Clinical trial NCT04110145
Conditions: Functional Constipation
Keywords: Functional constipation in children LINZESS
Sponsor: Allergan
Start date: 2019-10-14; Completion date: 2021-04-20
Enrollment: 35 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to evaluate the dose response, safety, and efficacy of linaclotide when compared with placebo in pediatric participants, 2 to 5 years of age, with Functional Constipation.

Detailed description:

Arms: arm 1: Linaclotide 18 microgram (μg), capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period. arm 2: Linaclotide 36 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period. arm 3: Linaclotide 72 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period. arm 4: Linaclotide at the highest dose tested/determined to be safe (72 μg), capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period. arm 5: Matching placebo, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period pooled from Cohorts 1, 2, 3, and Final Cohort.
Interventions: intervention 1: Linaclotide intervention 2: Placebo
Intervention descriptions: intervention 1: Linaclotide, capsules, mixed with water and administered orally, once daily in fasted state. intervention 2: Matching placebo, capsules, mixed with water and administered orally, once daily in fasted state

Protocol documents:
Prot_000.pdf: 
NCT04110145


CONFIDENTIAL
Protocol LIN-MD-67, Amendment 1
linaclotide
2
GRD-CLN-T-01-01 v2.0
Protocol Amendment Summary of Changes 
DOCUMENT HISTORY
Document
Date
Amendment 1
May 2020
Original Protocol
May 2019
Amendment 1 (May 2020)
The purpose of Global Protocol Amendment 1 is to include an assessment of modified Rome III 
criteria at the end of treatment as an ‘other’ efficacy endpoint, to include a fecal impaction 
assessment at Visit 3 prior to randomization and dosing, and to provide additional clarification 
and updates to the LIN-MD-67 protocol (dated 01 May 2019).
The following is a summary of changes made in Global Protocol Amendment 1. 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.
Approval Date: 04-May-2020 21:25:29 (GMT)


CONFIDENTIAL
Protocol LIN-MD-67, Amendment 1
linaclotide
3
GRD-CLN-T-01-01 v2.0
Protocol Section(s)
Description of Changes
Rationale for Changes
Section 1.1 Synopsis
!
EMEA was removed from the following sentence: Up to 40 sites from the United 
States, and Canada and EMEA are expected to participate in the study.
!
To reflect current information
Section 1.3 Schedule of 
Activities (SoA)
!
An assessment of modified Rome III criteria at EOT was added 
!
IWRS verification was added to the EOT Visit
!
A fecal impaction assessment at Randomization (Visit 3) was added for all 
participants. A footnote describing this has also been added and numbering of the 
subsequent footnotes has been updated accordingly.
!
Footnote ‘o’ was revised as follows: ‘…and the global change items will be 
completed beginning at from one week after randomization through End of
Study’
!
To assess participants for 
fulfilling modified Rome III
criteria at end of treatment as 
an ‘other’ efficacy endpoint.
!
For clarification
!
To ensure participants don’t 
have fecal impaction prior to 
receiving study intervention
!
To allow an appropriate 
amount of time from 
randomization to complete 
the weekly assessment
Section 2 Introduction
!
‘Australia’ was added to the list of countries where linaclotide is approved for 
treatment of IBS-C and CIC.
!
Text added to include the pediatric Phase 2 study LIN-MD-63 results. 
!
To reflect current information
Section 2.2.1 Adult Linaclotide 
Program
!
The following sentence was deleted: A summary of these studies and major 
conclusions are provided in Section 10.9.
!
Text added to include the recently completed Phase 3b study MCP-103-312.
!
To reflect current information
Section 2.2.2 Pediatric 
Linaclotide Program
!
A summary of results for the recently completed LIN-MD-63 study in pediatric 
IBS-C participants was added.
!
To reflect current information
Section 2.2.3.2 GC-C mRNA 
Expression
!
Corrected the study number for Study MCP-103-311 
!
Correction of typo
Section 4.1 Overall Design
!
The word ‘modified’ was added to the following sentence: ‘Study LIN-MD-67 is a 
Phase 2 randomized, double-blind, placebo-controlled, sequential, ascending 
multidose study with a 4-week Study Intervention Period in participants, 2 to 5 
years of age, who meet modified Rome III criteria for childhood FC.’
!
Europe was removed from the following sentence: Up to 40 sites from the United 
States, and Canada and Europe are expected to participate in the study.
!
For clarification
!
To reflect current information
Approval Date: 04-May-2020 21:25:29 (GMT)


CONFIDENTIAL
Protocol LIN-MD-67, Amendment 1
linaclotide
4
GRD-CLN-T-01-01 v2.0
Protocol Section(s)
Description of Changes
Rationale for Changes
Section 4.3 Justification for Dose
!
Corrected the study number for Study MCP-103-311
!
The source for Figure 4-2 was added
!
Correction of typo
!
For clarification
Section 5.2 Exclusion Criteria
!
‘Vital sign assessment’ was included in exclusion criteria 1.01 and edits were 
made to exclusion criteria 1.05 and 1.09 to add clarity. 
!
Exclusion criterion 1.04 was revised to add ‘fecal impaction at Visit 3’ as an 
exclusion criterion.
!
For clarification
!
To ensure participants don’t 
have fecal impaction prior to 
dosing
Section 6 Study Intervention
!
The following sentence was deleted: The study intervention does not have 
marketing authorization in the EU for the pediatric indication.
!
Removed since EU sites will 
not be included in the study
Section 6.3 Measures to 
Minimize Bias: Randomization 
and Blinding
!
Revised the study number from 301 to 267
!
Revised the site number from 00001-99999 to 10001-19999
!
To reflect what’s being used 
in the study
Section 6.5.1 Prohibited 
Interventions and Washout 
Before the Study
!
Added linaclotide to the list of prohibited medicines with a 14-day washout period
!
To provide additional clarity
Section 6.5.2 Rescue Medication
!
The following text regarding rescue medication options was deleted: Participants 
outside of the United States and Canada will have a choice of at least one of the 
following medications: senna (oral), mineral oil enema (rectal), or sodium 
picosulphate (oral) that will be dispensed according to the SOA (Section 1.3).
!
Removed since only sites 
from the US and Canada will 
participate in the study.
Section 7.1.1 Removal of 
Individual Participants from 
Therapy or Assessment
!
Text referring to signs of drug-induced liver injury was moved to newly added 
Appendix 9: Liver Safety: Suggested Actions and Follow-up Assessments.
!
To align with the liver 
appendix template
Section 8 Study Assessments and 
Procedures
!
The following text was added: ‘Additional details regarding study conduct 
during the novel coronavirus pandemic are provided in Appendix 10.’
!
To add a reference to newly 
added Appendix 10.
Section 8.1 Efficacy Assessment
!
The following text was deleted: ‘The relationship of the caregiver to the participant 
should be recorded in the eCRF.’
!
To reflect current information
Approval Date: 04-May-2020 21:25:29 (GMT)


CONFIDENTIAL
Protocol LIN-MD-67, Amendment 1
linaclotide
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GRD-CLN-T-01-01 v2.0
Protocol Section(s)
Description of Changes
Rationale for Changes
Section 8.1.2 Other Efficacy 
Assessments
!
Added an assessment of modified Rome III criteria at the end of the study 
intervention period 
!
The wording of the global change item question was revised along with the starting 
time of the assessment
!
To assess participants for 
fulfilling modified Rome III 
criteria at both screening and 
at end of treatment 
!
To reflect current information
Section 8.2.1 Physical 
Examinations
!
Added a fecal impaction assessment at randomization (Visit 3) prior to dosing 
!
To ensure participants don’t 
have fecal impaction prior to 
receiving study intervention
Section 8.2.3 Electrocardiograms
!
Revised text to clarify method for recording ECGs.
!
To provide additional clarity
Section 8.3.6 Potential Hy’s Law 
Cases
!
Details regarding liver safety assessments and follow-up for potential Hy’s law 
cases were moved to newly added Appendix 9: Liver Safety: Suggested Actions 
and Follow-up Assessments
!
To align with the liver 
appendix template
Section 9.1. Statistical Endpoints
!
Added the ‘other’ efficacy endpoint of ‘Proportion of participants who no 
longer fulfill modified Rome III criteria for functional constipation at the end 
of the Study Intervention Period.’
!
To assess whether 
participants no longer meet 
modified Rome III criteria at 
the end of the study 
intervention period as an 
‘other’ efficacy endpoint. 
Section 9.4.1.1 Key Efficacy 
Endpoints
!
The following text was added: ‘Stool consistency for each caregiver-observed 
BM will be measured daily in the eDiary using the 7-point ordinal BSFS’
!
The following text was added: ‘The participant’s daily straining score for each 
caregiver-observed BM will be derived based on the average of non-missing 
responses of the two straining questions.’
!
For clarification
!
For clarification
Section 9.4.1.2 Other Efficacy 
Endpoints
!
Added text for the other efficacy endpoint of ‘Proportion of participants who no 
longer fulfill modified Rome III criteria for functional constipation at the end 
of the Study Intervention Period.’
!
To reflect how fulfillment of 
modified Rome III criteria is 
being assessed in the study
Section 9.4.2.2 Clinical 
Laboratory Assessments
!
The following text was added: ‘The numerator will be the total number of 
participants with available non-PCS baseline values and at least 1 PCS 
postbaseline value …’
!
For clarification
Approval Date: 04-May-2020 21:25:29 (GMT)


CONFIDENTIAL
Protocol LIN-MD-67, Amendment 1
linaclotide
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GRD-CLN-T-01-01 v2.0
Protocol Section(s)
Description of Changes
Rationale for Changes
Section 10.1.11 Study 
Documentation
!
The following text was deleted: ‘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).’
!
Removed since EU sites will 
not be included in the study
Section 10.1.6.3 DSMB
!
Added ‘or ad hoc if needed’
!
For clarification
Section 10.2 Appendix 2: 
Clinical Laboratory Tests
!
%Reticulocytes was removed from Table 10-1 
!
Footnote ‘a’ was revised to refer to Appendix 9: Liver Safety: Suggested Actions 
and Follow-up Assessments for liver chemistry stopping criteria and required 
actions and follow-up assessments
!
To reflect what’s being 
assessed in the study
!
To align with the liver 
appendix template 
Section 10.3 Appendix 3: 
Adverse Events
!
Text updated to align with the timing of AE collection in the body of the protocol
!
Text regarding reporting of potential Hy’s Law cases was moved to newly added 
Appendix 9: Liver Safety: Suggested Actions and Follow-up Assessments
!
To reflect current information
!
To align with the liver 
appendix template
Section 10.6 Appendix 6: Study 
Tabular Summary
!
‘EMEA’ was removed from the Planned Country of Investigational Sites as 
follows: United States, and Canada, and EMEA
!
To reflect current information
Section 10.7 Appendix 7: 
Instructions for Dosing
!
Additional text was added regarding instructions for dosing and the capsule 
strengths to be used for dosing.
!
To provide additional clarity
Section 10.8.1 Screening 
(Visit 1)
!
The following procedure was added to the Screening Visit: ‘Complete modified 
Rome III assessment’. 
!
‘Lumbosacral’ was added to the physical exam description.
!
For clarification and update to 
reflect current information
Section 10.8.3 Randomization 
(Visit 3, Day 1)
!
A fecal impaction assessment was added to the randomization visit (Visit 3) as 
shown: ‘Perform a fecal impaction assessment prior to randomization. If fecal 
impaction is present, the participant will not be eligible for the study.’
!
To ensure participants don’t 
have fecal impaction prior to 
receiving study intervention
Section 10.8.5 Week 4/EOT 
(Visit 5)
!
The following was added to the EOT Visit: ‘IWRS verification’
!
‘Lumbosacral’ was added to the physical exam description
!
The following procedure was added to the EOT Visit: ‘Complete modified 
Rome III assessment.’
!
For clarification
!
For clarification
!
To assess participants for 
fulfilling modified Rome III
criteria at the end of 
treatment as an ‘other’
efficacy endpoint.
Approval Date: 04-May-2020 21:25:29 (GMT)


CONFIDENTIAL
Protocol LIN-MD-67, Amendment 1
linaclotide
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GRD-CLN-T-01-01 v2.0
Protocol Section(s)
Description of Changes
Rationale for Changes
Section 10.9 Appendix 9: Liver 
Safety: Suggested Actions and 
Follow-up Assessments
!
