source documents that the dosing regimen and dosing instructions were discussed with the 
participant and caregiver.
Throughout the study, it is recommended that participants take linaclotide at approximately the 
same time each day.
Study Intervention Name
Linaclotide 
Dosage Formulation
Capsules
Unit Dose Strength
72 µg, 145 µg, or 290 µg
Route of Administration 
Oral; capsule may be taken whole, or sprinkled into 30 mL of bottled water or 
applesauce for participants who do not wish to take a capsule
Dosing Instructions
Single dose, once daily at the same time each day, 30 minutes before any meal,
except for the Day 1 Visit, at which the linaclotide dose will be administered in 
the clinic. Instructions for sprinkled dose are provided in Appendix 8.
Packaging and Labeling
All bottles will be labeled with the protocol number, storage information, and 
warning language (viz, “Caution: New Drug—Limited by Federal Law to 
Investigational Use, Keep out of Reach of Children”)
Manufacturer
Forest Laboratories Ireland, Limited
Immediately before dispensing the study intervention, the investigator (or appropriately trained 
designee) will write the participant’s initials, the participant number, and the date on the label.
6.2.
Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention, and only
authorized site staff may supply or administer study intervention. All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to 
the investigator and authorized site staff.
3. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the Study Reference Manual or other specified location.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
46
GRD-CLN-T-01-01 v2.0
5. Study intervention in bottles containing solid oral capsules must be stored at the study site 
in an appropriate secure area (eg, a locked cabinet in a locked room) at 25°C (77°F); 
excursions are permitted between 15°C and 30°C (59°F to 86°F). Keep the 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.
6. The investigator or designee is responsible for recording the receipt and use of all study
intervention supplied and for ensuring the supervision of the storage and allocation of 
these supplies. All unused study intervention must be returned and, whenever study
intervention is returned, unit counts must be performed. All study intervention must be 
accounted for. At the end of the study, all unused study intervention and empty study
intervention bottles should be returned to the sponsor or the local distributor at the address 
provided in the Study Reference Manual.
6.3.
Measures to Minimize Bias: Randomization and Blinding
Participants with FC, 12 to 17 years of age, will be randomly assigned at a 1:1 ratio to 72 µg 
linaclotide or 145 µg linaclotide.
6.3.1.
Blinding and Unblinding
6.3.1.1.
Blinding
Study intervention in LIN-MD-66 is assigned via IWRS. For LIN-MD-64 completers with 
IBS-C who choose to remain on the same blinded linaclotide dose they were receiving in the 
lead-in study LIN-MD-64, participants, investigators, and all site personnel will remain blinded 
to the individual treatment assignments until all subjects have completed the study and the 
database has been locked, except in the case of emergency unblinding described below.  
6.3.1.2.
Unblinding
Any unblinding at the study site level should be done only in an emergency that requires the 
study intervention to be identified for the medical management of the participant. In case of an 
emergency, the investigator has the sole responsibility for determining if unblinding of a 
participant’s intervention assignment is warranted. Participant safety must always be the first 
consideration in making such a determination. If the investigator decides that unblinding is 
warranted, the investigator is encouraged to contact the sponsor prior to unblinding a 
participant’s study intervention assignment unless this could delay emergency treatment of the 
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
47
GRD-CLN-T-01-01 v2.0
participant (see Section 10.3). If a participant’s intervention assignment is unblinded, the sponsor 
must be notified within 24 hours after breaking the blind. The date and reason that the blind was 
broken must be recorded in the source documentation and eCRF, as applicable. Intervention 
codes may be broken by Global Patient Safety and Epidemiology for regulatory reporting 
purposes. In such cases, the study staff will be kept blinded and the participant will not need to 
be discontinued from study drug.
For IWRS Unblinding
In an emergency, the investigator can obtain the intervention assignment of any participant at his 
or her study site through the IWRS. In an emergency, the investigator will access the IWRS to 
break the blind and record the unblinding.
6.4.
Study Intervention Compliance
For home dosing, study intervention compliance will be closely monitored by counting the 
number of capsules dispensed and returned. Before dispensing new study intervention at each 
visit, study site personnel will make every effort to collect all unused study intervention and 
empty bottles.
The study site will keep an accurate drug disposition record that specifies the amount of study
intervention administered to each participant and the date of administration.
Study intervention compliance will be assessed through participant/caregiver and study site staff 
discussion at study visits and recorded on the eCRF. Every effort will be made to collect all 
unused study intervention at the final visit.
6.5.
Prior and Concomitant Therapy
Prior medicine is defined as any medicine taken before the date of the first dose of study
intervention in this study (LIN-MD-66). Concomitant medication is defined as any medication 
taken on or after the date of the first dose of study intervention in this study. Any medication 
started after last dose date will not be included in the summary of concomitant medications but 
will be included in the listing.
The use of both prior and concomitant medications will be summarized as the number and 
proportion of participants who took a particular medication within each therapeutic class. 
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
48
GRD-CLN-T-01-01 v2.0
Multiple medication use by a participant in the same category (based on Anatomical Therapeutic 
Chemical classification) will only be counted once.
For all participants, any changes in concomitant medications or new medications added will be 
recorded in the eCRF at visits throughout the study.
The following medicines are excluded during the study, including screening and study 
intervention periods:

Lubiprostone

Plecanatide

Prucalopride

Narcotics either alone or in combination (eg, tramadol, codeine, morphine, propoxyphene, 
loperamide, diphenoxylate, paregoric) if they are being used chronically (ie, 5 days or 
longer) and are expected to be taken indefinitely in the future 
Any investigational or imported drugs that have not been approved for human use.
6.6.
Dose Modification
At the discretion of the investigator, any participant who experiences an AE intolerable enough 
to prompt a consideration of study withdrawal may receive a temporary suspension of dosing.
The duration of a dosing suspension will be at the investigator’s discretion; however, after a 
participant has been off study intervention for 3 days, or if the participant requires a suspension 
of dosing on more than 1 occasion, the investigator must contact the sponsor to discuss the 
participant’s continued participation in the study.
Participants who experience an intolerable AE that may be related to the use of linaclotide can be 
dose reduced one dose level only during the course of the study at the investigator’s discretion as 
shown in Table 6-1. Subsequent dose adjustments (between the initial dose and reduced dose) are 
also permitted at the investigator’s discretion. Participants receiving blinded linaclotide treatment 
will be dose adjusted in a blinded fashion via IWRS.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
49
GRD-CLN-T-01-01 v2.0
Table 6-1
Dose Reductions
IBS-C
FC
Open-label (µg)
Blinded (µg)
Open-label (µg)
Initial dose
290
145
290
145
145
72
Reduced dose 
145
72
145
72
72
N/A
The decision of whether to temporarily suspend dosing or dose reduce following the occurrence 
of an intolerable AE is per the investigator’s discretion.
6.7.
Intervention after the End of the Study
No intervention is planned after the end of the study.
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1.
Discontinuation of Study Intervention
A premature discontinuation will occur when a participant who gave voluntary assent and whose 
parent/guardian/LAR and/or caregiver gave consent ceases participation in the study, regardless 
of circumstances, before the completion of the protocol-defined study procedures. 
Definitions of the standard terms that may lead to discontinuations are provided in Appendix 5.
See the SoAs for data to be collected at the time of intervention discontinuation and follow-up 
and for any further evaluations that need to be completed.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
50
GRD-CLN-T-01-01 v2.0
Reasons for discontinuation from the study intervention and/or the study may include the 
following commonly used or other acceptable terms:
Commonly Used Terms
Other Acceptable Terms
AE
Death
Completed
Disease relapse
Lack of efficacy
Progressive disease
Lost to follow-up
Recovery
Other
Technical problems
Physician decision
Withdrawal by parent/guardian
Pregnancy
Screen failure
Site terminated by sponsor
Study terminated by sponsor
Withdrawal by participant
7.1.1.
Removal of Individual Participants from Therapy or Assessment
Participants must be prematurely discontinued from the study for reasons of safety including 
those who experience:

An SAE considered by the investigator or the sponsor to be possibly related or related to 
study intervention

An AESI (evidence of significant volume depletion and/or significant electrolyte and/or 
ECG abnormalities that are considered by the investigator or sponsor to be related to 
diarrhea) related to the study intervention (ie, treatment-related AESIs) 

Pregnancy

Presence of intentional overdose or intentional misuse per investigator discretion

The occurrence of any other AE that in the opinion of the investigator or the sponsor is 
possibly related or related to the study intervention that represents a clinically significant 
safety risk to the participant
Participants may also be prematurely discontinued from the study for reasons of safety including 
those who experience:

A vital sign, ECG, and/or laboratory abnormality judged to be clinically significant by the 
investigator and that, in the opinion of the investigator or the sponsor, is possibly related 
or related to the study intervention
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
51
GRD-CLN-T-01-01 v2.0

An intolerable AE (defined as an AE that subjectively would cause a patient to consider 
study withdrawal), see Section 8.3
Additionally, discontinuation of study intervention for abnormal liver function should be 
considered by the investigator when a participant meets the criteria for Hy’s law or the 
appearance of abnormal laboratory test results suggesting severe drug-induced liver injury
(DILI) (refer to Appendix 9), or if the investigator believes that it is in best interest of the 
participant.
All enrolled participants who prematurely discontinue from the study, regardless of cause, are
required to return for the EOT study assessments. The EOT assessments are defined as 
completion of the evaluations scheduled for all participants.
Participants who discontinue from the study and do not return to the study site for EOT Visit 
must be requested in writing to return to the study site for procedures required at the EOT Visit 
as defined in SoA and return any unused study intervention. A copy of the letter, together with 
the source documentation, will be kept in the investigator’s files. The reason for premature 
discontinuation from the study will be recorded on the Study Termination Page of the eCRF. 
Study site staff will be contacted by the sponsor after each premature discontinuation to ensure 
proper characterization of the reason for discontinuation is captured.
See the SoAs for data to be collected at the time of intervention discontinuation and follow-up 
and for any further evaluations that need to be completed.
7.1.2.
Criteria for Consideration of Study Discontinuation
Monitoring of participant safety data will be performed by the DSMB. Study conduct may be 
interrupted or terminated by the sponsor based on the DSMB recommendation or if, following a 
thorough review of all clinical, laboratory, and other available safety data, safety data become 
available which appear to represent an undue risk to the study participants’ health or well-being.
7.2.
Participant Discontinuation/Withdrawal from the Study
A participant may withdraw from the study at any time at his/her own request, at the request of 
his/her parent/guardian/LAR and/or caregiver or may be withdrawn at any time at the discretion 
of the investigator for safety, behavioral, compliance, or administrative reasons.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
52
GRD-CLN-T-01-01 v2.0
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.
If a participant withdraws from the study, he/she or his/her parent/guardian/LAR and/or 
caregiver may request destruction of any samples taken and not tested, and the investigator must 
document this in the site study records.
See the SoA for data to be collected at the time of study intervention discontinuation and follow-
up and for any further evaluations that need to be completed.
7.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and/or the parent/guardian/LAR and/or 
caregiver and reschedule the missed visit as soon as possible and counsel the participant
on the importance of maintaining the assigned visit schedule and ascertain whether or not 
the participant wishes to and/or should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts will be documented in the participant’s 
source record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.
8.
Study Assessments and Procedures

Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
53
GRD-CLN-T-01-01 v2.0

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the informed consent form (ICF) may be utilized for 
screening or baseline purposes provided the procedures met the protocol-specified criteria 
and were performed within the timeframe defined in the SoA.