Appendix 9: Liver Safety: Suggested Actions and Follow-up Assessments was 
added.
!
To provide liver safety 
information in a consolidated 
location and to align with the 
liver appendix template
Section 10.10 Appendix 10: 
Study Conduct During the Novel 
Coronavirus Pandemic: Pre-
randomization
!
Appendix 10: Study Conduct During the Novel Coronavirus Pandemic: Pre-
randomization was added
!
To provide information on 
study conduct during the 
novel coronavirus pandemic
Approval Date: 04-May-2020 21:25:29 (GMT)


CONFIDENTIAL
Protocol LIN-MD-67, Amendment 1
linaclotide
8
GRD-CLN-T-01-01 v2.0
Table of Contents
Title Page ........................................................................................................................................1
Protocol Amendment Summary of Changes...............................................................................2
Table of Contents...........................................................................................................................8
List of Tables ................................................................................................................................11
List of Figures...............................................................................................................................11
1.
Protocol Summary........................................................................................................12
1.1.
Synopsis..........................................................................................................................12
1.2.
Schema............................................................................................................................16
1.3.
Schedule of Activities (SoA)..........................................................................................17
2.
Introduction...................................................................................................................19
2.1.
Study Rationale...............................................................................................................19
2.2.
Background.....................................................................................................................20
2.2.1.
Adult Linaclotide Program .............................................................................................20
2.2.2.
Pediatric Linaclotide Program ........................................................................................21
2.2.3.
Other Nonclinical Information........................................................................................23
2.2.3.1.
Nonclinical Toxicology ...............................................................................................23
2.2.3.2.
GC-C mRNA Expression.............................................................................................24
2.2.4.
Post-marketing Experience.............................................................................................24
2.3.
Benefit/Risk Assessment ................................................................................................24
3.
Objectives and Endpoints ............................................................................................25
4.
Study Design..................................................................................................................25
4.1.
Overall Design................................................................................................................25
4.2.
Scientific Rationale for Study Design ............................................................................27
4.3.
Justification for Dose......................................................................................................27
4.4.
End of Study Definition..................................................................................................29
4.5.
End of Cohort Definition................................................................................................29
5.
Study Population...........................................................................................................29
5.1.
Inclusion Criteria ............................................................................................................29
5.2.
Exclusion Criteria ...........................................................................................................31
5.3.
Lifestyle Considerations .................................................................................................34
5.4.
Screen Failures................................................................................................................35
6.
Study Intervention........................................................................................................35
6.1.
Study Intervention(s) Administered................................................................................35
6.1.1.
Selection and Timing of Dose for Each Participant........................................................36
6.2.
Preparation/Handling/Storage/Accountability................................................................36
6.3.
Measures to Minimize Bias: Randomization and Blinding............................................37
6.3.1.
Blinding and Unblinding.................................................................................................38
6.3.1.1.
Blinding........................................................................................................................38
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CONFIDENTIAL
Protocol LIN-MD-67, Amendment 1
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6.3.1.2.
Unblinding ...................................................................................................................38
6.4.
Study Intervention Compliance ......................................................................................38
6.5.
Prior and Concomitant Therapy......................................................................................39
6.5.1.
Prohibited Interventions and Washout Before the Study................................................39
6.5.2.
Rescue Medication..........................................................................................................41
6.6.
Dose Modification ..........................................................................................................41
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................42
7.1.
Discontinuation of Study Intervention............................................................................42
7.1.1.
Removal of Individual Participants from Therapy or Assessment .................................42
7.1.2.
Criteria for Consideration of Study Discontinuation......................................................43
7.2.
Participant Discontinuation/Withdrawal from the Study................................................44
7.3.
Lost to Follow-Up...........................................................................................................44
8.
Study Assessments and Procedures.............................................................................45
8.1.
Efficacy Assessments .....................................................................................................45
8.1.1.
Key Efficacy Assessments..............................................................................................46
8.1.2.
Other Efficacy Assessments ...........................................................................................48
8.2.
Safety Assessments.........................................................................................................49
8.2.1.
Physical Examinations....................................................................................................50
8.2.2.
Vital Signs.......................................................................................................................51
8.2.3.
Electrocardiograms .........................................................................................................51
8.2.4.
Clinical Safety Laboratory Assessments ........................................................................51
8.3.
Adverse Events and Serious Adverse Events .................................................................52
8.3.1.
Adverse Events of Special Interest (AESIs)...................................................................53
8.3.2.
Time Period and Frequency for Collecting Adverse Events, 
Serious Adverse Events, and Adverse Events of Special Interest 
Information .....................................................................................................................53
8.3.3.
Method of Detecting Adverse Events, Serious Adverse Events, 
and Adverse Events of Special Interest ..........................................................................54
8.3.4.
Follow-up of Adverse Events, Serious Adverse Events, and 
Adverse Events of Special Interest .................................................................................54
8.3.5.
Regulatory Reporting Requirements for Serious Adverse Events..................................54
8.3.6.
Potential Hy’s Law Cases...............................................................................................55
8.3.7.
Medication Errors ...........................................................................................................55
8.4.
Treatment of Overdose ...................................................................................................56
8.5.
Pharmacokinetics............................................................................................................56
8.5.1.
Blood Pharmacokinetic Sampling Procedure .................................................................56
8.5.2.
Pharmacokinetic Sample Bioanalysis.............................................................................57
8.6.
Pharmacodynamics.........................................................................................................57
8.7.
Genetics ..........................................................................................................................57
8.8.
Biomarkers and Other Assessments ...............................................................................57
8.9.
Health Economics...........................................................................................................57
9.
Statistical Considerations.............................................................................................57
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9.1.
Statistical Endpoints .......................................................................................................57
9.2.
Sample Size Determination ............................................................................................58
9.3.
Populations for Analyses ................................................................................................58
9.4.
Statistical Analyses.........................................................................................................59
9.4.1.
Efficacy Analyses ...........................................................................................................59
9.4.1.1.
Key Efficacy Endpoints ...............................................................................................60
9.4.1.2.
Other Efficacy Endpoints.............................................................................................61
9.4.2.
Safety Analyses...............................................................................................................61
9.4.2.1.
Adverse Events ............................................................................................................61
9.4.2.2.
Clinical Laboratory Assessments.................................................................................62
9.4.2.3.
Vital Signs....................................................................................................................62
9.4.2.4.
Electrocardiograms ......................................................................................................63
9.4.3.
Pharmacokinetic Analyses..............................................................................................63
9.4.4.
Subgroup Analyses .........................................................................................................63
9.5.
Interim Analyses.............................................................................................................63
10.
Supporting Documentation and Operational Considerations..................................64
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................64
10.1.1.
Regulatory and Ethical Considerations...........................................................................64
10.1.2.
Financial Disclosure........................................................................................................64
10.1.3.
Informed Consent Process ..............................................................................................65
10.1.4.
Data Protection................................................................................................................66
10.1.5.
Posting Clinical Study Data............................................................................................66
10.1.6.
Data Quality Assurance ..................................................................................................67
10.1.6.1.
Data Monitoring...........................................................................................................67
10.1.6.2.
Data Recording and Documentation............................................................................68
10.1.6.3.
Data and Safety Monitoring Board (DSMB)...............................................................68
10.1.7.
Source Documents ..........................................................................................................68
10.1.8.
Study and Site Closure....................................................................................................69
10.1.9.
Publication Policy...........................................................................................................69
10.1.10. Compliance with Protocol...............................................................................................69
10.1.11. Study Documentation......................................................................................................70
10.2.
Appendix 2: Clinical Laboratory Tests...........................................................................71
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.........................................................73
Definition of AE ............................................................................................................................73
Definition of SAE ..........................................................................................................................75
Recording and Follow-Up of AE and/or SAE...............................................................................77
Reporting of SAEs.........................................................................................................................78
10.4.
Appendix 4: Abbreviations.............................................................................................79
10.5.
Appendix 5: Standard Discontinuation Criteria..............................................................81
10.6.
Appendix 6: Study Tabular Summary............................................................................83
10.7.
Appendix 7: Instructions for Dosing ..............................................................................86
10.8.
Appendix 8: Study Schedule Supplement ......................................................................87
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10.8.1.
Screening (Visit 1)..........................................................................................................87
10.8.2.
Preintervention Period (Visit 2)......................................................................................88
10.8.3.
Randomization (Visit 3, Day 1)......................................................................................89
10.8.4.
Week 2 (Visit 4)..............................................................................................................91
10.8.5.
Week 4/EOT (Visit 5).....................................................................................................91
10.8.6.
End of Study Visit /Postintervention Follow-up (1 week)..............................................93
10.9.
Appendix 9: Liver Safety: Suggested Actions and Follow-up 
Assessments....................................................................................................................94
10.10.
Appendix 10: Study Conduct During the Novel Coronavirus 
Pandemic: Pre-randomization.........................................................................................96
10.11.
Appendix 11: Supporting Information from the Adult Linaclotide 
Program...........................................................................................................................97
11.
References......................................................................................................................98
List of Tables
Table 2–1
Dose Levels (μg) by Weight in Pediatric Participants Treated with Linaclotide in 
LIN-MD-62........................................................................................................... 22
Table 2-2
Dose Levels (μg) by Weight in Pediatric IBS-C Participants Treated with 
Linaclotide in LIN-MD-63 ................................................................................... 23
Table 10–1
Protocol-Required Safety Laboratory Assessments.............................................. 72
List of Figures
Figure 1-1
Assignment of Participants to Dose Cohorts ........................................................ 15
Figure 4-1
Assignment of Participants to Dose Cohorts ........................................................ 27
Figure 4-2
Change from Baseline in 4-week Overall SBM Frequency Rate by Dose in μg/kg 
(ITT Population, LIN-MD-62).............................................................................. 28
Figure 10–1
Change from Baseline over the First 4 Weeks in Observed SBM/Week by Dose in 
μg/kg: ITT Population of Phase 2 and 3 Adult CIC Population........................... 97
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1.
Protocol Summary
1.1.
Synopsis
Protocol Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Sequential, 
Ascending, Multidose Study to Evaluate the Safety and Efficacy of Linaclotide in Pediatric 
Participants (Age 2 to 5 Years) with Functional Constipation
Protocol Number: LIN-MD-67
Amendment Number: 1
Brief Title: Linaclotide Safety and Efficacy in 2 to 5-Year Old Participants with Functional 
Constipation 
Study Phase: 2
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 dis-impaction (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.
Despite the fact that children with FC are commonly prescribed various and miscellaneous 
pharmacologic agents for FC, it is notable that there are no approved products indicated for FC 
in children or well controlled trials of these frequently prescribed agents. Thus, effective 
treatments are needed to provide symptomatic relief in children and adolescents with FC, with 
the evidence for safety and efficacy of these based on the results of adequate and well-controlled 
studies in children.
For the primary and key secondary endpoints in the Phase 2 dose-ranging LIN-MD-62 study in 
children, 6 to 17 years of age, with FC, none of the 3 linaclotide doses (A [low dose], B [medium 
Approval Date: 04-May-2020 21:25:29 (GMT)


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Protocol LIN-MD-67, Amendment 1
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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 towards efficacy at the higher doses 
was observed for the primary endpoint of change from baseline in 4-week overall spontaneous 
bowel movement (SBM) frequency rate (SBMs/week). Overall, linaclotide was well tolerated 
across all doses in participants, 6 to 17 years of age. The safety profile was consistent with prior 
adult linaclotide chronic idiopathic constipation (CIC) studies.
As linaclotide was well tolerated across all doses tested in 6 to 17-year old participants treated in 
LIN-MD-62, LIN-MD-67 is being initiated in younger children with the primary objective of 
evaluating the dose response, safety, and efficacy of 4 weeks of linaclotide in pediatric 
participants, 2 to 5 years of age, with FC.
Objectives and Endpoints:
The objective of LIN-MD-67 is to evaluate the dose response, safety, and efficacy of 4 weeks of 
study intervention with linaclotide compared with placebo in pediatric participants, 2 to 5 years 
of age, with FC.
Key efficacy endpoints include:
!
Change from baseline in 4-week overall SBM frequency rate (SBMs/week) during the 
Study Intervention Period of each cohort
!
Change from baseline in 4-week stool consistency reported by the caregiver during the 
Study Intervention Period of each cohort
!
Change from baseline in 4-week straining reported by the caregiver during the Study 
Intervention Period of each cohort
!
Proportion of days with fecal incontinence during the Study Intervention Period (for 
participants who have acquired toileting skills during the daytime and nighttime or 
acquired toileting skills during daytime only) within each cohort
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:
Study LIN-MD-67 is a Phase 2 randomized, double-blind, placebo-controlled, sequential, 
ascending multidose study with a 4-week study intervention period in participants, 2 to 5 years of 
age, with FC. 
Number of Participants:
Up to 30 participants, 2 to 5 years of age, will be sequentially enrolled into LIN-MD-67; 8
participants each into Cohorts 1 to 3 and 6 participants in the final cohort. Participants will be 
randomly assigned to receive linaclotide or matching placebo as described below.
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Number of Sites:
Up to 40 sites from the United States and Canada are expected to participate in the study.
Study Intervention Groups and Study Duration:
The study will consist of up to 4 cohorts, each of which will be studied for 9 to 12 weeks in 
duration: 2 to 4-week Screening Period, a 2 to 3-week Preintervention Period, followed by a 
4-week double-blind Study Intervention Period, and a 1-week Postintervention Period 
(Section 1.2).
Participants will not receive study intervention during the Screening/Preintervention Period and 
the Postintervention Period. 
After at least 6 participants in Cohorts 1 to 3 complete at least 2 weeks of double-blind study 
intervention, an independent DSMB will review unblinded interim safety data. Based on this 
review, the DSMB will recommend whether the subsequent planned dose level should be tested. 
New participants will be recruited for each cohort.
Please refer to Figure 1-1 for assignment of participants to dose cohorts.
!
Cohorts 1-3: 8 participants will be randomized at a ratio of 3:1 to receive linaclotide or 
matching placebo:
o
Cohort 1: linaclotide 18 μg or matching placebo once daily for 4-week Study 
Intervention Period.  
o
Cohort 2: linaclotide 36 μg or matching placebo once daily for 4-week Study 
Intervention Period. The DSMB will have the option to recommend the lower 
dose of linaclotide  μg instead of the 36 μg dose, based on review of unblinded 
interim safety data from Cohort 1.
o
Cohort 3: linaclotide 72 μg or matching placebo once daily for 4-week Study 
Intervention Period. Participants will only be assigned to this cohort if the DSMB 
recommends proceeding to this 72 μg dose based on unblinded interim safety data 
from Cohort 2 with the linaclotide 36 μg dose. 
!
Final Cohort: 6 participants will be randomized at a ratio of 5:1 to receive linaclotide at 
the highest dose tested/determined to be safe or matching placebo for 4-week Study 
Intervention Period (ie,
18, 36, 72 μg depending on the recommendation of the 
DSMB).
Data and Safety Monitoring Board (DSMB): Yes
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1.2.
Schema
Study duration will be 9 to 12 weeks for each cohort with 4 weeks of study intervention as 
described below. 
Note: There is no Day 0.
a
The participant must complete at least 4 weeks (28 days) of double-blind study intervention before Week 4 Visit. 
The last dose of study intervention will be administered at the study site for the Visit 5 (Week 4) visit on Day 29 
(+2) at approximately the same time as on other days of study intervention administration. The participant should 
arrive at the study site in fasted state. On the same day, a PK sample will also be taken at the same time as other 
safety laboratory assessments required at this visit (Section 8.5.1). 
b
All randomized participants who prematurely discontinue from the study, regardless of cause, must be seen for 
the assessments to be completed at this EOT Visit (Week 4/Visit 5).
c
The Postintervention Visit has to be at least 7 days after the Week 4 visit.
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1.3.
Schedule of Activities (SoA)
Schedule of Evaluations LIN-MD-67
Study Periods (Duration)
Screening 
(14-28 Days)
Preintervention 
(14-21 Days)
Study Intervention (29 Days)
Postintervention
(7 Days)
Screeninga
Preintervention
Randomizationb Week 2 Week 4/EOTc,d
1 Week 
Postintervention
Visit
End of Study 
Study Visit 
1
2
3
4
5
6
Study Day 
1
15 (± 2)
29 (+ 2)
Week 4/EOT + 7 
(+2)
Parent/LAR/Caregiver Consente
X
Inclusion and Exclusion Criteria
X
X
X
Modified Rome III Assessment
X
X
Assess Rome IV statusf
X
IWRS 
X
X
X
X
PK Random Assignment in 
IWRSg
X
Medical History
X
Lifestyle Modification 
Information Given to Caregiver
X
Physical Examinationh
X
X
Fecal Impaction Assessmenti
X
Xi
Xj
Height
X
Vital Signs, Postural Vital 
Signsk
X
X
X
X
X
X
ECG
X
X
Clinical Laboratory Testsl
X
X
PK Sampleg
Xm
AE Evaluation
X
X
X
X
X
X
Prior and Concomitant 
Medications
X
X
X
X
X
X
Dispense Rescue Medicationn
X
X
X
X
eDiary and Instructions Given 
to Caregivero
X
eDiary Eligibility Reportp
X
eDiary Complianceo
X
X
X
X
Study intervention administered 
in the clinic
Xb
Xc
Study intervention dispensed
X
IP and Rescue Medication 
Compliance and Accountability
X
X
X
Xq
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a
During the Screening Period, caregivers will receive information regarding lifestyle modifications. There should be at least a 
2-week interval between discussing the lifestyle modifications during the Screening Period and the participant’s entry into 
the Preintervention Period.
b
Study intervention will be administered in the study site after confirming the participant has fasted for at least 2 hours during 
the Randomization Visit (Day 1) after running the Eligibility report. IWRS will be contacted to obtain the study intervention
(bottle number) to be dispensed. Participants may eat 30 minutes after dosing (the requirement for study intervention to be 
administered 30 minutes prior to the meal will not apply for the first dose).
c
The participant must complete at least 4 weeks (28 days) of study intervention before returning for Visit 5 (Week 4). The 
last dose of study intervention will be administered at the study site at the Visit 5 (Week 4) visit on Day 29 (+2) at 
approximately the same time as on other days of study intervention administration. Caregivers will be instructed when the 
participants should fast to ensure they have fasted for at least 2 hours before receiving their last dose of study intervention
(Section 10.8.3)
d
All randomized participants who prematurely discontinue from the study, regardless of cause, are required to be seen for the
assessments completed at EOT (Visit 5, Week 4), except for PK sample collection.
e
The parent/guardian/legally authorized representative must provide written informed consent before the participant’s 
enrollment in the study. If a parent or legal guardian is also the participant’s caregiver, he or she will be asked to sign a
combined parent and caregiver written informed consent. Caregivers other than parent or legal guardian must provide 
written informed consent.
f
Prior to dosing, the investigator or appropriate site staff member will assess if Rome IV criteria for Child FC was met and 
record the outcome in the eCRF. Eligibility for the study is not based on this assessment.
g
Participants in Cohorts 1-3 will be randomized on Study Day 1 (Visit 3) at a 1:3 ratio to either a predose or postdose PK 
sample respectively. The 6 additional participants in the final cohort will be randomized at a 1:2 ratio to either a pre-dose or 
post-dose PK sample, respectively (Section 8.5.1).
h
Physical examinations will be performed by medically qualified site personnel at Screening (Visit 1) and Week 4 (Visit 5) 
and may be repeated at the investigator’s discretion. If fecal impaction (as defined in footnote h below) is documented 
during an optional repeat physical examination, the study physician must be notified.
i
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. A fecal impaction assessment is 
only performed at the Preintervention Visit (Visit 2) if a fecal impaction was documented during the fecal impaction 
assessment at Screening (Visit 1). If there is no fecal impaction at the Preintervention Visit (Visit 2), the participant may
enter the Preintervention Period after adhering to any washout requirements. If fecal impaction is present upon re-
examination, the participant will not be eligible for the study.
j
A fecal impaction assessment is performed at the Randomization Visit (Visit 3) prior to randomization and dosing for all 
participants. If there is no fecal impaction at the Randomization Visit (Visit 3) (as defined in footnote i above), the 
participant may enter the Randomization Period. If fecal impaction is present upon examination, the participant will not be 
eligible for randomization.
k
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. Blood pressure and pulse measurements should be 
preceded by at least 5 minutes of rest for the participant in a quiet setting. 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. Temperature may be recorded as oral, rectal or tympanic (ear). If possible, temperature should be obtained using 
the same method at each visit.
l
Clinical laboratory tests consist of clinical chemistry, hematology, and urinalysis. All laboratory tests requiring blood draws 
should be collected at the same time.
m
Participants will arrive in a fasted state for this visit to receive their last dose of study intervention before or after assigned 
PK sample is collected. PK samples should be collected at the same time as clinical labs. This visit should be scheduled at 
approximately same time as when participants take their daily dose. 
n
Protocol-permitted rescue medication will be dispensed in IWRS where applicable. The parent/caregiver/guardian/LAR may 
choose a different protocol-permitted rescue medication at any subsequent visit, where available. Additional protocol-
permitted rescue medications may be dispensed as needed at any subsequent visits, where available.
o
At the Preintervention Visit, caregivers will be trained on the use of the eDiary and instructed to complete the daily evening 
assessment. At subsequent visits, study site staff will verify compliance with the eDiary and remind caregivers to complete 
their assessments daily. The global severity items will be completed beginning at the Preintervention Period through End of
Study, and the global change items will be completed from one week after randomization through End of Study.
p
Eligibility report must be run prior to randomization.
q
Protocol-permitted rescue medications only.
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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 receptor guanylate cyclase subtype C (GC-C). 
Linaclotide is approved for the treatment of irritable bowel syndrome with constipation (IBS-C) 
and CIC in the United States, Canada, Australia, Japan, and Mexico; for the treatment of IBS-C 
in China, the 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 both intestinal fluid 
secretion and intestinal transit and to also 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 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. 
2.1.
Study Rationale
Functional constipation 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.
There are no approved products for FC in children. Thus, effective treatments are needed to 
provide symptomatic relief in children and adolescents with FC, with the evidence for the safety 
and efficacy of these based on the results of adequate and well-controlled studies in children. 
For the primary and key secondary endpoints in the Phase 2 dose-ranging LIN-MD-62 study in 
children, 6 to 17 years of age, 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 the 
ITT population. However, a numerical trend towards efficacy at the higher doses was observed 
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for the primary endpoint of change from baseline in 4-week overall SBM frequency rate 
(SBMs/week). In addition, the safety profile was consistent with prior adult linaclotide studies in CIC.
As linaclotide was well tolerated across all doses tested in 6 to 17-year old participants treated in 
LIN-MD-62, LIN-MD-67 is being initiated in younger children with the primary objective of 
evaluating the dose response, safety, and efficacy of 4 weeks of linaclotide in pediatric 
participants, 2 to 5 years of age, with FC.
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 for the treatment of CIC and 290 ug 
for the treatment of IBS-C in adults. The adult linaclotide clinical development program 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 
development program revealed no pattern to suggest that linaclotide causes any specific serious 
condition.
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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 in China. Results 
from these studies were consistent with those 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 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 to17 years of age, using the approved adult dose) 
compared with placebo in pediatric participants who fulfill modified Rome III criteria for 
child/adolescent FC with the goal of selecting an optimal dose of linaclotide to evaluate in a 
confirmatory study. 
A total of 173 participants were randomized to receive 1 of 3 proposed linaclotide doses (Dose 
A, B, and C) for pediatrics (n = 116 participants), the approved adult linaclotide dose (145 μg, 
n = 16 participants), or placebo (n = 41 participants) for 4 weeks of study intervention followed 
by a 1-week Postintervention Period (Table 2–1). For the primary and key secondary endpoints 
in the Phase 2 dose-ranging LIN-MD-62 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 were considered by the investigator or sponsor to 
be related to diarrhea) or deaths. There were 2 SAEs (suicidal ideation and vomiting), each
reported in 1 participant, in the 12 to 17 years of age group, neither were considered related to 
study intervention. Moreover, in the younger pediatric participants, 6 to 11 years of age, no 
SAEs or AEs leading to discontinuation were reported. 