The maximum amount of blood collected from each participant over the duration of the 
study will not exceed 5 mL for Phase 2 LIN-MD-63 and Phase 3 LIN-MD-64 participants 
who enroll in LIN-MD-66 within ≤28 days of last study intervention in the lead-in studies
and will not exceed 10 mL for LIN-MD-62, LIN-MD-63, or LIN-MD-64 completers who 
enroll in LIN-MD-66 > 28 days from last study intervention. Repeat or unscheduled 
samples may be taken for safety reasons or for technical issues with the samples.

Additional details regarding study conduct during the novel coronavirus pandemic are 
provided in Appendix 11.
8.1.
Efficacy Assessments
Rome III criteria will be assessed by the investigator at the Screening Visit (Visit 1) and at the 
end of the study intervention period at the EOT Visit (Visit 7 for FC participants and Visit 10 for 
IBS-C participants) as an additional efficacy assessment.

For participants who enroll in LIN-MD-66 within ≤28 days since last study intervention 
in lead-in study LIN-MD-64, the Week 12 Visit/EOT Rome III assessment will be used as 
the Screening Visit assessment in LIN-MD-66. 

For participants who enroll in LIN-MD-66 after > 28 days from last study intervention in 
their lead-in study, Rome III assessment at Screening will be assessed over the 2 month 
period immediately prior to the LIN-MD-66 Screening Visit (Visit 1), or over the 1 month 
period immediately prior to the LIN-MD-66 Screening Visit if 2 months have not elapsed.
A participant will be considered as fulfilling Rome III criteria if a “yes” response is recorded to 
the overall question of whether the participant meets Rome III criteria for FC or IBS-C. For the 
EOT assessment, the criteria will be assessed over the last 4 weeks of the study intervention 
period. In the event a participant discontinues the study prematurely, these criteria will be 
assessed over the last 4 weeks of study intervention, or over the duration of study intervention if 
less than 4 weeks.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
54
GRD-CLN-T-01-01 v2.0
8.2.
Safety Assessments
Participants must be evaluated by a physician or an appropriately trained health care professional 
at every visit and the evaluation must be documented. The procedures discussed below will be 
completed at the designated visits. Safety assessments should not be administered to the 
participant unless the participant is accompanied by his or her consented caregiver.
The safety parameters will comprise physical examination, AEs, clinical laboratory parameters
(clinical chemistry, CBC, urinalysis), vital signs, postural vital signs, height, weight, and ECG.
Evidence of severe diarrhea, especially when accompanied by dehydration, volume depletion 
and/or significant electrolyte or ECG abnormalities will be actively monitored throughout the 
study.
All AEs will be monitored until symptom resolution or until the condition stabilizes. A DSMB 
will oversee AEs and safety of the overall study.
Planned timepoints for all safety assessments are provided in the SoAs (Section 1.4 FC 
participants and Section 1.5 IBS-C participants).
8.2.1.
Physical Examinations
A complete physical examination will be done 

At screening for participants who enroll > 28 days after completion of the lead-in studies

At the EOT Visit for all FC participants (Week 24) and all IBS-C participants (Week 52).
Physical examinations may be repeated at the investigator’s discretion. Any new significant 
physical examination abnormalities for the postbaseline physical examination or worsening of 
the change will be reported as an AE.
A complete physical examination will include, at a minimum, assessments of general 
appearance, skin, HEENT (head, ears, eyes, nose, and throat), neck, thorax/lungs, cardiovascular, 
abdomen, musculoskeletal, lymph nodes, neurologic (including mental status), and visual 
inspection of the lumbosacral and perianal region. Breast and genitourinary examinations are 
optional at the discretion of the investigator. Investigators should pay special attention to clinical 
signs related to previous serious illnesses.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
55
GRD-CLN-T-01-01 v2.0
All participants are required to have a fecal impaction assessment prior to dosing. For those 
participants who do not combine Visit 1 and Visit 2, a fecal impaction assessment will be 
performed at the Screening Visit (Visit 1) and at the Day 1 Visit (Visit 2) prior to dosing. Fecal 
impaction is defined as a hard mass in the lower abdomen identified on physical examination or 
a dilated rectum filled with a large amount of stool on rectal examination. If a rectal examination 
is performed, the medically qualified site personnel should assess for and document the presence 
of anal wink and normal anal tone. If fecal impaction is identified at the Screening Visit (Visit 1), 
Visit 1 and Visit 2 cannot be combined. Participants will receive a disimpaction regimen with 
either oral or rectal medication. The choice of treatment will be determined by the investigator 
after discussing the options with the participant and the caregiver. Options will include any
over-the-counter or prescription laxative, suppository, or enema (eg, polyethylene glycol, 
lactulose, Fleet enema). The fecal impaction assessment will be repeated for all participants at 
Visit 2 (if visits are not combined) prior to study intervention administration. If there is no fecal 
impaction, the participant may enter the study intervention period. If fecal impaction is present 
during the Visit 2 assessment, the participant will not be eligible for the study.
For those participants who plan to combine Visit 1 and Visit 2, a fecal impaction assessment will 
be performed prior to receiving study intervention. If there is no fecal impaction, the participant 
may enter the study intervention period. If fecal impaction is present during this assessment
participants will receive a disimpaction regimen with either oral or rectal medication. The choice 
of treatment will be determined by the investigator after discussing the options with the 
participant and the caregiver. Options will include any over-the-counter or prescription laxative, 
suppository, or enema (eg, polyethylene glycol, lactulose, Fleet enema). The participant will need 
to return for a Visit 2 where the fecal impaction assessment will be repeated. If fecal impaction is 
present during this repeat assessment, the participant will not be eligible for the study.
If fecal impaction is documented during an optional repeat physical examination, the sponsor
must be notified.
8.2.2.
Vital Signs
Refer to the appropriate SoAs for the timing and frequency of height and vital signs 
measurements (Section 1.4 FC participants and Section 1.5 IBS-C participants).
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
56
GRD-CLN-T-01-01 v2.0
Vital signs will be assessed as follows:

Vital signs include weight, temperature (oral, rectal, or tympanic), and respiratory rate. 
Temperature may be recorded as oral, rectal or tympanic (ear). If possible, temperature 
should be obtained using the same method throughout the course of the study.

Postural vital signs (supine and standing) include pulse rate and systolic and diastolic 
blood pressure. At all visits, postural vital signs must be obtained after participants have 
been in a supine position for at least 2 to 3 minutes, followed by a standing position for at 
least 1 minute. 
8.2.3.
Electrocardiograms
A standard 12-lead ECG will be performed at Screening (Visit 1) for participants who complete
LIN-MD-62 and participants who enroll in LIN-MD-66 after > 28 days from last study
intervention in LIN-MD-63 or LIN-MD-64. In addition, ECGs will be performed at the EOT
Visit for all FC participants (Week 24) and all IBS-C participants (Week 52). ECGs will be 
performed and electronically transmitted to a central ECG laboratory for analysis according to 
the instructions provided by the central ECG laboratory. Measurements (in msec) will be 
recorded for the following parameters: heart rate, RR interval, PR interval, QRS duration, and 
uncorrected QT interval. QTcB (Bazett-corrected QT interval) and QTcF (Fridericia-corrected 
QT interval) will be calculated.
Participants with clinically significant ECG abnormalities considered to be secondary to diarrhea 
(ie, an AESI) must be reported to the sponsor within 24 hours on an SAE form if considered to 
be serious. Non-serious events do not require submission on an SAE form; rather, these events 
only need to be entered into the eCRF (Appendix 3).
If the AE is assessed as causally related to the use of study intervention, the participant should be 
discontinued from the study; however, the sponsor and investigator may discuss individual 
participants and AEs to make this determination (Appendix 3).
The overall interpretation and determination of the clinical relevance of ECG findings using the 
central ECG interpretation report will be the responsibility of the investigator and will be 
recorded in the participant’s eCRF.
Sites shall transmit all study-required ECGs obtained to the ECG vendor. All ECGs performed 
during a given visit should be recorded on the repeating eCRF in the respective visit. Only ECGs 
done at unscheduled visits will be recorded as unscheduled ECGs. All readable ECGs received 
by the vendor shall be sent for cardiologist over-read. The sponsor will receive all ECG data, 
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
57
GRD-CLN-T-01-01 v2.0
including cardiologist over-read interpretation, in the data transfer, including those ECGs that 
could not be evaluated.
8.2.4.
Clinical Safety Laboratory Assessments
See Section 10.2 for the list of clinical laboratory tests to be performed and the SoAs 
(Section 1.4 FC participants and Section 1.5 IBS-C participants) for the timing and frequency.
For all participants:

At Screening (Visit 1), the investigator will assess the clinical significance of any
laboratory values outside the reference ranges for clinical labs done at EOT in the lead-in 
study, if applicable, or done at Screening, and participants with abnormalities judged to be 
clinically significant will be excluded from the study.

The investigator must review the laboratory reports, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the
participant’s condition.

All laboratory tests with values considered clinically significant during participation in the 
study or within 30 days after the last dose of study intervention should be repeated until 
the values return to normal or baseline or are no longer considered clinically significant by 
the investigator or medical safety physician.