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As with adults, linaclotide is minimally absorbed with low systemic availability in this pediatric 
population.
Table 2–1
Dose Levels (μg) 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 6-11 years
18 to < 35 kg
9
18
36
-
≥ 35 kg
18
36
72
-
Participants 12 to 17 years
18
36
72
145
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.
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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 
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.
Nonclinical 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 – 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 
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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 years old to 
7 years old without supplemental fluid administration. Based on these nonclinical results, the 
Linzess PI (Jan 2017) has a contraindication in pediatric patients less than 6 years of age and a 
boxed warning regarding its use in pediatric patients.
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, from 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 participants 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.   
Linaclotide has a safety profile that has been well established in adults with IBS-C and CIC
(linaclotide IB). Moreover, the safety profile in the first completed pediatric linaclotide study in 
FC, LIN-MD-62, was consistent with prior adult linaclotide studies in CIC. 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.
There are no pharmacologic therapies approved in the pediatric population specifically for the 
treatment of FC. Thus, there is a need for new agents with favorable safety and tolerability 
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profiles that are effective in providing relief for the variety of symptoms associated with FC in 
pediatrics. 
Linaclotide provides an important treatment option for adult patients with FC. Linaclotide may 
offer a therapeutic option to treat the symptoms in the pediatric population with FC. The 
sponsors consider the benefit-risk balance is favorable and supports further clinical development 
of linaclotide as a treatment for FC in the pediatric population.
See Section 4, Study Design for details of study procedures, dose, and study design justification.
3.
Objectives and Endpoints
The objective of LIN-MD-67 is to evaluate the dose response, safety, and efficacy of 4 weeks of 
study intervention with linaclotide compared with placebo in pediatric participants, 2 to 5 years 
of age, with FC.
Key efficacy endpoints include:
!
Change from baseline in 4-week overall SBM frequency rate (SBMs/week) during the 
Study Intervention Period of each cohort
!
Change from baseline in 4-week stool consistency reported by the caregiver during the 
Study Intervention Period of each cohort
!
Change from baseline in 4-week straining reported by the caregiver during the Study 
Intervention Period of each cohort
!
Proportion of days with fecal incontinence during the Study Intervention Period (for 
participants who have acquired toileting skills during the daytime and nighttime or 
acquired toileting skills during daytime only) within each cohort
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.
4.
Study Design
4.1.
Overall Design
Study LIN-MD-67 is a Phase 2 randomized, double-blind, placebo-controlled, sequential, 
ascending multidose study with a 4-week Study Intervention Period in participants, 2 to 5 years 
of age, who meet modified Rome III criteria for childhood FC. 
Up to 30 participants, 2 to 5 years of age, will be sequentially enrolled into LIN-MD-67; eight 
participants each into Cohorts 1 to 3 and six participants in the final cohort. Participants will be 
randomly assigned to receive linaclotide or matching placebo as described below. 
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Number of Sites: 
Up to 40 sites from the United States and Canada are expected to participate in the study.
Study Intervention Groups and Study Duration:
The study will consist of up to 4 cohorts, each of which will be 9 to 12 weeks in duration: 2 to 
4-week Screening Period, a 2 to 3-week Preintervention Period, followed by a 4-week 
double-blind Study Intervention Period, and a 1-week Postintervention Period (Section 1.2).
Participants will not receive study intervention during the Screening/Preintervention Period and 
the Postintervention Period. 
After at least 6 participants in Cohorts 1 to 3 complete at least 2 weeks of double-blind study 
intervention, an independent DSMB will review unblinded interim safety data. Based on this 
review, the DSMB will recommend whether the subsequent planned dose level should be tested. 
New participants will be recruited for each cohort.
Please refer to Figure 4-1 for assignment of participants to dose cohorts.
!
Cohorts 1-3: 8 participants will be randomized at a ratio of 3:1 to receive linaclotide or 
matching placebo:  
o
Cohort 1: linaclotide 18 μg or matching placebo once daily for 4-week Study 
Intervention Period.  
o
Cohort 2: linaclotide 36 μg or matching placebo once daily for 4-week Study 
Intervention Period. The DSMB will have the option to recommend the lower 
dose of linaclotide  μg instead of the 36 μg dose, based on review of unblinded 
interim safety data from Cohort 1.
o
Cohort 3: linaclotide 72 μg or matching placebo once daily for 4-week Study 
Intervention Period. Participants will only be assigned to this cohort if the DSMB 
recommends proceeding to this 72 μg dose based on unblinded interim safety data 
from Cohort 2 with the linaclotide 36 μg dose. 
!
Final Cohort: 6 participants will be randomized at a ratio of 5:1 to receive linaclotide at 
the highest dose tested/determined to be safe or matching placebo for 4-week Study 
Intervention Period (ie,  18, 36, 72 μg depending on the recommendation of the 
DSMB).
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in the pediatric participants, and linaclotide was well tolerated across all doses and age groups. 
For participants in the 6 to 11 years age group in LIN-MD-62, the highest dose tested was 
2 μg/kg. The linaclotide dose selected for Cohort 1 in the current LIN-MD-67 study, 18 μg, is 
consistent with the highest μg /kg dose tested in LIN-MD-62 in the 6 to 11 years age group (not 
to exceed 1.8 μg /kg) given minimum weight requirement for eligibility is 10kg. Dose escalation 
between cohorts will be implemented based on the review of all available safety/tolerability data 
by an independent DSMB.
Figure 4-2
Change from Baseline in 4-week Overall SBM Frequency Rate by 
Dose in μg/kg (ITT Population, LIN-MD-62)
Abbreviations: CFB = change from baseline; ITT = intent-to-treat; SBM = spontaneous bowel movement
Source: Figure 14.2-1.3 of the LIN-MD-62 CSR
Assuming that the DSMB recommends proceeding to the next subsequent higher dose cohort, the 
following doses are planned to be tested in an ascending cohort design in the current study:
!
Cohort 1: 18 μg (not to exceed 1.8 μg /kg, assuming minimum body weight of 10 kg*)
!
Cohort 2: 36 μg (not to exceed 3.6 μg /kg, assuming minimum body weight of 10 kg*)
!
Cohort 3: 72 μg (not to exceed 7.2 μg /kg, assuming minimum body weight of 10 kg*)
*10 kg =10% for 2-year old based on the CDC Stature for Age and Weight for Age percentiles in 
2 to 20-year old boys (See Section 5.1, Inclusion Criteria 1.02)
Please refer to Section 4.1 and Figure 1-1 for assignment of participants to dose cohorts. 
After at least 6 participants in each of the serial Cohorts 1 to 3 complete at least 2 weeks of 
double-blind study intervention, an independent DSMB will review unblinded interim safety 
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data. Based on this review, the DSMB will recommend whether the subsequent planned dose 
level should be tested. New participants will be recruited for each cohort.
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 of the 
study including the last visit.
4.5.
End of Cohort Definition
The end of the cohort is defined as the date of the last visit of the last participant in the cohort or 
last scheduled procedure shown in the SoA for the last participant in the cohort globally.
5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
Where applicable for this pediatric population, the term “participant” refers to the participant, 
parent, and/or caregiver. 
5.1.
Inclusion Criteria
The targeted participant population will include male and female participants, 2 to 5 years of age. 
Participants are eligible to be included in the study only if all of the following criteria apply:
1.
Age and Weight
1.01
Male and female participants must be ages 2 to 5 years, (inclusive) at the time the
parent/guardian/LAR has provided signed consent
1.02
Participant weighs ≥ 10 kg at the time the parent/guardian/LAR has provided signed 
consent
2.
Type of Participant and Disease Characteristics
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2.01
Participant meets modified Rome III criteria for FC: For at least 2 months before 
Screening (Visit 1) (for participants aged ≥ 4 years old), or for at least 1 month 
before Screening (Visit 1) (for participants aged < 4 years old), the participant has 
had 2 or fewer defecations (with each defecation occurring in the absence of any 
laxative, suppository, or enema use during the preceding 24 hours) per week.
In addition, at least once per week, participant must meet 1 or more of the following:
a. History of retentive posturing or excessive volitional stool retention
b. History of painful or hard bowel movements (BMs)
c. Presence of a large fecal mass in the rectum
d. History of large diameter stools that may obstruct the toilet 
e. At least one episode of fecal incontinence per week after the acquisition of 
toileting skills
2.02
Participant is willing to discontinue any laxatives used before the Preintervention 
Visit in favor of the protocol- permitted rescue medicine.
2.03
Participant has an average of fewer than 3 SBMs per week during the 14 days before 
the randomization day and up to the randomization (including the clinic eDiary
assessments reported before administration of first dose of double-blind study 
intervention on the randomization day). An SBM is defined as a BM that occurs in 
the absence of laxative, enema, or suppository use on the calendar day of the BM or 
the calendar day before the BM
2.04
Caregiver is compliant with eDiary requirements by completing daily assessments 
for 10 out of the 14 days immediately preceding the Randomization Visit. 
3.
Informed Consent
3.01
Parent/guardian/LAR and caregiver must provide written informed consent before 
the initiation of any study-specific procedures
3.02
Caregiver who will be completing the eDiary is able to read and/or understand the 
assessments in the eDiary device and must undergo training 
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5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1.
Medical Conditions
1.01
Participant has clinically significant findings on a physical examination, vital sign 
assessment, ECG, or clinical laboratory tests at Screening (Visit 1), as determined by the 
investigator, based on consideration of whether the finding 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
Caregiver reports the participant had more than 1 loose, mushy stool (eDiary-recorded 
stool consistency of 6 on the Bristol Stool Form Scale [BSFS]) or any watery stool 
(eDiary-recorded stool consistency of 7 on the BSFS) with any SBM that occurred in the 
absence of laxative use on the calendar day of the BM or the calendar day before the BM 
during the 14 days before the randomization day and up to the randomization (including 
the daily eDiary assessment reported before administration of first dose of double-blind 
study intervention on the randomization day)
1.03
For participants aged ≥ 4 years old: Participant meets Rome III criteria for 
Child/Adolescent IBS: At least once per week for at least 2 months before Screening 
(Visit 1), the participant has experienced abdominal discomfort (an uncomfortable 
sensation not described as pain) or pain associated with 2 or more of the following at 
least 25% of the time:
a. Improvement with defecation
b. Onset associated with a change in frequency of stool
c. Onset associated with a change in form (appearance) of stool
1.04
Participant has (a) fecal impaction at Visit 2 after failing outpatient clean-out during the 
Screening Period or (b) fecal impaction at Visit 3.
1.05
Participant has required manual dis-impaction any time prior to randomization or dis-
impaction during in-patient hospitalization (for impaction) within 1 year prior to 
randomization
1.06
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
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1.07
Participant has had surgery that meets any of the following criteria:
a. Surgery to remove a segment of the GI tract at any time before Screening (Visit 1)
b. Surgery of the abdomen, pelvis, or retroperitoneal structures during the 6 months 
before the Screening Visit
c. An appendectomy or cholecystectomy during the 60 days before Screening (Visit 1)
d. Other major surgery during the 30 days before Screening (Visit 1)
1.08
Participant has an acute or chronic condition that, in the investigator's opinion, would 
limit the participant’s ability to complete or participate in this clinical study
1.09
Participant has a known or suspected mechanical bowel obstruction or pseudo-
obstruction.
1.10
Participant has a known allergy or sensitivity to the study intervention or its components 
or other medications in the same drug class
1.11
Participant has any of the following conditions:
a.
Celiac disease, or positive serological test for celiac disease or the condition is 
suspected but 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 Screening (Visit 1)
d. Down's syndrome or any other chromosomal disorder
e.
Active anal fissure (ie, participant reports having streaks of blood on the stool or 
on toilet paper and/or pain/crying with bowel movement within 2 weeks prior to 
Screening). (Note: Anal fissures that have resolved at least 2 weeks prior to 
screening would not be exclusionary.) However, if in the investigator’s opinion,
an anal fissure(s) may be the primary cause of participant’s modified Rome III FC 
criteria, the participant would not be eligible to participate in the study.
f.
Anatomic malformations (eg, imperforate anus, anal stenosis, anterior displaced 
anus) 
g. Intestinal nerve or muscle disorders (eg, Hirschprung disease, visceral 
myopathies, visceral neuropathies)
h. Neuropathic conditions (eg, spinal cord abnormalities, neurofibromatosis, 
tethered cord, spinal cord trauma)
i.
Lead toxicity, hypercalcemia
j.
Neurodevelopmental disabilities (early-onset, chronic disorders that share the 
essential feature of a predominant disturbance in the acquisition of cognitive, 
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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 and completion of the daily eDiary or other 
study-related questionnaires (Note: Participants are excluded if the person who 
will be completing the daily eDiary or other study-related questionnaires meets 
this criterion.)
k. Inflammatory bowel disease
l.
Childhood functional abdominal pain syndrome
m. Childhood functional abdominal pain 
n. Poorly treated or poorly controlled psychiatric disorders that might influence his 
or her ability to participate in the study
o. Lactose intolerance that is associated with symptoms which could confound the 
assessments in this study
p. 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 before the Randomization Visit. A complete 
remission is defined as the disappearance of all signs of cancer in response to 
treatment.)
2.
Prior/Concomitant Therapy
2.01
Participant used a protocol-specified prohibited medicine before the start of the 
Preintervention Period or failed to meet the stable-dose requirements of certain 
medications
2.02
Participant used rescue medication on the calendar day before the Randomization Visit 
and on the day of the Randomization Visit until randomized
2.03
Breastfeeding is allowed unless the mother is taking protocol-specified prohibited 
medicines (Section 6.5.1)
3.
Prior/Concurrent Clinical Study Experience
3.01
Participant received a study intervention during the 30 days before Screening (Visit 1) or 
is planning to receive study intervention (other than that administered during this study)
4.
Other
4.01
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.
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4.02
Participant’s parent/guardian/LAR or caregiver has been directly or indirectly involved in 
the conduct and administration of this study as an investigator, study coordinator, or 
other study staff member. In addition, any participant, parent/guardian/LAR or caregiver 
who has a first-degree family member, significant other, or relative residing with him/her 
directly or indirectly who is involved in this study
4.03
For participants aged ≥ 4 years old: Participant has a history of non-retentive fecal 
incontinence
Rationale for Inclusion and Exclusion Criteria
The inclusion and exclusion criteria are meant to identify a population of pediatric participants 
that is well characterized as having FC who fulfill modified Rome III criteria for childhood FC.
5.3.
Lifestyle Considerations
Caregivers will be advised to have participants adopt the following nonpharmacologic habits and 
instructed to maintain them throughout the study. There should be at least a 2-week interval 
between discussing the lifestyle modifications during the Screening Period and the participant’s 
entry into the Preintervention Period.
!
Adequate fluids: The investigator will discuss the fluid intake necessary to maintain a 
hydrated state (intake requirements may vary amongst children - eg, child athletes, 
children in hot climates).
!
A high-fiber diet: Adequate intake values for fiber range from 19 to 25 g/day for 
children 1 to 8 years of age. High-fiber foods include beans, whole grains, fruits, and 
vegetables. Start slowly, adding just several grams of fiber a day over the Screening 
Period to reduce the amount of gas and bloating that can occur in someone who is not 
used to consuming high-fiber foods. 
!
Increased physical activity: Participants should be physically active throughout the day. 
Caregivers of participants should encourage active play that includes a variety of activity 
types. 
!
Adequate time for bowel movements: 
o
For participants who have acquired toileting skills prior to Screening (Visit 1) 
encourage the child to sit on the toilet for 5 to 10 minutes twice daily within 
30 minutes after a meal (breakfast and dinner). Follow the routine every day, even 
during holidays and vacations. 
o
For participants who have started toilet training prior to Screening (Visit 1) but are 
not yet toilet trained, encourage the child to continue with same toilet training 
regimen (defined as sitting on the toilet for 5 to 10 minutes twice daily within 
30 minutes after a meal (breakfast and dinner) during the study. Participants should 
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impact bowel habits and accurate reporting of bowel movements and fecal 
incontinence. 
o
Parents/caregivers will be requested not to start the toilet training process with their 
child during the child’s participation in the study. Changes in toileting skills may 
impact bowel habits and accurate reporting of bowel movements and fecal 
incontinence
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in 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 (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any SAE.
Participants 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 washout 
requirements, etc). A participant who has not yet received any e-Diary training at Visit 2 
(Preintervention Period) may be rescreened under special circumstances (eg, failure to meet 
prohibited medication washout requirements). All requests for rescreening must be sent to the 
sponsor and approved by the study physician. Any participant approved for rescreening by the 
study physician will be assigned a new participant identification (PID) and repeat the study 
screening procedures.
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.
Participants meeting the eligibility criteria during the Randomization Visit will be randomized in 
a double-blind fashion to linaclotide or placebo. 
A rationale for selection of the doses is provided in Section 4.3 (Justification for Dose).
6.1.
Study Intervention(s) Administered
Linaclotide in the form of capsules will be packaged in bottles and provided by the sponsor. 
Study intervention will be administered at the study site during the Randomization Visit and at 
EOT (Visit 5) after confirming the participant has fasted for at least 2 hours. Participants may eat 
30 minutes after dosing; the requirement is for study intervention to be administered 30 minutes 
before any meal at approximately the same time each day, with the exception of the first dose at 
Day 1 (Randomization Visit) and last dose at EOT (Week 4/Visit 5) when participants will 
receive the last dose of linaclotide or placebo in the clinic. At this EOT (Week 4/Visit 5) visit, 
participants will arrive in a fasted state for this visit to receive their last dose of study 
intervention before or after assigned PK sample. Confirmation will be recorded in the source 
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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 or Placebo
Dosage Formulation
Capsules (refer to Study Reference Manual for capsule strength information)
Dose Strength
Refer to Section 4.1 for dose information
Route of Administration 
Oral; capsule contents are to be sprinkled into 20 mL of bottled water, and 5 
mL of this solution is dosed to the participant using an oral syringe. 
Instructions for dosing are provided in Appendix 7.
Dosing Instructions
Single dose, once daily at approximately the same time each day, 30 minutes 
before any meal
Packaging and Labeling
All bottles will be labeled with the protocol number, storage information, and 
warning language (“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.
6.1.1.
Selection and Timing of Dose for Each Participant
Participants who continue to meet all eligibility criteria on the Randomization Visit will be 
dispensed the corresponding double-blind study intervention and receive their first dose of study 
intervention at the study site. Participants will receive 1 bottle containing study intervention.
Participants will be instructed to take their assigned dose orally as a single daily dose 30 minutes 
prior to any meal at approximately the same time each day. 
Participants will be instructed to return the bottle(s) at the next study visit whether there is any 
remaining study intervention or if the bottle is empty per instructions in the Study Reference 
Manual. Study intervention will be dispensed as per the schedule shown in Section 1.3.
The investigator may allow a participant to stop taking study intervention for up to 3 days 
because of an intolerable AE. If the investigator believes that the participant is unable to resume 
dosing after 3 days or requires a suspension of dosing on more than 1 occasion, the investigator 
is required to contact the study physician to discuss the participant’s continued participation in 
the study.
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 
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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.
5. Study interventions in bottles containing 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 - 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 
interventions supplied and for ensuring the supervision of the storage and allocation of these 
supplies. All unused study interventions and protocol-permitted rescue medication must be 
returned; and, whenever study interventions are returned, unit counts must be performed. All 
study interventions must be accounted for. At the end of the study, all unused or empty study 
intervention containers 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
After a parent/LAR/caregiver sign the permission/consent at Screening (Visit 1), study personnel 
will register the participant in the IWRS, and the system will assign the participant a sequential 
PID number. The first participant entered in the system at each study site will be assigned the 
first number in the sequence by the system. 
!
Component 1: Study number (3 digits) = 267
!
Component 2: Site number (5 digits) = 10001-19999
!
Component 3: Participant number (3 digits) = 001-999
The randomization number encodes the participant’s assignment to 1 of the 2 study intervention 
groups of the study, according to the randomization schedule generated prior to the study by the 
statistics department at the sponsor. Each participant will be dispensed blinded study 
intervention, labeled with his/her unique PID number, throughout the study.
This PID number will be used to identify the participant throughout the study (ie, at all study 
phases). A detailed description of IWRS procedures is contained in the IWRS Manual in the 
Study Reference Manual.
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6.3.1.
Blinding and Unblinding
6.3.1.1.
Blinding
A list of participant randomization codes will be generated by statistical programming and 
implemented by the IWRS vendor (an electronic version will be stored on a secure server). This 
list will identify each participant by randomization number and include the participant’s 
corresponding study intervention assignment.
6.3.1.2.
Unblinding
Any unblinding at the study site level should be done only in an emergency that requires for 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 study 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 
participant (see Section 10.3). If a participant’s study 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. Study 
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 disqualified from the study. The unblinding of the bioanalytical representatives is to 
be carried out in a secure manner following the sponsor’s standard operating procedures. 
Extreme care will be taken to ensure no other individuals outside the bioanalytical team will be 
unblinded.
For IWRS Unblinding
In an emergency, the investigator can obtain the study 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 visits 
designated in the SoA, study site personnel will make every effort to collect all unused study
intervention and empty/partially used 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. 
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6.5.
Prior and Concomitant Therapy
Prior medicine is defined as any medicine taken before the date of the first dose of study 
intervention. Concomitant medication is defined as any medication taken on or after the date of 
the first dose of study intervention. Any medication started after last dose date of study 
intervention will not be included in the summary of concomitant medications but will be 
included in listing.
The use of both prior and concomitant medications will be summarized as the number and 
proportion of participants who took a particular medicine within each therapeutic class. Multiple 
medicine use by a participant in the same category (based on Anatomical Therapeutic Chemical 
classification) will only be counted once.
Medication history during the previous 3 months will be recorded at Screening (Visit 1) in the 
eCRF. Any changes in concomitant medicines or new medicines added will be recorded in the 
eCRF at visits throughout the study.
6.5.1.
Prohibited Interventions and Washout Before the Study
Prohibited Medications
All medicines listed in the sections below (1-day washout and 14-day washout) will be excluded 
during the Preintervention, Intervention, and Postintervention Periods. A 1-day washout means 
that the particular medicine is not allowed during the calendar day before the Preintervention
Visit; a 14-day washout means that the particular medicine is not allowed during the 14 calendar 
days before the Preintervention Visit.
1-Day Washout
1. Any over-the-counter or prescription laxative, suppository, or enema (eg, polyethylene 
glycol, lactulose, Fleet enema) and any herbal or natural agent that might be taken for 
constipation. (Note: The use of fiber, bulk laxatives, stool softeners [surfactants such as 
docusate], and probiotics is acceptable, provided that the participant has been on a stable 
dose for 30 days before Screening (Visit 1) and plans to continue stable dosing for the 
duration of the study)
2. Any medicine used to treat diarrhea (eg, bismuth subsalicylate, kaolin)
14-Day Washout
1.
Drugs with known pharmacologic activity at 5-HT4, 5-HT2b or 5-HT3 receptors 
(eg, cisapride, tegaserod, prucalopride, ondansetron, tropisetron, granisetron, 
dolasetron, mirtazapine)
2.
Any of the following treatments, either alone or in combination: plecanatide, 
lubiprostone, colchicine, linaclotide, and misoprostol
3.
Prokinetic agents (eg, metoclopramide, itopride, domperidone)
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4.
Anticholinergic agents (eg, dicyclomine, flavoxate, scopolamine, hyoscyamine, 
propantheline, oxybutynin, tolterodine, solifenacin, darifenacin, trospium). (Note: 
inhaled ipratropium and tiotropium are permitted)
5.
Bile acid sequestrants (eg, cholestyramine, colestipol)
6.
Cholinomimetic agents (eg, bethanechol, pyridostigmine, tacrine, physostigmine). 
(Note: intraocular cholinomimetic agents such as pilocarpine are permitted)
7.
Antipsychotic agents (eg, risperidone, haloperidol, droperidol, chlorpromazine, 
perphenazine, all phenothiazines, quetiapine, olanzapine, clozapine), unless the 
participant has been on a stable dose for 30 days before Screening (Visit 1) and plans 
to continue stable dosing for the duration of the study. (Note: paliperidone is 
permitted without restriction)
8.