If such values do not return to normal/baseline within a period of time judged reasonable 
by the investigator, the etiology should be identified and the sponsor notified.
o
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the SoAs and the laboratory manual.
o
If laboratory values from non-protocol-specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the eCRF.

Participants with clinically significant electrolyte abnormalities that are considered to be 
secondary to diarrhea (ie, an AESI) must be reported to the sponsor within 24 hours on an 
SAE form if considered to be serious. Non-serious events do not require submission on an 
SAE form; rather, these events only need to be entered into the eCRF (Appendix 3). If the 
AE is assessed as causally related to the use of study intervention, the participant should 
be discontinued from the study; however, the sponsor and investigator may discuss 
individual participants and AEs to make this determination (Appendix 3).
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
58
GRD-CLN-T-01-01 v2.0

A pregnancy test will be obtained for female participants of childbearing potential. Serum 
β-hCG will be performed at Screening (Visit 1) for participants who complete 
LIN-MD-62, LIN-MD-63, and LIN-MD-64 and enroll in LIN-MD-66 after > 28 days 
from last study intervention in the lead-in studies. Urine pregnancy test will be performed 
at Screening (Visit 1) for participants who complete LIN-MD-62, LIN-MD-63, and LIN-
MD-64 and enroll in LIN-MD-66 after ≤ 28 days from last study intervention in the lead-
in studies. LIN-MD-64 completers who enroll in this study on the same day as their EOT
Visit in the lead-in study do not need to repeat the urine pregnancy test. Urine pregnancy
test will be performed at Day 1 for all study participants prior to dosing and during study
intervention period as specified in the SoAs (Section 1.4 and Section 1.5).

Positive results on the pregnancy test at Screening (Visit 1) or Day 1 Visit (Visit 2) will 
exclude participants from enrolling in the study. Positive pregnancy test results during the 
study will result in participant termination from the study. Investigators must inquire at 
every study visit about the use of acceptable methods of contraception in participants of 
childbearing potential who are, or become, sexually active (see Inclusion Criterion 5, 
Section 5.1.1). Repeat pregnancy tests may be performed at the investigator’s discretion at 
other times during the study.

A central laboratory will be used to evaluate all urine (except urine pregnancy tests) and 
blood samples, which will be collected, processed, and stored according to the instructions 
provided by the laboratory. The urine pregnancy test will be completed on site at the study
site.
8.3.
Adverse Events and Serious Adverse Events
An AE is any untoward medical occurrence in a participant or clinical investigation participant 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this study intervention. 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). The definitions of an AE or SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s parent/legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study (see Section 7).
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
59
GRD-CLN-T-01-01 v2.0
Particular attention must be given to the AE of diarrhea, which was the most frequently reported 
AE in the adult linaclotide program. Please refer to Appendix 3 for details about AE reporting.
Examples of AEs are as follows:

Changes in the general condition of the participant

Subjective symptoms offered by or elicited from the participant

Objective signs observed by the investigator or other study site personnel

All diseases that occur after signing the informed consent, including any change in 
severity or frequency of preexisting disease

All clinically relevant abnormalities in laboratory values or clinically relevant physical 
findings that occur during the study schedule
Please note medical procedures scheduled prior to consenting, but occurring during the study, 
should not be captured as AEs, but should be listed in the medical history if related to a 
pre-existing condition.
8.3.1.
Adverse Events of Special Interest
AESIs are defined as significant volume depletion and/or significant electrolyte abnormalities 
and/or ECG abnormalities that are considered by the investigator or sponsor to be related to 
diarrhea. The investigator should contact the sponsor if there is any question whether the 
criterion for an AE of special interest has been met. All AESIs must be reported to the sponsor as 
described in Appendix 3.
8.3.2.
Time Period and Frequency for Collecting Adverse Events, Serious Adverse 
Events, and Adverse Events of Special Interest Information
At each visit, participants are to be queried regarding any AEs or SAEs that have occurred since 
the previous visit. Participants 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 participant’s eCRF.

All SAE from the signing of the ICF until 30 days after the last dose of study intervention 
will be collected at the timepoints specified in the SoAs (Section 1.4 and Section 1.5), and 
as observed or reported spontaneously by study participants.

All AEs from the signing of the ICF until 30 days after the last dose of study intervention 
will be collected at the timepoints specified in the SoAs (Section 1.4 and Section 1.5), and 
as observed or reported spontaneously by study participants.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
60
GRD-CLN-T-01-01 v2.0

Medical occurrences that begin before the start of study intervention, but after obtaining 
informed consent will be recorded in the AE section of the eCRF.
All SAEs (including serious AESIs) will be recorded and reported to the sponsor or designee 
within 24 hours on an SAE form, as indicated in Appendix 3. Nonserious AESIs do not require 
submission on an SAE form; rather, these events only need to be entered into the eCRF. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available.
Investigators are not obligated to actively seek AE or SAE information after conclusion of the 
study participation. However, if the investigator learns of any SAE including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must promptly
notify the sponsor.
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
8.3.3.
Method of Detecting Adverse Events, Serious Adverse Events, and Adverse 
Events of Special Interest
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.4.
Follow-up of Adverse Events, Serious Adverse Events, and Adverse Events of 
Special Interest
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All AE/SAE and non-serious AESIs (as defined in Appendix 3) will 
be followed until resolution, stabilization, the event is otherwise explained, or the participant is 
lost to follow-up (as defined in Section 7.3). 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.
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
61
GRD-CLN-T-01-01 v2.0
additional laboratory tests or investigations, histopathological examinations, or consultation with 
other health care professionals.
New or updated information will be recorded in the originally completed eCRF.
The investigator will submit any updated SAE data to the sponsor within 24 hours of receipt of 
the information.
8.3.5.
Regulatory Reporting Requirements for Serious Adverse Events

Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/ IECs, and investigators.

Investigator safety reports must be prepared for SUSARs according to local regulatory
requirements and sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the investigator’s brochure and will notify the IRB/IEC, if 
appropriate according to local requirements.
At each visit, participants are to be queried regarding any AEs or SAEs that have occurred since 
the previous visit. Participants 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 participant’s eCRF. 
Additional information is provided in Appendix 3 for the recording and follow-up of AEs and 
SAEs.
8.3.6.
Pregnancy

Details of all pregnancies that occur in female participants after the start of study
intervention, from the time the ICF was signed until 30 days after the last dose of study
intervention, will be collected.

If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 7.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
62
GRD-CLN-T-01-01 v2.0

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) or genetic abnormalities (whether leading to an 
elective abortion or not) are considered SAEs.
8.3.7.
Potential Hy’s Law Cases
Criteria for possible Hy’s law cases are as follows:

ALT or AST ≥ 3 × ULN AND

Total bilirubin ≥ 2 × ULN AND

ALP < 2 × ULN
Study site personnel must report every participant who meets the criteria for potential Hy’s law 
as SAEs (see Appendix 9 for a detailed description on handling potential Hy’s law cases and 
liver toxicity). Typically, all analytes will be obtained from the same sample, but they may come 
from multiple samples taken within a 24-hour period. This requirement applies from the time the 
participant signs the ICF for the study until 30 days after the last known dose of study 
intervention.
Additional details regarding liver safety assessments and follow-up are provided in Appendix 9.
8.3.8.
Medication Errors
Medication error refers to any unintended error in the dosing and/or administration of the study
intervention as per instructions in the protocol. Medication errors generally fall into 4 categories 
as follows:

Wrong study drug/device

Wrong dose (including dosing regimen, strength, form, concentration, amount)

Wrong route of administration

Wrong participant (ie, not administered to the intended participant)
Medication errors include occurrences of overdose and underdose of the study intervention.
Overdose: Unintentional administration of a quantity of the study intervention given per 
administration or per day that is above the maximum recommended dose according to the 
reference safety information or protocol for the study intervention or comparator as applicable.
This also takes into account cumulative effects due to overdose. 
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
63
GRD-CLN-T-01-01 v2.0
Underdose: Unintentional administration of a quantity of the study intervention given per 
administration or per day that is under the minimum recommended dose according to the 
reference safety information or protocol. 
8.4.
Treatment of Overdose
The sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator should:
1. Contact the medical safety physician (MSP) immediately.
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until study
treatment can no longer be detected systemically.
3. Document the quantity of the excess dose as well as the duration of the overdose in the 
site’s source documents for the participant.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the MSP based on the clinical evaluation of the participant.
8.5.
Pharmacokinetics
Not applicable
8.6.
Pharmacodynamics
Not applicable
8.7.
Genetics
Not applicable
8.8.
Biomarkers and Other Assessments
Not applicable
8.9.
Health Economics
Not applicable
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
64
GRD-CLN-T-01-01 v2.0
9.
Statistical Considerations
9.1.
Statistical Hypotheses
There are no preconceived statistical hypotheses to be assessed in this long-term safety study. 
9.2.
Sample Size Determination
At least 120 participants are planned to be enrolled in this long-term safety study, LIN-MD-66.
However, the actual number of participants in this study will depend on the number of 
participants who complete the lead-in studies (LIN-MD-62, LIN-MD-63, and LIN-MD-64) and 
who are eligible to be enrolled into this long-term study after fulfilling the eligibility criteria. The 
sample size in this study is not driven by any statistical consideration. 
9.3.
Populations for Analyses
For this long-term safety study, only 1 analysis population, ie, Safety Population, is considered. 
The Safety Population is defined as all treated study participants who receive/take ≥1 
administration of study intervention in this study. Participants will be summarized according to 
the study intervention they actually received.
9.4.
Statistical Analyses
The Statistical Analysis Plan (SAP) will be developed and finalized before database lock.
The summary of the other efficacy endpoint of proportion of participants who no longer fulfill 
Rome III criteria at the end of the study intervention period will be discussed in the SAP.
This section is a summary of the planned statistical analyses for safety. Further details will be 
included in the SAP. All safety analyses or summaries will be performed using the Safety
Population, for overall and for each age group (unless mentioned otherwise) by study
intervention group separately for the FC and IBS-C pediatric populations. 
The safety parameters will include AEs, clinical laboratory parameters, vital sign measurements, 
weight, height, and ECG parameters. For each safety parameter, the baseline value for all 
analyses of the corresponding safety parameter (laboratory, vital signs, body weight, height, and 
ECG) will be defined as below:
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
65
GRD-CLN-T-01-01 v2.0
1) If participants enroll into LIN-MD-66 within 28 days of last dose date of the lead-in 
study, baseline of the lead-in study will be used as the baseline value in LIN-MD-66.
2) If participants enroll into LIN-MD-66 after 28 days of last dose date of the lead-in study, 
the last non-missing assessment made before the first dose of study intervention in this 
study will be used as the baseline value in LIN-MD-66.
Safety data analyses will be provided descriptively based on the observed safety data, without 
data imputation for missing safety parameter assessment(s).
9.4.1.
Adverse Events
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
Version 23.0 or newer.
An AE will be considered a TEAE if:

The AE began on or after the date of the first dose of study intervention in LIN-MD-66; or

The AE was present before the date of the first dose of study intervention in LIN-MD-66
but increased in severity or became serious on or after the date of the first dose of study
intervention in LIN-MD-66.
An AE that occurs more than 1 day after the last dose of study intervention in LIN-MD-66 will 
not be counted as a TEAE.
An AE will be considered a treatment-emergent SAE (TESAE) if it is a TEAE that additionally
meets any SAE criteria.
The number and percentage of participants reporting TEAEs in each study intervention group
will be tabulated by SOC and preferred term and by SOC, preferred term, and severity.
The number and percentage of participants reporting treatment-related TEAEs in each study 
intervention group will be tabulated by SOC and preferred term. 
If more than 1 AE is coded to the same preferred term for the same participant, the participant 
will be counted only once for that preferred term using the most severe and most related 
occurrence for the summarizations by severity and by relationship to study intervention.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
66
GRD-CLN-T-01-01 v2.0
Summary tables will be provided for participants with TESAEs, AESIs, and participants with 
TEAEs leading to discontinuation if 5 or more participants reported such events. Listings of all 
AEs, SAEs, AESIs, and AEs leading to discontinuation by participant will be presented.
The definitions of an AE and SAE can be found in Appendix 3.
9.4.2.
Clinical Laboratory Assessments
Descriptive statistics for clinical laboratory values (in SI units) at baseline and changes from 
baseline at each assessment timepoint will be presented by study intervention group for each 
clinical laboratory assessment.
The criteria for PCS laboratory values will be detailed in the SAP. The number and percentage of 
participants who have PCS postbaseline clinical laboratory values will be tabulated by study
intervention. The percentages will be calculated relative to the number of participants who have 
available non-PCS baseline values and at least 1 postbaseline assessment. The numerator will be 
the total number of participants with at least 1 PCS postbaseline value. A supportive listing of 
participants with PCS postbaseline values will be provided for the Safety Population.
9.4.3.
Vital Signs
Descriptive statistics for height, weight, and vital signs (supine systolic and diastolic blood 
pressure, supine pulse rate, respiration rate, and temperature) at baseline and changes from 
baseline at each assessment timepoint will be presented by study intervention.
Vital sign values will be considered to be PCS values if they meet both the observed-value 
criteria and the change-from-baseline-value criteria (as defined in the SAP). The number and 
percentage of participants who have PCS postbaseline vital sign values will be tabulated by study
intervention group. The percentages will be calculated relative to the number of participants who 
have available non-PCS baseline values and at least 1 postbaseline assessment. The numerator 
will be the total number of participants with at least 1 PCS postbaseline value. A supportive 
listing of participants with PCS postbaseline values will be provided for the Safety Population.
9.4.4.
Electrocardiograms
Descriptive statistics for ECG parameters (ie, ventricular heart rate, RR interval, PR interval, 
QRS interval, QT interval, and QTc) and changes from baseline values at each assessment time 
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
67
GRD-CLN-T-01-01 v2.0
point will be presented by study intervention group. The QTc is calculated using both the Bazett 
and Fridericia corrections.
The number and percentage of participants with PCS postbaseline ECG values will be tabulated
by study intervention group. The criteria for PCS ECG values will be detailed in the SAP. The 
percentages will be calculated relative to the number of participants with available non-PCS 
baseline values and at least 1 postbaseline assessment. The numerator will be the total number of 
participants with available non-PCS baseline values and at least 1 PCS postbaseline value. A 
supportive listing of participants with PCS postbaseline values will be provided for the Safety 
Population.
9.5.
Interim Analyses
An interim analysis to assess long-term safety of linaclotide may be performed after at least 120 
participants have completed the study. Data will be locked after performing data cleaning. 
Results from the interim analysis will be described in an interim clinical study report.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
68
GRD-CLN-T-01-01 v2.0
10.
Supporting Documentation and Operational Considerations
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:
o
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines
o
Applicable ICH/ISO Good Clinical Practice (GCP) guidelines
o
Applicable laws and regulations

The protocol, protocol amendments, ICF, investigator’s brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 

Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 

The investigator will be responsible for the following:
o
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC
o
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
o
Providing oversight of the overall conduct of the study at the site and adherence to 
requirements of applicable local regulations, for example 21 CFR, ICH guidelines, 
the IRB/IEC, and European regulation 536/2014 for clinical studies (if applicable)
10.1.2.
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
69
GRD-CLN-T-01-01 v2.0
10.1.3.
Informed Consent Process
Procedures will comply with 21 CFR, Parts 50 and 312. Signed informed consent will be 
obtained for the participant from the parent/guardian/LAR and/or the caregiver of each 
participant participating in a clinical research study. 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 participant’s 
participation

A description of any reasonably foreseeable risks or discomforts to the participant

A description of any benefits to the participant or to others that may reasonably be 
expected from the research. If the participant 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 participant

A statement describing the extent, if any, to which confidentiality of records identifying 
the participant will be maintained and noting the possibility that the health authority; the 
sponsor, the IRB/EC; 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 participant’s rights and whom to 
contact in the event of a research-related injury to the participant. (Note: In some cases, it 
may be necessary to identify a person other than the investigator as the contact. The 
guidance of the IRB/EC may be required)

A statement that participation is voluntary, that refusal to participate will involve no 
penalty or loss of benefits to which the participant is otherwise entitled, and that the 
participant may discontinue participation at any time without penalty or loss of benefits to 
which the participant is otherwise entitled

A statement that the particular treatment or procedures may involve risks to the participant
(or to the embryo or fetus if the participant is, or may become, pregnant) that are at 
present unforeseeable
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
70
GRD-CLN-T-01-01 v2.0

The expected circumstances for which the participant’s participation may be terminated
by the investigator without regard to the participant’s consent

Any additional costs to the participant that may result from participation in the research

The consequences of a participant’s decision to withdraw from the research and 
procedures for an orderly termination of the participant’s participation

A statement that significant new findings developed during the course of the research that 
may relate to the participant’s willingness to continue participation will be provided to the 
participant

The approximate number of participants involved in the study

A statement of consent (eg, “I agree to allow (my child) to participate . . .”)

A place for the participant’s parent/guardian/LAR signature and date of signing

A statement indicating that information about this study has been, or will be, entered into a 
databank that is publicly accessible at www.ClinicalTrials.gov.
A copy of the signed consent form must be given to the participant’s parent/guardian/LAR.
Signed informed consent will be obtained from caregiver of a participant and will include a 
statement agreeing to participate in the study.
In addition, the participant will be asked to provide assent that will include a statement agreeing 
to participate in the study.
10.1.4.
Data Protection

Participants will be assigned a unique identifier. Any participant records or datasets that 
are transferred to the sponsor will contain the identifier only; participant names or any
information which would make the participant identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be used by
the sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant. 

The participant must be informed that his/her medical records may be examined by
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
71
GRD-CLN-T-01-01 v2.0
10.1.5.
Posting Clinical Study Data
All data generated in this study are the property of the sponsor. An integrated clinical and 
statistical report will be prepared at the completion of the study.
10.1.6.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or eCRFs unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator 
is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF. 

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 

The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any
other study agreements, ICH GCP, and all applicable regulatory requirements. 

Records and documents, including signed ICFs, pertaining to the conduct of this study
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor. 
10.1.6.1.
Data Monitoring
Before any participant enters the study, a representative of the sponsor will meet with the 
investigator and the study site staff to review the procedures to be followed during the study.
Electronic data capture (EDC) functionality training is provided via computer-based training to 
train investigators and authorized designees on recording the data in the eCRFs using the EDC 
system. After the first participant is enrolled, the sponsor’s representative, a Regional Site 
Manager or designee, will periodically monitor the progress of the study by conducting on-site 
visits. This Regional Site Manager or designee will review query statuses remotely, possibly 
warranting more frequent communication and/or site visits with the investigator and the study
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
72
GRD-CLN-T-01-01 v2.0
site staff. The investigator will make available to the Regional Site Manager or designee source 
documents (written notes and electronic medical records, if used), signed consent forms, and all 
other study-related documents. The investigator and the study site staff will be responsible for 
data entry of participant 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 
participant data within the EDC system. This approval method will include applying an 
electronic signature linked to a uniquely assigned username and password that together will 
represent a traditional handwritten signature used in the past.
10.1.6.2.
Data Recording and Documentation
Data collection will involve the use of the sponsor’s EDC system, to which only authorized 
personnel will have access. Participant’s data are to be entered into the EDC system by the 
investigator or designee using their assigned EDC user account. After data entry into the EDC 
system by the investigator or designee, a combination of manual and programmatic edit checks 
will be used to review the data for completeness, logic, and adherence to study protocol. As a 
result of these edits checks, data monitoring and reviews, queries may be electronically issued to 
the site and should be answered electronically via the EDC system.
Each query will carry identifying information (assigned username, date, and time) to assist the 
sponsor and the investigator on the origin of the data clarification request and the response 
provided by the investigator. All data changes made to the participant’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 participant confidentiality in accordance with the legal 
stipulations applying to confidentiality of data. Study records (eg, copies of eCRFs, laboratory
reports, participant diaries, regulatory documents) will be retained at the site, along with 
adequate source documentation, according to FDA and ICH requirements. All study records must 
be available for inspection by the sponsor, its authorized representatives, and health authorities.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
73
GRD-CLN-T-01-01 v2.0
10.1.6.3.
Data and Safety Monitoring Board
An independent DSMB will review interim safety data at defined intervals throughout the study
or ad hoc if needed. The DSMB will communicate their recommendations to the sponsor after 
each meeting but will serve in an advisory capacity only. Further details of the DSMB 
(composition, policy, and procedures) are specified in a separate DSMB Charter.
10.1.7.
Source Documents

Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current source documents must be available.
10.1.8.
Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor’s procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
74
GRD-CLN-T-01-01 v2.0
10.1.9.
Publication Policy

Allergan as the sponsor has proprietary interest in this study. Authorship and manuscript 
composition will reflect joint cooperation between multiple investigators and sites and 
Allergan personnel. Authorship will be established prior to the writing of the manuscript. 
As this study involves multiple centers, no individual publications will be allowed prior to 
completion of the final report of the multicenter study except as agreed with Allergan.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
10.1.10.
Compliance with Protocol
The investigator is responsible for compliance with the protocol at the investigational site. A 
representative of the sponsor will make frequent contact with the investigator and his/her 
research staff and will conduct regular monitoring visits at the site to review participant and 
study intervention accountability records for compliance with the protocol. Protocol deviations 
will be discussed with the investigator upon identification. The use of the data collected for the 
participant will be discussed to determine if the data are to be included in the analysis. The 
investigator will enter data that may be excluded from analysis as defined by the protocol 
deviation specifications. Significant protocol deviations will be reported to the IRB/IEC 
according to the IRB/IEC’s reporting requirements.
Deviating from the protocol is permitted only if absolutely necessary for the safety or clinical 
management of the participants and must immediately be reported to the sponsor. Protocol 
deviations should be reported to the sponsor (either verbally or electronically) in a timely manner 
from the day of discovery.
Protocol deviations that may impact participant’s rights (eg, failure to obtain informed consent 
prior to initiating study procedures), safety, or well-being (eg, deviations that resulted in an SAE, 
exposure during pregnancy), or the integrity and authenticity of the study data should be reported 
to the sponsor within 24 hours, if possible. 
The IRB/IEC must be notified according to the criteria and time period dictated by the IRB/IEC 
associated with this study. 
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
75
GRD-CLN-T-01-01 v2.0
10.1.11.
Study Documentation
The investigator must provide the following to the sponsor before the start of the study:

For sites in the United States, a completed and signed Form FDA 1572. If, during the 
course of the study, any changes are made that are not reflected on Form FDA 1572, a new 
Form FDA 1572 must be completed and returned to the sponsor for submission to 
the FDA

A fully executed contract

For sites in the United States, the curricula vitae for the investigator and all 
subinvestigators listed on Form FDA 1572, including a copy of each physician’s license

A copy of the original IRB/EC approval for conducting the study. If the study is ongoing, 
renewals must be submitted at yearly intervals. All subsequent modifications must be 
submitted and approved by the IRB/EC, as stated in Section 10.1.1.

A copy of the IRB/EC-approved parent/LAR, Caregiver ICFs, and participant’s assent

A copy of the HIPAA authorization form, or other local privacy applicable forms

A list of the IRB/EC members or the US Department of Health and Human Services 
general assurance number

The Investigator’s Statement page in this protocol signed and dated by the investigator

For sites in the United States, financial disclosure agreement completed and signed by the 
investigator and all subinvestigators listed on Form FDA 1572. The investigator and all 
subinvestigators will provide an updated financial disclosure agreement to the sponsor 1 
year after the completion of the study

For sites in the EU and European Economic Area the study must be conducted in 
accordance with the national legislation that is set forth in the Directives 2001/20/EC, 
2001/83/EC, and 2005/28/EC (and the Regulation [EU] No 536/2014 when in force).
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
76
GRD-CLN-T-01-01 v2.0
10.2.
Appendix 2: Clinical Laboratory Tests
Blood and urine samples for clinical laboratory tests will be collected as detailed in the SoAs
(Section 1.4 and Section 1.5). During the screening period, the investigator will assess the 
clinical significance of any values that are outside the reference ranges provided by the central 
laboratory. Participants with abnormalities judged to be clinically significant will be excluded 
from the study.
Participants with clinically significant electrolyte abnormalities that are considered to be 
secondary to diarrhea (ie, an AE of special interest) must be reported to the sponsor within 
24 hours on an SAE form if considered to be serious. Nonserious events do not require 
submission on an SAE form; rather, these events only need to be entered into the eCRF 
(Appendix 3). If the AE is assessed as causally related to the use of study intervention, the 
participant should be discontinued from the study; however, the sponsor and investigator may
discuss individual participants and AEs to make this decision.
Clinical laboratory levels that will be measured are summarized in Table 10–1.
The clinical significance of a positive urine drug screen will be assessed by the investigator. 
Participants will be excluded from study participation if urine drug screening results are positive 
for cocaine, barbiturates, opiates, or cannabinoids.
For female participants of childbearing potential urine pregnancy test will be obtained at 
Screening (Visit 1) for participants who enroll ≤ 28 days from last study intervention and serum 
pregnancy test will be obtained at Screening (Visit 1) for participants who enroll > 28 days from 
last study intervention. Urine pregnancy test will be performed for all participants at the Day 1 
Visit (Visit 2) prior to dosing as specified in the SoAs (Section 1.4 and Section 1.5) and Visits 4 
to 7 during study intervention for FC participants and Visits 4 to 10 for IBS-C participants. 
Positive results on the pregnancy test at Screening (Visit 1) or Day 1 Visit (Visit 2) will exclude 
participants from participating in the study. Positive pregnancy test results during the study will 
result in participant termination from the study. Investigators must inquire at every study visit 
about the use of acceptable methods of contraception in participants of childbearing potential 
who are, or become, sexually active. Repeat pregnancy tests may be performed at the 
investigator’s discretion at other times during the study.
Other laboratory assessments may be repeated at any visit if there was an abnormal finding at the 
most recent previous evaluation or if additional information is clinically necessary to 
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
77
GRD-CLN-T-01-01 v2.0
appropriately evaluate the participant’s current condition, follow up, and/or manage an adverse 
experience.
A central laboratory will be used to evaluate all urine (except urine pregnancy tests) and blood 
samples, which will be collected, processed, and stored according to the instructions provided by 
the laboratory. The urine pregnancy tests will be completed on site at the study site.

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined necessary
by the investigator or required by local regulations.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
78
GRD-CLN-T-01-01 v2.0
Table 10–1
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet count
RBC indices:
MCV
MCH
MCHC
White blood cell (WBC) 
count with differential 
(absolute):
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Red blood cell (RBC) count
Hemoglobin
Hematocrit
Clinical 
Chemistrya
Blood urea nitrogen 
(BUN)
Potassium
Aspartate 
aminotransferase 
(AST)
Total, direct and 
indirect bilirubin
Creatinine
Sodium
Bicarbonate
Magnesium
Phosphate
Total Protein
Total Bilirubin
Alanine 
aminotransferase 
(ALT)
Total protein
Total Cholesterol 
chloride,
albumin
Glucose nonfasting
Calcium
Alkaline 
phosphatase
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones microscopic examination (if blood or protein is 
abnormal)
Other Screening 
Tests

Urine alcohol and drug screen (to include at minimum: benzoylecgonine (cocaine), 
barbiturates, amphetamines, benzodiazepines, cannabinoids, ethanol, opiates)

For female participants of childbearing potential: Serum human chorionic gonadotropin 
(hCG) pregnancy test at screening for LIN-MD-62, LIN-MD-63, and LIN-MD-64 
completers who enroll > 28 days from last study intervention; urine pregnancy test for 
participants who enroll ≤ 28 days from last study interventionb. LIN-MD-64 completers 
who enroll in this study on the same day as their EOT Visit in the lead-in study do not 
need to repeat the urine pregnancy test. 

For all female participants of childbearing potential: Urine pregnancy test at Visit 2 prior 
to dosing and at Visits 4 to 7 for FC participants and Visits 4 to 10 for IBS-C 
participants during study interventionb.