Antidepressants, unless the participant has been on a stable dose for 30 days before 
Screening (Visit 1) and plans to continue stable dosing for the duration of the trial. 
Specifically included are the following:
a.
Tricyclic antidepressants (eg, amitriptyline, imipramine, nortriptyline)
b.
Monoamine oxidase inhibitors (eg, furazolidone, isocarboxazid, pargyline 
phenelzine, selegiline, tranylcypromine)
c.
Selective serotonin reuptake inhibitors (eg, fluoxetine, sertraline, paroxetine, 
escitalopram, citalopram, vilazodone)
d. Serotonin-norepinephrine-reuptake inhibitors (eg, levomilnacipran, duloxetine, 
venlafaxine, desvenlafaxine succinate)
e.
Other antidepressants (eg, trazodone, bupropion)
9.
Calcium-channel blocker verapamil, unless the participant has been on a stable dose 
for 30 days before Screening (Visit 1) and plans to continue stable dosing for the 
duration of the study. (Note: all other calcium-channel blockers [eg, nifedipine, 
diltiazem, amlodipine, felodipine, nicardipine, nimodipine, nisoldipine] are permitted 
and may be used without restriction).
10.
Oral and parenteral antibiotics; however, 1 standard regimen (up to 10 days) of oral 
antibiotics is permitted during the Study Intervention and Postintervention Periods
11.
Any study intervention or imported drugs that have not been approved for human use 
12.
All narcotics (eg, tramadol, codeine, morphine, propoxyphene, loperamide, 
diphenoxylate, paregoric), either alone or in combination. Note: narcotics used as 
anesthesia for a colonoscopy require a 5-calendar day wash-out prior to the 
participant entering into the Preintervention Period. Dextromethorphan, the cough 
suppressant in many over-the-counter cold and cough medicines, is allowed.   
13.
Any medication to treat attention-deficit/hyperactivity disorder, unless the participant 
has been on a stable dose for ≥ 30 days before Screening (Visit 1) and plans to 
continue stable dosing for the duration of the study 
14.
Any medicine that is known to cause diarrhea (eg, acarbose)
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15.
Proton pump inhibitors (eg, omeprazole, lansoprazole, esomeprazole, pantoprazole, 
rabeprazole), unless the participant has been on a stable dose for 30 days before 
Screening (Visit 1) and plans to continue stable dosing for the duration of the study
16.
Other drugs such as barbiturates (eg, butalbital, phenobarbital) and chronic oral or 
parenteral glucocorticoids, which must be discontinued at least 3 months before 
screening; however, one 10-day course of oral or 1 injection of parenteral 
glucocorticoids is permitted during the Study Intervention and Postintervention
Periods. Pregabalin is acceptable, provided the participant has been on a stable dose 
during the 30 days before Screening (Visit 1) and plans to continue stable dosing 
throughout the study.
6.5.2.
Rescue Medication
In the United States and Canada, protocol-permitted rescue medication will be a choice of senna 
(oral), mineral oil enema (rectal), or magnesium hydroxide (oral) that will be dispensed 
according to the SOA (Section 1.3). 
When there is more than one option available, the participants will choose a rescue medication(s) 
at the Preintervention Visit (Visit 2) and study site staff will register the rescue medication in 
IWRS, where applicable. The study site must contact the IWRS (if applicable) at all subsequent 
study visits to obtain the protocol-permitted rescue medication to be dispensed to the participant 
at each visit as needed. 
Rescue medication may be taken when at least 72 hours have passed since the participant’s 
previous BM or when their symptoms become intolerable.
Where available, the participant may continue using their original selection received from the 
study site throughout the duration of the study or may switch to another protocol-permitted 
rescue medication in coordination with the site staff.
6.6.
Dose Modification
Dose modifications will not be allowed during this study. However, the investigator may allow a 
participant to stop taking study intervention for up to 3 days because of an AE. If the investigator 
believes that the participant is unable to resume dosing after 3 days or requires a suspension of 
dosing on more than 1 occasion, the investigator is required to contact the Study Physician to 
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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1.
Discontinuation of Study Intervention
A premature discontinuation will occur when a participant whose parent/guardian/LAR 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
(Section 10.5).
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.
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
Adverse event
Death
Completed
Disease relapse
Lack of efficacy
Withdrawal by parent/guardian
Lost to follow-up
Progressive disease
Other
Recovery
Physician decision
Technical problems
Screen failure
Site terminated by sponsor
Study terminated by sponsor
Withdrawal by subject
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, intervention-related AESIs) see Section 8.3.1,
Participants may also be prematurely discontinued from the study for reasons of safety including 
those who experience:
!
The presence of intentional overdose or intentional misuse per investigator discretion
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!
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
!
An intolerable AE (defined as an AE that subjectively would cause a participant to consider 
study withdrawal), see Section 6.1.1
!
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
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 the best interest of the 
participant.
All enrolled participants who prematurely discontinue from the study, regardless of cause, should 
be seen for the assessments to be completed at the EOT Visit. The EOT assessments are defined 
as completion of 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 the 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 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.
7.1.2.
Criteria for Consideration of Study Discontinuation
Dosing and enrollment will be immediately paused for all participants at all sites and a thorough 
review will be initiated after any one of the following conditions has been met in participants 
who have received study intervention at any time in the study:
!
Any life-threatening SAE that is considered by the investigator or the sponsor to be possibly 
related or related to the study intervention.
!
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In the event of a pause in enrollment and dosing, the Data Safety and Monitoring Board (DSMB) 
will be notified and their recommendation on an appropriate course of action will be sought. This 
may include resuming enrollment, continuing a hold on enrollment, resuming the study 
intervention, amending the protocol or stopping the study (Section 10.1.6.3). The decision to 
restart or to stop the study will be made by the sponsor, following a thorough review of all 
clinical, laboratory, DSMB recommendations and other available safety data. 
In addition to the above, 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 becomes 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/parent/LAR may withdraw from the study at any time at their request or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons.
!
If the participant/parent/LAR 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/parent/LAR withdraws from the study, they 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 discontinuation and follow-up and 
for any further evaluations that need to be completed.
Participants in this study who prematurely discontinue study intervention will not be replaced.
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/parent/LAR and reschedule the missed visit 
as soon as possible and counsel them 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/parent/LAR (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing address or 
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local equivalent methods). These contact attempts will be documented in the participant’s 
study record.
!
Should the participant/parent/LAR continue to be unreachable, he/she will be considered to 
have withdrawn from the study.
8.
Study Assessments and Procedures
A detailed listing of study assessments by day is presented in Appendix 8.
!
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.
!
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 12 mL. Repeat or unscheduled samples may be taken for safety reasons or for 
technical issues with the sample.
!
Additional details regarding study conduct during the novel coronavirus pandemic are
provided in Appendix 10.
8.1.
Efficacy Assessments
An observer-reported outcome (ObsRO) instrument assessing key signs and symptoms of FC for 
use in children (2 to 5 years of age) with FC was developed by Allergan and Ironwood 
Pharmaceuticals based on extensive qualitative research with caregivers of children with FC, as 
well as feedback from pediatric gastroenterologists, measurement experts, and health authorities. 
The ObsRO instrument was developed for completion by caregivers on an electronic diary 
(eDiary). Data collected in the eDiary will be used to derive the efficacy endpoints.
All efficacy assessments will be determined by responses entered in the eDiary by the caregiver.
The caregiver is identified as the individual who completes the eDiary and should be the same 
individual throughout the course of the study and must be able to read and understand the eDiary 
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as a condition for study participation (Inclusion Criterion 3.02). At the start of the 
Preintervention Period, caregivers will receive full training in the use and completion of the 
eDiary at the study visit in which they are given the eDiary device. If the caregiver completing 
the diary changes, the study team should be notified and should document the date when it 
changed and who the new caregiver is. The new caregiver must also provide written informed 
consent before the initiation of any study-specific procedures.
8.1.1.
Key Efficacy Assessments
The key efficacy assessments, which will be used to determine the efficacy parameter of SBM 
frequency, are the items assessing BM frequency and rescue medication use. Caregivers will 
report their child’s BM frequency (the number of BMs) by responding to the following: 
Bowel Movement Frequency
Rescue medication use
Stool Consistency (Bristol Stool Form Scale)
If the caregiver was present for the BM, he/she will be asked to rate the child’s observed stool 
consistency for each BM he/she was present for. 
Stool consistency will be based on the BSFS. The BSFS is a widely used measurement of stool 
consistency (Lewis 1997). Caregivers will use the BSFS 7-point ordinal scale to rate their child’s 
stool consistency as follows:
!
"Choose the option that is most like the Xth (eg, 1st, 2nd, 3rd, ...) bowel movement you were 
with the child for"
o
Type 1: Separate hard lumps, like nuts (hard to pass)
o
Type 2: Sausage-shaped, but lumpy
o
Type 3: Like a sausage but with cracks on its surface
o
Type 4: Like a sausage or snake, smooth and soft
o
Type 5: Soft blobs with clear cut edges (easy to pass)
o
Type 6: Fluffy pieces with ragged edges, a mushy stool
o
Type 7: Watery, no solid pieces. Entirely liquid
o
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Straining With BM
If the caregiver was present for the BM, they will be asked to rate the amount of straining they 
observed when the child passed the BM. They will be asked this for every bowel movement for 
which they were present. 
Fecal Incontinence (For Participants Who Have Acquired Toileting Skills Only)
Caregivers of children who have acquired toileting skills for bowel movements will be asked 
about their child’s fecal incontinence episodes. 
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8.1.2.
Other Efficacy Assessments
Modified Rome III Criteria
Modified 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 5). A participant will be 
considered as fulfilling modified Rome III criteria if a “yes” response is recorded to the overall 
question of whether the participant meets modified Rome III criteria for functional constipation. 
For the EOT assessment, these criteria will be assessed over the 4-week double-blind study 
intervention period. In the event a participant discontinues the study prematurely, these criteria 
will be assessed over the duration of time the participant received double-blind study 
intervention.
Global Items
Assessments of global change in symptoms and global severity of symptoms will be completed 
weekly in the eDiary.
The global items consist of 2 items, 1 assessing global change in the child’s symptoms and 1 
assessing the global severity of the child’s symptoms. Both global items will be completed 
weekly on the eDiary by the caregiver. The global severity item will be completed beginning at 
the Preintervention Period through the End of Study and the global change item will be 
completed from 1 week after randomization through the End of Study.
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Global Change Item
The global change item assesses the change in the child’s constipation (1 item) as follows:
Global Severity Item
The global severity item assesses the severity of the child’s constipation symptoms (1 item) as 
follows:
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 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. Evidence of severe diarrhea, especially when accompanied by 
dehydration, volume depletion and/or significant electrolyte or ECG abnormalities will be 
actively monitored throughout.
All AEs will be monitored until symptom resolution or until the condition stabilizes. A DMSB
will oversee AEs and safety of the overall study (Section 10.1.6.3).
Planned timepoints for all safety assessments are provided in the SoA. 
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8.2.1.
Physical Examinations
A complete physical examination will be done at screening and at the Week 4/EOT Visit by a 
professionally trained physician or health professional listed on Form FDA 1572 or the 
Delegation of Authority log and licensed to perform physical examinations. Physical 
examinations may be repeated at the investigator’s discretion. If fecal impaction is documented 
during an optional repeat physical examination, the study physician must be notified.
Any new physical examination abnormalities for the post-baseline physical examination or 
worsening of the change from Screening (Visit 1) 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.
In addition to the physical examination, a fecal impaction assessment will be performed for all 
participants at both Screening (Visit 1) and Randomization (Visit 3) prior to randomization and 
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 Screening (Visit 1), 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). After the participant has received treatment for 
the impaction, the investigator must re-evaluate the participant for the presence of fecal 
impaction at the Preintervention Visit (Visit 2). If there is no fecal impaction at the 
Preintervention Visit, the participant may enter the Preintervention Period after adhering to 
any washout requirements (Section 10.8.2). If fecal impaction is present upon re-
examination, the participant will not be eligible for the study (ie, they have failed their out-
patient clean-out regimen). 
!
If fecal impaction is present upon examination at Randomization (Visit 3), the participant 
will not be eligible to be randomized into the study.
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8.2.2.
Vital Signs 
Vital signs and postural vital signs will be obtained and documented as noted in the SOA (see 
Section 1.3). Vital signs will be assessed as follows:
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.
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.
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) and at the Week 4/EOT Visit. 
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 (Section 10.3). If the AE is assessed as causally related to 
the use of study intervention, the participant should be discontinued from the study; however, the 
study physician and investigator may discuss individual participants and AEs to make this 
determination (Section 10.3).
The overall interpretation and determination of the clinical relevance of ECG findings using the 
central ECG interpretation report 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. 
Unscheduled ECGs are recorded for unscheduled visits only. All readable ECGs received by the 
vendor shall be sent for cardiologist over-read. The sponsor will receive all ECG data, including 
cardiologist assessments and 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 SoA 
(Section 1.3) for the timing and frequency.
!
At Screening (Visit 1), the investigator will assess the clinical significance of any values 
outside the reference ranges provided by the laboratory, and participants with 
abnormalities judged to be clinically significant will be excluded from the study.
!
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
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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.
o
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 Section 10.2, must be 
conducted in accordance with the SoA 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 AE of special interest) 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 (Section 10.3). If the AE is assessed as causally related to the use of study 
intervention, the participant should be discontinued from the study; however, the study 
physician and investigator may discuss individual participants and AEs to make this 
determination (Section 10.3).
!
A central laboratory will be used to evaluate all blood samples, which will be collected, 
processed, and stored according to the instructions provided by the laboratory.
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 
Section 10.3.
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 
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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).
Particular attention must be given to the AE of diarrhea, which was the most frequently reported 
AE in the adult linaclotide program. Please refer to Section 10.3 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)
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 AESIs has been met. All AESIs must be reported to the sponsor as described in 
Section 10.3.
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 SoA 
(Section 1.3), 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 SoA (Section 1.3), and as observed or reported 
spontaneously by study participants.
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.
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All SAEs and serious AESIs of special interest will be recorded and reported to the sponsor or 
designee within 24 hours on an SAE form, as indicated in Section 10.3. Non-serious 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 Section 10.3.
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 
non-leading 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 AEs of special interest (as 
defined in Section 10.3) 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 
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 and AESI 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. 
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!
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. Any AEs reported in diaries will also be reported on the 
relevant eCRF page.
Additional information is provided in Section 10.3 for the recording and follow-up of AEs and 
SAEs.
8.3.6.
Potential Hy’s Law Cases
Criteria for possible Hy’s law cases are as follows:
!
ALT or AST ≥ 3 × upper limit of normal [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 3 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.
8.3.7.
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
!
Wrong dose (including dosing regimen, strength, form, concentration, amount)
!
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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. 
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
An important consideration is whether oral bioavailability of linaclotide is similar in children as 
in adults or whether systemic exposure may be higher in children. Sparse PK sampling will 
therefore be included in this study to assess the PK of linaclotide in children. Sparse PK blood 
samples will be collected at the pre-specified times to determine plasma concentration of 
linaclotide and its active metabolite (MM-419447).
8.5.1.
Blood Pharmacokinetic Sampling Procedure
Participants in Cohorts 1-3 will be randomized on Study Day 1 (Visit 3) at a 1:3 ratio to either a 
pre-dose or post-dose PK sample and the 6 participants in the final cohort will be randomized at 
a 1:2 ratio to either a pre-dose or post-dose PK sample, respectively, to be completed before or 
after the last dose of study intervention at Visit 5 (Week 4) for determination of linaclotide and 
active metabolite (MM-419447) concentrations in plasma. One blood sample will be collected 
from each participant at Visit 5 (Week 4) before or after the last dose of study intervention, along 
with all laboratory blood samples at same time. Postintervention PK sample will be collected at 1 
to 8 hours post-dose.
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Blood samples will be collected in 2-mL Vacutainer tubes containing K2EDTA as an 
anticoagulant. Blood samples will be processed, stored, and shipped as directed in the Study 
Manual.
All participants will be instructed to hold their last dose of linaclotide/placebo for Visit 5 
(Week 4) and will take their dose at the site that day in a fasted state. Every attempt should be 
made to ensure that the dosing time during Visit 5 (Week 4) is consistent with the time 
linaclotide has been taken during the course of the study intervention. Sites will also be 
instructed to encourage caregivers to schedule Visit 5 (Week 4) early in the study once the 
participant is randomized as the participants will need to take linaclotide in a fasted state 
(Section 10.8.3). Sites will also document the date and time of the dose administered prior to the 
PK sample collection.
8.5.2.
Pharmacokinetic Sample Bioanalysis
Plasma concentrations of linaclotide and its active metabolite (MM-419447) will be determined 
using a validated liquid chromatography-tandem mass spectrometry method.
8.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7.
Genetics
Not applicable
8.8.
Biomarkers and Other Assessments
Biomarkers are not evaluated in this study.
8.9.
Health Economics 
Not applicable.
9.
Statistical Considerations
9.1.
Statistical Endpoints
Key efficacy endpoints include:
!
Change from baseline in 4-week overall SBM frequency rate (SBMs/week) during the 
Study Intervention Period of each cohort
!
Change from baseline in 4-week stool consistency reported by the caregiver during the 
Study Intervention Period of each cohort
!
Change from baseline in 4-week straining reported by the caregiver during the Study 
Intervention Period of each cohort
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!
Proportion of days with fecal incontinence during the Study Intervention Period (for 
participants who have acquired toileting skills during daytime and nighttime or acquired 
toileting skills during daytime only) within each cohort
Other efficacy endpoints include:
!
Proportion of participants who no longer fulfill modified Rome III criteria for functional 
constipation at the end of the Study Intervention Period.
!
Proportion of participants with each individual item score for the global change in 
symptoms and the global severity of symptoms at each week during the Study 
Intervention Period.
9.2.
Sample Size Determination
Up to 30 participants, 2 to 5 years of age, will be sequentially enrolled into LIN-MD-67; 8 
participants each into Cohorts 1 to 3 will be randomly assigned with 3:1 allocation ratio either to 
linaclotide dose or matching placebo and 6 additional participants in the final cohort will be 
randomly assigned with 5:1 allocation ratio either to linaclotide dose or matching placebo. 
Participants will be randomly assigned to receive linaclotide or matching placebo as described in 
Section 4.1. 
Sample size in this study is not driven by any statistical consideration. Instead, this study is 
designed to enroll sufficient pediatric participants to observe the clinical response trends and
monitor safety.
9.3.
Populations for Analyses
Four analysis populations will be defined as follows:
!
Screened population includes all participants who undergo Screening (Visit 1) and receive a 
PID number.
!
Randomized population includes all participants in the Screened population who are 
randomized to a study intervention group.
!
Safety population includes all participants in the Randomized population who receive at least 
1 dose of double-blind study intervention. Participants will be summarized according to the 
study intervention they actually receive for all safety analysis variables/endpoints.
!
Modified intent-to-treat (mITT) population includes all participants in the Randomized 
population who receive at least 1 dose of double-blind study intervention and who had at 
least 1 postbaseline entry on BM characteristic assessments that determine occurrences of 
SBMs (ie, BM frequency and rescue medication use). Participants will be summarized 
according to the randomized study intervention for all efficacy analysis variables/endpoints. 
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9.4.
Statistical Analyses
The SAP will be developed and finalized before database lock and unblinding and will describe 
the participant populations to be included in the analyses, and procedures for accounting for 
missing data. This section is a summary of the main feature for the planned statistical analyses in 
this study.
9.4.1.
Efficacy Analyses
All efficacy analyses will be performed based on the mITT population. 
Baseline values for efficacy parameters related to daily eDiary responses will be derived from 
the eDiary in the Preintervention Period, specifically the period of time from 14 days before 
randomization up to the time of randomization. The numerator of the baseline weekly SBM rate 
will be derived based on the total number of caregiver-observed SBMs a participant had during 
this period. Caregiver-observed SBMs are defined as SBMs reported in the eDiary for which the 
caregiver identified being with the child for.
Baseline stool consistency reported by the caregiver based on daily assessments will be 
calculated as a mean of the participant’s non-missing BSFS scores from each caregiver-
observed SBM during this period. Baseline straining score reported by the caregiver will be 
calculated as a mean of the participant’s non-missing daily average straining score 
 
 from caregiver-observed SBMs during this period. A participant’s 
baseline stool consistency and straining reported by the caregiver cannot be assessed if the
participant does not have at least 1 caregiver-observed SBM during the Preintervention Period. 
For participants with no caregiver-observed SBMs reported in the eDiary during a study period, 
the consistency and straining assessments reported by caregiver will be considered missing for 
that study period in the analyses. Participants with missing baseline consistency and straining 
reported by the caregiver will be excluded from the respective consistency and straining change 
from baseline analyses.
Baseline value for the global severity in symptoms will be based on the last non-missing 
assessment on or before the date of first dose of study intervention.
An observed-cases approach to missing postbaseline data will be applied. The descriptive 
statistics for efficacy endpoints including placebo and the corresponding linaclotide dose in each 
cohort will be provided to evaluate the main objective of this study. No statistical testing will be 
performed to compare linaclotide dose with placebo. No multiplicity adjustment will be applied 
in this dose-ranging study. 
Descriptive statistics for continuous endpoints in terms of mean, median, standard deviation, 
standard error of mean, minimum, and maximum will be provided for placebo and corresponding 
linaclotide dose within each cohort. For categorical endpoints, count and percentages will be 
provided for placebo and corresponding linaclotide dose within each cohort.
If any cohort has linaclotide dose similar to the other cohort, summary statistics will be provided
for these efficacy parameters combining the participants from similar dose cohorts. Any 
additional analysis will be discussed further in Statistical Analysis Plan.
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9.4.1.1.
Key Efficacy Endpoints
Change from baseline in 4-week overall SBM frequency rate (SBMs/week) during the 
Study Intervention Period of each cohort
The numerator of the SBM rate (SBMs/week) during the Study Intervention Period of each 
cohort will be derived based on the total number of SBMs reported by a caregiver as being 
directly observed during this period in the eDiary. Additional analysis will also be performed 
based on the total number of SBMs reported during the Study Intervention Period (including 
SBMs not directly observed by the caregiver) and the corresponding baseline SBM frequency 
rate will be determined based on the total number of SBMs reported during the Preintervention 
period.
Change from Baseline in 4-Week Stool Consistency Reported by the Caregiver During the 
Intervention Period of Each Cohort
Stool consistency for each caregiver-observed BM will be measured daily in the eDiary using the 
7-point ordinal BSFS. A participant’s BSFS score for the Study Intervention Period will be the 
average of the non-missing BSFS scores from the caregiver-observed SBMs during the 4-week 
Study Intervention Period. If no caregiver-observed SBMs are present at baseline, the baseline 
BSFS score reported by caregiver will be missing and, therefore, that participant will not be 
included in the change from baseline stool consistency analysis.
Change from Baseline in 4-Week Straining Reported by the Caregiver During Study 
Intervention Period for Each Cohort
Straining for each caregiver-observed BM will be collected daily in the eDiary device, using a 
4-point scale based on two questions as discussed in Section 8.1.1. The participant’s daily 
straining score for each caregiver-observed BM will be derived based on the average of non-
missing responses of the two straining questions. The participant’s straining score in the 4-week 
Study Intervention Period will be the average of the non-missing daily average straining scores 
from the caregiver-observed SBMs during the 4-week Study Intervention Period for each cohort. 
If a participant has no caregiver-observed SBMs at baseline, then the baseline straining score 
reported by the caregiver will be missing and, therefore, that participant will not be included in 
the change from baseline straining analysis.
Proportion of days with fecal incontinence during study intervention period (for 
participants who have acquired toileting skills during daytime and nighttime or acquired 
toileting skills during daytime only) within each cohort
Fecal incontinence will be collected daily in the eDiary. Any "yes" response for the question 
 will be counted as presence of fecal incontinence
in the corresponding day (Section 8.1.1).
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9.4.1.2.