All study-required laboratory assessments will be performed by a central laboratory, with 
the exception of urine pregnancy test that will be performed locally at the site at all visits 
during study intervention.
a
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring events are provided in Appendix 9.
b
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IRB/IEC.
Investigators must document their review of each laboratory safety report.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
80
GRD-CLN-T-01-01 v2.0
communication by the investigator to the sponsor. Such an event might warrant further 
investigation in order to characterize and understand it. 
The following AESIs have been identified for the study intervention in this protocol: 
significant volume depletion and/or significant electrolyte abnormalities and/or ECG 
abnormalities that are considered by the investigator or sponsor to be related to diarrhea. The 
investigator should contact the sponsor if there is any question whether the criterion for an 
AESIs has been met. All serious AESIs must be reported to the sponsor on an SAE form
within 24 hours as noted below for SAEs.
Non-serious AESI do not require submission on an SAE form; rather, these events only need 
to be entered into the eCRF.
If the AESI is assessed as causally related to the use of study intervention, the participant 
should be discontinued from the study (Section 10.5 Appendix 5).
Potential Hy’s Law Cases
For potential Hy's Law cases, refer to Appendix 9.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
88
GRD-CLN-T-01-01 v2.0
10.4.
Appendix 4: Abbreviations
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AT
aminotransferase
BP
blood pressure
CBC
complete blood count
CFR
Code of Federal Regulations
CIC
chronic idiopathic constipation
CIOMS
Council for International Organizations of Medical Sciences
CRF
case report form
DILI
drug-induced liver injury
DSMB
Data and Safety Monitoring Board
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
EMA
European Medicines Agency
EOS
End-of Study
EOT
End-of Treatment
EU
European Union
FC
functional constipation
FDA
Food and Drug Administration
GC-C
guanylate cyclase subtype C
GCP
Good Clinical Practice
GI
gastrointestinal
HIPAA
Health Insurance Portability and Accountability Act
IB
investigator’s brochure
IBS
irritable bowel syndrome
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
89
GRD-CLN-T-01-01 v2.0
IBS-C
irritable bowel syndrome with constipation
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
INR
international normalized ratio
IRB
Institutional Review Board
ITT
intent to treat
IV
intravenous
IWRS
interactive web response system
LAR
legally authorized representative
mRNA
messenger ribonucleic acid
MSP
medical safety physician
NASH
non-alcoholic steatohepatitis
PCS
potentially clinically significant
PI
package insert
SAE
serious adverse event
SAP
Statistical Analysis Plan
SBM
spontaneous bowel movement
SoA
Schedule of Activities
SOC
System Order Class
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
TESAE
treatment emergent serious adverse event
ULN
upper limit of normal
US
United States
WOCBP
woman of childbearing potential
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
90
GRD-CLN-T-01-01 v2.0
10.5.
Appendix 5: Standard Discontinuation Criteria
CDISC Submission Value
CDISC Definition
Adverse event
Any untoward medical occurrence in a participant
or clinical investigation subject administered a 
pharmaceutical product and which does not 
necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be 
any unintended sign (including an abnormal 
laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal 
(investigational) product, whether or not related 
to the medicinal (investigational) product. For 
further information, see the ICH Guideline for 
Clinical Safety Data Management: Definitions 
and Standards for Expedited Reporting (modified 
from ICH E2A) Synonyms: side effect, adverse 
experience. See also serious adverse event, 
serious adverse experience. (CDISC glossary)
Completed
To possess every necessary or normal part or 
component or step; having come or been brought 
to a conclusion (NCI)
Death
The absence of life or state of being dead (NCI)
Disease relapse
The return of a disease after a period of remission
Lack of efficacy
The lack of expected or desired effect related to a 
therapy (NCI)
Lost to follow-up
The loss or lack of continuation of a subject to 
follow-up
Other
Different than the one(s) previously specified or 
mentioned (NCI)
Physician decision
A position, opinion or judgment reached after 
consideration by a physician with reference to 
subject (NCI)
Pregnancy
Pregnancy is the state or condition of having a 
developing embryo or fetus in the body (uterus), 
after union of an ovum and spermatozoon, during 
the period from conception to birth. (NCI)
Progressive disease
A disease process that is increasing in extent or 
severity (NCI)
Recovery
A healing process and/or an outcome implying 
relative health. The term is typically used in the 
context of direct and indirect effects of sickness 
or injury. (NCI)
Screen failure
The potential subject who does not meet one or 
more criteria required for participation in a trial
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
91
GRD-CLN-T-01-01 v2.0
CDISC Submission Value
CDISC Definition
Site terminated by sponsor
An indication that a clinical study was stopped at
a particular site by its sponsor (NCI)
Study terminated by sponsor
An indication that a clinical study was stopped by 
its sponsor (NCI)
Technical problems
A problem with some technical aspect of a 
clinical study, usually related to an instrument 
(NCI)
Withdrawal by parent/guardian
An indication that a study participant has been 
removed from the study by the parent or legal 
guardian
Withdrawal by subject
An indication that a study participant has 
removed itself from the study (NCI)
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
92
GRD-CLN-T-01-01 v2.0
10.6.
Appendix 6: Study Tabular Summary
Parameter Group
Parameter
Value
Trial information
Trial Title
A Long-term Safety Study of Oral 
Linaclotide Administered to Pediatric 
Participants with Functional Constipation 
(FC) or Irritable Bowel Syndrome with 
Constipation (IBS-C)
Clinical Study Sponsor
Allergan Sales LLC
Trial Phase Classification
Extension Study
Trial Indication
FC and IBS-C
Trial Indication Type
Study intervention
Trial Type
Safety
Trial Length
24 weeks (FC participants)
52 weeks (IBS-C participants)
Planned Country of Investigational Sites
United States of America (USA), Canada,
Europe, and the Middle East
Planned Number of Participants
At least 120
FDA-Regulated Device Study
No
FDA-Regulated Drug Study
Yes
Pediatric Study
Yes
Participant 
information
Diagnosis Group
Pediatric participants with FC or IBS-C; 
specifically, participants who have 
completed study intervention in Phase 2 
Studies LIN-MD-62, LIN-MD-63 or 
Phase 3 Study LIN-MD-64
Healthy Participant Indicator
No
Planned Minimum Age of Participants
6 years
Planned Maximum Age of Participants
18 years
Sex of Participants
Both
Stable Disease Minimum Duration
Not applicable
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
93
GRD-CLN-T-01-01 v2.0
Parameter Group
Parameter
Value
Treatments
Investigational Therapy or Treatment
Linaclotide
Intervention Type
Drug
Pharmacological Class of Invest. Therapy
Agonist of guanylate cyclase C
Dose per Administration
Single
Dose Units
72 µg, 145 µg, or 290 µg
Dosing Frequency
Once daily
Route of Administration
Oral
Current Therapy or Treatment
None
Added on to Existing Treatments
No
Control Type
None
Comparative Treatment Name
Not applicable
Trial design
Study Type
Interventional
Intervention Model
Open-label and blinded
Planned Number of Arms
2 arms for FC participants: open-label 72 
and 145 µg
4 arms for IBS-C participants: 2 arms for 
open-label (145 and 290 µg) and 2 arms 
for blinded (145 and 290 µg)
Trial is Randomized
Applicable to FC participants 12 to 17 
years of age only: will be randomly 
assigned at 1:1 ratio to 72 µg linaclotide 
or 145 µg linaclotide
Randomization Quotient
Not applicable
Trial Blinding Schema
Open-label and blinded
Stratification Factor
None
Adaptive Design
No
Study Stop Rules
Monitoring of participant safety data will 
be performed by the DSMB. Study 
conduct may be interrupted or terminated 
by the sponsor based on DSMB 
recommendation or if, following a 
thorough review of all clinical, laboratory, 
and other available safety data; safety 
data become available which appear to 
represent an undue risk to the study 
participants’ health or well-being. 
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
94
GRD-CLN-T-01-01 v2.0
10.7.
Appendix 7: Contraceptive Guidance and Collection of Pregnancy 
Information 
10.7.1.
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
Women in the following categories are not considered WOCBP:
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview.
10.7.2.
Contraception Guidance:
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 10–2.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
95
GRD-CLN-T-01-01 v2.0
Table 10–2
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of < 1% per year when used consistently and correctly
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationb

Oral 

Intravaginal 

Transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation

Oral 

Injectable 
Highly Effective Methods That Are User Independenta
Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Etonogestrel implant (ie, Nexplanon®)
Bilateral tubal occlusion
Intrauterine copper contraceptive (ie, ParaGard®)
Vasectomized Partner 
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used.
Sexual Abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant.
a
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies.
b
Hormonal contraception may be susceptible to interaction with the study intervention, which may reduce the 
efficacy of the contraceptive method. In this case, 2 highly effective methods of contraception should be utilized 
during the study intervention period.
10.7.3.
Pregnancy Testing:

Phase 3 Study LIN-MD-64 completers and Phase 2 Study LIN-MD-63 completers who 
are WOCBP and who enroll in LIN-MD-66 within ≤28 days from last study intervention 
must have a negative urine test at Screening (Visit 1) and on Study Day 1 (Visit 2). LIN-
MD-64 completers who enroll in this study on the same day as their EOT Visit in the lead-
in study do not need to repeat the urine pregnancy test.

Phase 2 LIN-MD-62, Phase 2 LIN-MD-63, and Phase 3 LIN-MD-64 completers who are 
WOCBP and who enroll in LIN-MD-66 after > 28 days from last study intervention 
should have a negative serum pregnancy test at Screening (Visit 1) and also a negative 
urine test on Study Day 1 (Visit 2).
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
96
GRD-CLN-T-01-01 v2.0

Additional urine pregnancy testing will be performed in female participants of 
childbearing potential at Visits 4 to 7 (FC participants) and at Visits 4 to 10 (IBS-C 
participants) during study intervention. 

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 

Pregnancy testing, with a sensitivity of ≤ 25 mIU/mL will be performed.
Additional details regarding pregnancy testing are provided in Section 10.2.
10.7.4.
Collection of Pregnancy Information:
Study site personnel must report every pregnancy. Within 24 hours of learning of the pregnancy, 
the study site personnel must report the event to Global Drug Safety on the Clinical Trial 
Pregnancy Form, even if no AE has occurred. Email is the preferred method to transmit 
pregnancy information. The email address is IR-Clinical-SAE@allergan.com. Facsimile 
transmission of the pregnancy information is also acceptable. The fax number is 
+1-714-796-9504 (backup number is +1-714-246-5295). In rare circumstances and in the 
absence of facsimile equipment, notification by telephone is acceptable with a copy of the 
Clinical Trial Pregnancy Form, sent by overnight mail or courier service. Initial notification via 
telephone does not replace the need for the investigator to complete and sign the Clinical Trial 
Pregnancy Form within the designated reporting time frames. 
The pregnancy must be followed to term and the outcome reported by completing a follow-up a 
Clinical Trial Pregnancy Form. If the pregnancy is associated with an SAE (eg, if the mother is 
hospitalized for hemorrhage), a separate SAE Form for Clinical Trials must be filed as described 
in Appendix 3 with the appropriate serious criterion (eg, hospitalization) indicated in addition to 
the Pregnancy Form.
Female Participants Who Become Pregnant 

The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the sponsor within 24 hours of learning of a 
participant’s pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The investigator will collect follow-up information on the participant and the 
neonate, and the information will be forwarded to the sponsor. Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence 
of anomalies) or indication for the procedure.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
97
GRD-CLN-T-01-01 v2.0

While pregnancy itself is not considered to be an AE or SAE any pregnancy complication 
will be reported as an AE or SAE. A spontaneous or elective abortion is always considered 
to be an SAE and will be reported as such. Any poststudy pregnancy-related SAE 
considered reasonably related to the study intervention by the investigator will be reported 
to the sponsor as described in Section 8.3.5. While the investigator is not obligated to 
actively seek this information in former study participants, he or she may learn of an SAE 
through spontaneous reporting. 

Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention and be withdrawn from the study.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
98
GRD-CLN-T-01-01 v2.0
10.8.
Appendix 8: Instructions for Sprinkled Dose
For participants who do not wish to take the dose as a capsule, a sprinkled dose may be prepared 
as follows:
Oral Administration in Applesauce:
1. Place one teaspoonful of room-temperature applesauce into a clean container.
2. Open the capsule.
3. Sprinkle the entire contents (beads) on applesauce.
4. Consume the entire contents immediately. Do not chew the beads. Do not store the bead-
applesauce mixture for later use.
Oral Administration in Bottled Water:
1. Pour approximately 30 mL of room-temperature bottled water into a clean cup. 
2. Open the capsule.
3. Sprinkle the entire contents (beads) into the water.
4. Gently swirl beads and water for at least 20 seconds. 
5. Swallow the entire mixture of beads and water immediately. 
6. Add another 30 mL of water to any beads remaining in cup, swirl for 20 seconds, and swallow 
immediately. 
7. Do not store the bead-water mixture for later use. 
Note that the drug is coated on the surface of the beads and will dissolve off the beads into the 
water. The beads will remain visible and will not dissolve. Therefore, it is not necessary to 
consume all the beads to deliver the complete dose.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
99
GRD-CLN-T-01-01 v2.0
10.9.
Appendix 9: Liver Safety: Suggested Actions and Follow-up 
Assessments
Close monitoring should be initiated for the following participants:

Participants with normal baseline serum aminotransferases (AT) who develop an increase 
of serum AT ≥ 3 × ULN

Participants with elevated baseline AT who develop an increase of serum AT > 2 × the 
baseline value 
The participant should return to the study site and be evaluated for potential drug-induced liver 
injury (DILI) as soon as possible, preferably within 48 to 72 hours from the time the investigator 
becomes aware of the abnormal results. Evaluation should typically include repeat testing of all 
4 of the usual serum biochemical measures (ALT, AST, ALP, and TBL) to confirm the 
abnormalities and to determine if they are increasing or decreasing. 
If it is difficult for the participant to return to the study site promptly, the participant should be 
retested locally, but normal laboratory ranges should be recorded, results should be made 
available to sponsor’s study physician and the investigator immediately, and the data should be 
included in the eCRF. If repeat testing within this time frame is not possible, the study
intervention should be discontinued.
It is critical to initiate close monitoring immediately upon detection and confirmation of signals 
of potential DILI as early as possible and not to wait until the next scheduled visit or monitoring 
interval. Close monitoring of the participant should be initiated in conjunction with the sponsor 
and consideration given to the following:

Obtain a more detailed history of symptoms and prior or concurrent diseases. 

Obtain a history of concomitant drug use, including nonprescription medications, herbal 
products and dietary supplements, alcohol and recreational drug use, and special diets. 

Obtain a history of exposure to environmental chemical agents. 

Initiation of appropriate evaluations including applicable laboratory tests (eg, direct 
bilirubin, INR), physical assessments, and other assessments (eg, imaging)
o
Rule out other potential causes of biochemical abnormalities, eg, acute viral hepatitis 
types A, B, C, D, and E; autoimmune or alcoholic hepatitis; NASH; hypoxic/ischemic 
hepatopathy; and biliary tract disease. 

Consider gastroenterology or hepatology consultations.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
100
GRD-CLN-T-01-01 v2.0
If any of the following criteria are met, discontinuation of study intervention should be 
considered (if indicated, prior to receipt of confirming retest biochemistry laboratory test results) 
and the sponsor notified of the discontinuation:

ALT or AST ≥ 3 × ULN and the participant is symptomatic with the appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia 
(> 5%)

ALT or AST ≥ 3 × ULN and total bilirubin > 2 × ULN or INR > 1.5 

ALT or AST ≥ 5 × ULN for more than 2 weeks

ALT or AST ≥ 8 × ULN
If the study intervention is discontinued, the participant may be re-challenged with study
intervention only after consultation with the Allergan MSP. All participants showing potential 
DILI should be followed until all abnormalities return to normal or to the baseline state.
Reporting of Potential Hy’s Law Cases
Potential Hy’s law cases are defined by biochemical test results of hepatocellular injury and 
impaired hepatic function. They are considered Adverse Events of Special Interest (AESIs) and 
should be evaluated and followed further (ie, close monitoring initiated) to determine whether 
these laboratory abnormalities are indicative of DILI. As indicated above, discontinuation of 
study intervention should also be considered. Criteria that identify a potential Hy’s law case are 
as follows:

ALT or AST ≥ 3 × ULN AND

Total bilirubin ≥ 2 × ULN AND

Alkaline phosphatase < 2 × ULN
Sites must report every participant who meets the Hy’s law criteria if this occurs within the time 
the participant signs the ICF until 30 days after the last dose of study intervention.
A laboratory alert for a potential DILI case will be sent immediately to the sponsor and 
investigators when the above criteria have been met, even if no clinical symptoms have been 
experienced. In addition, both an SAE and Adverse Event of Interest Abnormal Liver Function 
Reporting Form (GPSE PVOPS-F-01-28) for all potential Hy’s law DILI cases should be 
completed as soon as possible (within 24 hours of learning that a participant fulfills the potential 
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
101
GRD-CLN-T-01-01 v2.0
Hy’s law criteria) and submitted to the sponsor as noted in Appendix 3. The eCRF pages 
associated with the potential Hy’s law cases must be completed within 7 calendar days.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
102
GRD-CLN-T-01-01 v2.0
10.10.
Appendix 10: Study Schedule Supplement 
The schedule of study procedures and assessments is tabulated by visit in the SoAs in Section 1.4
(FC participants) and Section 1.5 (IBS-C participants). The descriptions of the procedures to be 
performed at each visit are provided below.
10.10.1.
Screening (Visit 1)
Study procedures for screening may be combined with EOT Visit or EOS Visit in the lead-in 
LIN-MD-64 or LIN-MD-63 studies. The screening period will occur 0 to 14 days before Study
Day 1 (Visit 2) and last for up to 14 days during which time study procedures will be reviewed 
with the participant, parent/guardian/LAR, and/or caregiver; and informed assent (from 
participant), and parent/guardian/LAR and/or caregiver consent will be obtained and documented 
(Section 10.1.3). After informed consent is obtained, participants will be registered in IWRS and 
assigned a unique PID number (Section 6.3). A review of inclusion/exclusion criteria and other 
screening assessments will be conducted to determine the participant’s eligibility for enrollment 
(Section 5.1 and Section 5.2). Screening Visit may be combined with Study Day 1 Visit in 
participants who enroll within ≤28 days from last study intervention in the lead-in study
provided no fecal impaction is found at Screening Visit.
For all participants, the following procedures will also be performed at Screening (Visit 1):

Obtain informed consent from parent/guardian/LAR and caregiver

Obtain informed assent from participant

Review inclusion and exclusion criteria 

Register participant in IWRS

Obtain medical history, medication history, and current medication status

A fecal impaction assessment will be performed. Fecal impaction is defined as a hard 
mass in the lower abdomen identified on physical examination or a dilated rectum filled 
with a large amount of stool on rectal examination. If a rectal examination is performed, 
the medically qualified site personnel should assess for and document the presence of anal 
wink and normal anal tone. If fecal impaction is identified, participants will receive a 
disimpaction regimen with either oral or rectal medication. The choice of treatment will 
be determined by the investigator after discussing the options with the participant and the 
caregiver. Options will include any over-the-counter or prescription laxative, suppository, 
or enema (eg, polyethylene glycol, lactulose, Fleet enema). Refer to Section 8.2.1 for 
additional details. 
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
103
GRD-CLN-T-01-01 v2.0

Participants and caregivers will be instructed to have the participant fast for at least 2 
hours before receiving their first dose of linaclotide at the study site during study Day 1. 
Water will be allowed.

Review any AEs occurring after assent/consent is obtained. Ongoing AEs from the prior 
study should be entered into the eCRF.
Participants who enroll into LIN-MD-66 from LIN-MD-63 or LIN-MD-64 within ≤28 days of 
last study intervention may have the Screening (Visit 1) combined with Study Day 1 (Visit 2). 

Obtain informed consent for participants who turn 18 and enroll within ≤28 days of the 
last study intervention.

Obtain urine pregnancy test in female participants of childbearing potential. Participants 
from LIN-MD-63 or LIN-MD-64 studies who enroll in this study on the same day as their 
EOT Visit in the lead-in study do not need to repeat the urine pregnancy test
(Section 10.7). 
In addition, for Phase 2 LIN-MD-62, LIN-MD-63, and Phase 3 LIN-MD-64 study intervention 
completers who enroll in LIN-MD-66 > 28 days from last study intervention, the following 
procedures will be performed at Screening (Visit 1):

Complete Rome III assessment

Instruct participants and caregivers about lifestyle modifications: increased water and 
fiber intake, increased physical activity, and consistent toileting habits. 

Perform a complete physical examination, including, at a minimum: general appearance, 
skin, HEENT (head, ears, eyes, nose, and throat), neck, thorax/lungs, cardiovascular, 
abdomen, musculoskeletal, lymph nodes, neurologic (including mental status), and visual 
inspection of the lumbosacral and perianal region. Breast and genitourinary examinations 
are optional at the discretion of the investigator

Obtain height, vital signs (weight, temperature [oral, rectal, or tympanic], and respiratory
rate), and postural vital signs (supine and standing systolic and diastolic BP and pulse 
rate) (Section 8.2.2)

Obtain standard 12-lead ECG (supine)

Obtain clinical laboratory tests consisting of clinical chemistry, hematology, and urinalysis
(see Table 10–1); all laboratory tests requiring blood draws should be collected at the 
same time

Obtain serum β-hCG pregnancy test for female participants of childbearing potential. 
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
104
GRD-CLN-T-01-01 v2.0

Obtain a urine drug screen at Screening (Visit 1) for all participants 12 to 17 years of age; 
a urine drug screen will be obtained for participants 6 to 11 years of age only if deemed 
necessary by the investigator. Urine drug screens may be repeated at the investigator’s 
discretion at any time during the study.
10.10.2.
Study Day 1 (Visit 2)
Screening Visit may be combined with Study Day 1 Visit in participants who enroll within 
≤28 days from last study intervention in the lead-in study provided no fecal impaction is found 
at Screening Visit. A fecal impaction assessment will be performed for all participants to 
determine continued eligibility for study participation. If there is no fecal impaction at Study
Day 1 (Visit 2) the participant may enter the study intervention period. If fecal impaction is 
present upon examination, the participant will not be eligible for the study. Participants will have 
to be in a fasted state for at least 2 hours before receiving their first dose of study intervention at 
the study site during Study Day 1 (Visit 2). Water will be allowed.
During the Study Day 1 (Visit 2), the following procedures will be performed for all participants:

Review inclusion and exclusion criteria 

Perform a fecal impaction assessment prior to dosing (Section 8.2.1)

Obtain vital signs (weight, temperature [oral, rectal, or tympanic], and respiratory rate) 
and postural vital signs (supine and standing systolic and diastolic BP and pulse rate)
(Section 8.2.2).

Obtain a urine pregnancy test for female participants of childbearing potential per 
guidance in Appendix 7: Pregnancy Testing.

Review any AEs occurring since the last visit, if applicable 

Review prior and concomitant medications

Contact IWRS to obtain study intervention

Administer the first dose of linaclotide after completion of all Visit 2 assessments and 
after confirming the participant has fasted for at least 2 hours. Participants may resume 
eating 30 minutes after receiving their first dose of study intervention at the study site
o
Participants who took their last dose of lead-in study intervention on the day of the 
EOT Visit and enroll into this study on that same day will take their first dose of 
study intervention outside of the clinic at a designated time the following day. 
Qualified site personnel will complete a follow-up phone call to participants within 
48 hours following initial study intervention administration to assess safety.

Dispense 1 bottle of linaclotide for this study after the first dose has been administered. 
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
105
GRD-CLN-T-01-01 v2.0

Record the date and time the first dose was administered

Remind participant and caregiver to bring the bottle of linaclotide to the next on-site visit
10.10.3.
Week 2 (Visit 3)
During Week 2 (Visit 3), the following will be performed via a phone visit with the participant:

Review any AEs occurring since the last visit

Review concomitant medications

Remind participant and caregiver to bring the bottle(s) of linaclotide to the next visit
10.10.4.
Week 4 (Visit 4)
During Week 4 (Visit 4), the following procedures will be performed:

Obtain urine pregnancy test for female participants of childbearing potential

Review any AEs occurring since the last visit

Review concomitant medications

Obtain vital signs (weight, temperature [oral, rectal, or tympanic], and respiratory rate) 
and postural vital signs (supine and standing systolic and diastolic BP and pulse rate)
(Section 8.2.2).

Review linaclotide compliance and accountability

Remind participant and caregiver to bring the bottle of linaclotide to the next visit

Contact IWRS to obtain study intervention

Dispense 1 bottle of linaclotide for this study
10.10.5.
Week 8 (Visit 5)
During Week 8 (Visit 5), the following procedures will be performed:

Obtain vital signs (weight, temperature [oral, rectal, or tympanic], and respiratory rate) 
and postural vital signs (supine and standing systolic and diastolic BP and pulse rate)
(Section 8.2.2).

Obtain urine pregnancy test for female participants of childbearing potential

Review any AEs occurring since the last visit

Review concomitant medications

Remind participant and caregiver to bring the bottles of linaclotide to the next visit
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
106
GRD-CLN-T-01-01 v2.0

Contact IWRS to obtain study intervention

Dispense 2 bottles of linaclotide
10.10.6.
Week 16 (Visit 6)
During Week 16 (Visit 6), the following procedures will be performed:

Obtain vital signs (weight, temperature [oral, rectal, or tympanic], and respiratory rate) 
and postural vital signs (supine and standing systolic and diastolic BP and pulse rate)
(Section 8.2.2).

Obtain urine pregnancy test for female participants of childbearing potential

Review any AEs occurring since the last visit

Review concomitant medications

Review linaclotide compliance and accountability

Remind participant and caregiver to bring the bottles of linaclotide to the next visit

Contact IWRS to obtain study intervention

Dispense 2 bottles of linaclotide
10.10.7.
Week 24/EOT Visit (Visit 7) for FC Participants
All enrolled participants who prematurely discontinue from the study, regardless of cause, are 
required to return for the EOT study assessments.
During Week 24/EOT (Visit 7), the following procedures will be performed:

Perform a complete physical examination, including general appearance, skin, HEENT
(head, ears, eyes, nose, and throat), neck, thorax/lungs, cardiovascular, abdomen, 
musculoskeletal, lymph nodes, neurologic (including mental status), and visual inspection 
of the lumbosacral and perianal region. Breast and genitourinary examinations are 
optional at the discretion of the investigator

Complete Rome III assessment

Obtain height, vital signs (weight, temperature [oral, rectal, or tympanic], and respiratory
rate), and postural vital signs (supine and standing systolic and diastolic BP and pulse 
rate) (Section 8.2.2).

Obtain standard 12-lead ECG (supine)

Obtain clinical laboratory tests consisting of clinical chemistry, hematology, and 
urinalysis. All laboratory tests requiring blood draws should be collected at the same time
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
107
GRD-CLN-T-01-01 v2.0

Obtain urine pregnancy test for female participants of childbearing potential

Review any AEs occurring since the last visit

Review concomitant medications

Review linaclotide compliance and accountability

Return study intervention
10.10.8.
Week 24 (Visit 7) for IBS-C Participants
During Week 24 (Visit 7), the following procedures will be performed:

Obtain vital signs (weight, temperature [oral, rectal, or tympanic], and respiratory rate) 
and postural vital signs (supine and standing systolic and diastolic BP and pulse rate) 
(Section 8.2.2).

Obtain urine pregnancy test for female participants of childbearing potential

Review any AEs occurring since the last visit

Review concomitant medications

Review linaclotide compliance and accountability

Remind participant and caregiver to bring the bottles of linaclotide to the next visit

Contact IWRS to obtain study intervention

Dispense 2 bottles of linaclotide
10.10.9.
Week 32 (Visit 8) for IBS-C Participants
During Week 32 (Visit 8), the following procedures will be performed:

Obtain vital signs (weight, temperature [oral, rectal, or tympanic], and respiratory rate) 
and postural vital signs (supine and standing systolic and diastolic BP and pulse rate)
(Section 8.2.2).

Obtain urine pregnancy test for female participants of childbearing potential

Review any AEs occurring since the last visit

Review concomitant medications

Review linaclotide compliance and accountability

Remind participant and caregiver to bring the bottles of linaclotide to the next visit

Contact IWRS to obtain study intervention

Dispense 2 bottles of linaclotide
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
108
GRD-CLN-T-01-01 v2.0
10.10.10. Week 40 (Visit 9) for IBS-C Participants
During Week 40 (Visit 9), the following procedures will be performed:

Obtain vital signs (weight, temperature [oral, rectal, or tympanic], and respiratory rate) 
and postural vital signs (supine and standing systolic and diastolic BP and pulse rate)
(Section 8.2.2).

Obtain urine pregnancy test for female participants of childbearing potential

Review any AEs occurring since the last visit

Review concomitant medications

Review linaclotide compliance and accountability

Remind participant and caregiver to bring the bottles of linaclotide to the next visit

Contact IWRS to obtain study intervention

Dispense 3 bottles of linaclotide
10.10.11. Week 52/EOT (Visit 10) for IBS-C Participants
All enrolled participants who prematurely discontinue from the study, regardless of cause, are 
required to return for the EOT study assessments.
During Week 52/EOT (Visit 10), the following procedures will be performed:

Perform a complete physical examination, including general appearance, skin, HEENT
(head, ears, eyes, nose, and throat), neck, thorax/lungs, cardiovascular, abdomen, 
musculoskeletal, lymph nodes, neurologic (including mental status), and visual inspection 
of the lumbosacral and perianal region. Breast and genitourinary examinations are 
optional at the discretion of the investigator

Complete Rome III assessment

Obtain height, vital signs (weight, temperature [oral, rectal, or tympanic], and respiratory
rate), and postural vital signs (supine and standing systolic and diastolic BP and pulse 
rate) (Section 8.2.2).

Obtain standard 12-lead ECG (supine)

Obtain clinical laboratory tests consisting of clinical chemistry, hematology, and urinalysis 
All laboratory tests requiring blood draws should be collected at the same time

Obtain urine pregnancy test for female participants of childbearing potential

Review any AEs occurring since the last visit.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
109
GRD-CLN-T-01-01 v2.0

Review concomitant medications

Review linaclotide compliance and accountability

Return study intervention
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
110
GRD-CLN-T-01-01 v2.0
10.11.
Appendix 11: Study Conduct During the Novel Coronavirus 
Pandemic
Any participant who was designated as a screen failure or a preintervention failure during the 
screen hold due to the novel coronavirus pandemic may be rescreened.
Any participant that terminated study treatment early due to the novel coronavirus pandemic may
be rescreened.
In the event of a prolonged persistence or re-emergence of the novel coronavirus pandemic, 
interim actions to mitigate the potential risks to participants and study staff while continuing 
study conduct will be communicated to sites via a Protocol Clarification Letter, which would be 
implemented in accordance with the appropriate local IRB/EC approval process.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure

CONFIDENTIAL
Protocol LIN-MD-66, Amendment 2
Linaclotide
111
GRD-CLN-T-01-01 v2.0
11.
References
Bryant AP, Busby RW, Bartolini WP, et al. Linaclotide is a potent and selective guanylate cyclase 
C agonist that elicits pharmacological effects locally in the gastrointestinal tract. Life Sci 
2010;86:760-765.
Chiou E, Nurko S. Management of functional abdominal pain and irritable bowel syndrome in 
children and adolescents. Expert Rev Gastroenterol Hepatol. 2010;4(3):293-304.
Cohen MB, Guarino A, Shukla R, Giannella RA. Age-related differences in receptors for 
Escherichia coli heat-stable enterotoxin in the small and large intestine of children. 
Gastroenterology. 1988;94:367-373.
Drossman DA. The Functional Gastrointestinal Disorders and the Rome III Process. 
Gastroenterology 2006;130(5):1377-1390.
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.
Guarino A, Cohen MB, Giannella RA. Small and large intestinal guanylate cyclase activity in 
children: Effect of age and stimulation by Escherichia coli heat-stable enterotoxin. Pediatr Res 
1987;21:551-555.
Hyams JS, Di Lorenzo C, Saps M, Shulman RJ, Staiano A, van Tilburg M. Childhood Functional 
Gastrointestinal Disorders: Child/Adolescent. Gastroenterology. 2016;150:1456-1468.
Koppen LJN, Saps M, Lavigne JV, et al. Recommendations for pharmacological clinical trials in 
children with functional constipation: The Rome foundation pediatric subcommittee on clinical 
trials. Neurogastroenterol Motil. 2018;30(4):e13294.
Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional 
bowel disorders. Gastroenterol. 2006;130:1480-1491.
Thompson WG, Longstreth GF, Drossman DA, Heaton KW, Irvine EJ, Muller-Lissner SA. 
Functional bowel disorders and functional abdominal pain. Gut 1999;45(Suppl II):II43-II47.
Approval Date: 30-Apr-2021 22:48:03 (GMT)
Anonymized Document for Public Disclosure