Other Efficacy Endpoints
Proportion of participants who no longer fulfill modified Rome III criteria for functional 
constipation at the end of the study intervention period
Modified 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 5). A participant will be 
considered as fulfilling modified Rome III criteria if a “yes” response is recorded to the overall 
question of whether the participant meets modified Rome III criteria for functional constipation. 
For the EOT assessment, these criteria will be assessed over the 4-week double-blind study 
intervention period. In the event a participant discontinues the study prematurely, these criteria 
will be assessed over the duration of time the participant received double-blind study 
intervention (Section 8.1.2).
Proportion of participants with each individual item score for the global change in 
symptoms and the global severity of symptoms at each week during the study intervention 
period
The global change in symptoms and the global severity of symptoms will be assessed on a 
weekly basis in the eDiary with a 7-point scale and a 5-point scale respectively as discussed in 
Section 8.1.2.
9.4.2.
Safety Analyses
The safety analysis will be performed using the safety population. The safety parameters will 
include AEs, clinical laboratory parameters, vital sign measurements, weight, and ECG 
parameters. For each safety parameter, the last non-missing assessment made before the first 
dose of double-blind study intervention will be used as the baseline for all analyses of that safety 
parameter.
Safety summaries will be provided for each cohort separately. If any cohort has a similar 
linaclotide dose with another cohort, the safety summaries will also be provided combining 
participants from the similar dose cohorts, as appropriate. 
9.4.2.1.
Adverse Events
An AE will be considered a TEAE if:
!
The AE began on or after the date of the first dose of study intervention; or
!
The AE was present before the date of the first dose of study intervention, but increased in 
severity or became serious on or after the date of the first dose of study intervention
An AE that occurs more than 1 day after the last dose of study intervention will not be counted 
as a TEAE.
An AE will be considered a treatment-emergent SAE if it is a TEAE that additionally meets any 
SAE criteria.
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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 within 
each cohort separately.
The number and percentage of participants reporting treatment-related TEAEs in each study 
intervention group will be tabulated by system organ class and preferred term within each cohort.
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 causal relationship to study intervention.
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 Section 10.3.
9.4.2.2.
Clinical Laboratory Assessments
Descriptive statistics for clinical laboratory values (in SI units) at baseline (screening) and 
changes from baseline at each assessment time point will be presented by study intervention 
group within each cohort.
The criteria for potentially clinically significant (PCS) laboratory values will be detailed in the 
SAP. The number and percentage of participants who have PCS postbaseline clinical laboratory 
values within the corresponding cohort during the double-blind study intervention period 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 
for the double-blind Study Intervention Period of the corresponding cohort. The numerator will 
be the total number of participants with available non-PCS baseline values and at least 1 PCS 
postbaseline value during the double-blind Study Intervention Period of the corresponding 
cohort. A supportive listing of participants with PCS postbaseline values will be provided for the 
safety population. 
9.4.2.3.
Vital Signs
Descriptive statistics for weight and postural vital signs (supine and standing systolic and 
diastolic BP and pulse rate), respiration rate, and temperature at baseline and changes from 
baseline at each assessment time point will be presented by study intervention group within each 
cohort. 
Vital sign values will be considered PCS within the corresponding cohort if they meet both the 
observed-value criteria and the change-from-baseline-value criteria that will be detailed in the 
SAP. The number and percentage of participants who have PCS postbaseline vital sign values 
will be tabulated by study intervention within the double-blind Study Intervention Period and 
Postintervention Period separately for the corresponding cohort. The percentages will be 
calculated relative to the number of participants who have available non-PCS baseline values and 
at least 1 postbaseline assessment in the specific period for the corresponding cohort. The 
numerator will be the total number of participants with at least 1 PCS postbaseline value during 
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the specific period of the corresponding cohort. A supportive listing of participants with PCS 
postbaseline values will be provided for the safety population.
9.4.2.4.
Electrocardiograms
Descriptive statistics for ECG parameters (ie, ventricular heart rate, RR interval, PR interval, 
QRS interval, QT interval, and QTc) at baseline and changes from baseline values at each 
assessment time point will be presented by study intervention group within each cohort. 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 within the corresponding cohort. 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 one postbaseline assessment for 
the double-blind Study Intervention Period within the corresponding cohort. The numerator will 
be the total number of participants with available non-PCS baseline values and at least one PCS 
postbaseline value during the double-blind Study Intervention Period of the corresponding 
cohort. A supportive listing of participants with PCS postbaseline values will be provided for the 
safety population. 
9.4.3.
Pharmacokinetic Analyses
Individual plasma concentrations of linaclotide and its active metabolite (MM-419447) will be 
listed by participant. Summary statistics of plasma concentrations for each analyte will be 
provided by dose group and time after the most recent dose if there are sufficient data to perform 
such an evaluation. In addition, population PK parameters of linaclotide and MM-419447 may 
be calculated via population PK modeling if data permits.
9.4.4.
Subgroup Analyses
Subgroup analyses (if planned) will be defined in the SAP. 
9.5.
Interim Analyses
No interim analyses are planned.
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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 sub-investigators 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.
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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. 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; 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/IEC 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 
that are at present unforeseeable
!
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
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!
The consequences of a participant’s decision to withdraw from the research and procedures 
for an orderly termination of 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.
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.
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.
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10.1.6.
Data Quality Assurance
!
All participant data relating to the study will be recorded on printed or electronic CRFs 
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 CRF. 
!
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
!
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 CRF 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 at least 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 
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.
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The study site staff will be fully trained by a representative of the eDiary vendor on the use of 
the eDiary device and how to train caregivers in the use of the eDiary device (ie, how to 
complete their daily assessments and download their data). The study site staff will then be 
responsible for ensuring that all caregivers enrolled in the study are given full training and 
support materials in relation to the completion of the eDiary. 
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, eDiaries, 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.
10.1.6.3.
Data and Safety Monitoring Board (DSMB)
An independent DSMB will review unblinded 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; the Board will not be 
empowered to stop the study or require changes in the protocol. 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. 
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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
10.1.9.
Publication Policy
!
Allergan, as the sponsor, and its partner, Ironwood, have 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 
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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), 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. 
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 sub-investigators 
listed on Form FDA 1572, including a copy of each physician’s license
!
A copy of the original IRB/IEC 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/IEC, as stated in Section 10.1.1.
!
A copy of the IRB/EC-approved parent/LAR, Caregiver ICFs
!
A copy of the HIPAA authorization form, or other local privacy applicable forms
!
A list of the IRB/IEC 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
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10.2.
Appendix 2: Clinical Laboratory Tests
Blood and urine samples for clinical laboratory tests will be collected as detailed in the SOA 
(Section 1.3). 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 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 (Section 10.3). 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.
Clinical laboratory levels that will be measured are summarized in Table 10–1.
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 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 and blood samples, which will be 
collected, processed, and stored according to the instructions provided by the laboratory. 
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.
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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
AST
Total, direct and 
indirect bilirubin
Creatinine
Sodium
Bicarbonate
Magnesium
Phosphate
Total protein
Total bilirubin
ALT
Total protein 
Total cholesterol 
chloride,
albumin
Glucose non-fasting
Calcium
ALP
Routine 
Urinalysis
!
Specific gravity
!
pH, glucose, protein, blood, ketones Microscopic examination (if blood or protein is 
abnormal)
Other Screening 
Tests
!
All study-required laboratory assessments will be performed by a central laboratory
a
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are provided in Appendix 9.
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c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or intervention 
that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether hospitalization occurred or was necessary, the AE should be considered serious.
Hospitalization for elective intervention of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity
!
The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.
!
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:
!
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.
Examples of such events include invasive or malignant cancers, intensive intervention in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse.
All cancers that occur during a study are considered SAEs and will be documented and reported 
per Section 10.3.
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10.4.
Appendix 4: Abbreviations
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BM
bowel movement
BSFS
Bristol Stool Form Scale
CBC
complete blood count
CFR
Code of Federal Regulations
CC
chronic constipation
CIC
chronic idiopathic constipation
DILI
drug-induced liver injury
DSMB
Data and Safety Monitoring Board
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
eDiary
electronic diary
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
HEENT
head, ears, eyes, nose, and throat
HIPAA
Health Insurance Portability and Accountability Act
IB
investigator’s brochure
IBS
irritable bowel syndrome
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
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IV
intravenous
IWRS
interactive web response system
LAR
legally authorized representative
mITT
modified intent-to-treat
mRNA
messenger ribonucleic acid
MSP
medical safety physician
ObsRO
observer-reported outcome 
PCS
potentially clinically significant
PID
participant identification 
PK
pharmacokinetic
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
ULN
upper limit of normal
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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)
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
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)
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CDISC Submission Value
CDISC Definition
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)
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10.6.
Appendix 6: Study Tabular Summary
Parameter Group
Parameter
Value
Trial information
Study Title
A Phase 2, Randomized, Double-Blind, 
Placebo-Controlled, Sequential, 
Ascending, Multidose Study to Evaluate 
the Safety and Efficacy of Linaclotide in 
Pediatric Participants (Age 2 to 5 Years) 
with Functional Constipation.
Clinical Study Sponsor
Allergan Sales LLC
Study Phase Classification
2
Study Indication
FC
Study Indication Type
Study Intervention
Study Type
Efficacy
Safety
Study Length
9 to 12 weeks per cohort
Planned Country of Investigational Sites
United States and Canada 
Planned Number of Participants
up to 30
FDA-Regulated Device Study
No
FDA-Regulated Drug Study
Yes
Pediatric Study
Yes
Participant 
information
Diagnosis Group
Children, Ages 2 to 5 Years with 
Functional Constipation
Healthy Participant Indicator
No
Planned Minimum Age of Participants
2
Planned Maximum Age of Participants
5
Sex of Participants
Both
Stable Disease Minimum Duration
2 months (for participants aged ≥ 4 years 
old), or 1 month (for participants aged < 4 
years old)
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Parameter Group
Parameter
Value
Treatments
Study Intervention Therapy or Treatment
linaclotide
Intervention Type
drug
Pharmacological Class of Invest. Therapy
GC-C agonist
Dose per Administration
!
Cohort 1: linaclotide 18 μg or 
matching placebo once daily for 
4-week Study Intervention Period.  
!
Cohort 2: linaclotide 36 μg or 
matching placebo once daily for 
4-week Study Intervention Period. 
!
Cohort 3: linaclotide 72 μg or 
matching placebo once daily for 
4-week Study Intervention Period.  
!
Final Cohort highest dose of
linaclotide tested/determined to be 
safe or matching placebo for 4-week 
Study Intervention Period.
Dose Units
μg
Dosing Frequency
single dose, once daily at approximately 
the same time each day, 30 minutes prior 
to any meal.
Route of Administration
Oral
Current Therapy or Treatment
None
Added on to Existing Treatments
No
Control Type
Placebo
Comparative Treatment Name
NA
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Parameter Group
Parameter
Value
Study design
Study Type
Double-blind, placebo-controlled, 
Sequential, Ascending, Multidose Study 
to evaluate safety and efficacy 
Intervention Model
Sequential
Planned Number of Groups
8 participants each in Cohorts 1 to 3, 6 
participants in final cohort, study 
intervention and placebo in each cohort
Study is Randomized
Yes
Randomization Quotient
8 participants 3:1 linaclotide or placebo in 
Cohorts 1- 3; 6 participants 5:1 linaclotide 
or placebo in final cohort
Study Blinding Schema
Double blind
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. 
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10.7.
Appendix 7: Instructions for Dosing
Four capsule strengths will be provided:
!
36 μg capsules, which are used to prepare the  μg dose
!
72 μg capsules, which are used to prepare the 18 μg dose
!
145 μg capsules, which are used to prepare the 36 μg dose
!
290 μg capsules, which are used to prepare the 72 μg dose
!
Placebo preparation is identical for all dose cohorts
Instructions for dose preparations are as follows: dose must be prepared at the time of 
administration and should not be prepared ahead of time and stored.
1. Pour exactly 20 mL of room-temperature bottled water into the provided medicine 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. Withdraw 5 mL into the provided oral syringe and discard this portion per instructions in the 
Study Reference Manual.
6. Withdraw a second portion of 5 mL into the oral syringe and administer dose to the 
participant, swallowing immediately.
7. Discard the remaining solution per instructions in the Study Reference Manual.
8. Rinse the syringe and medicine cup with bottled water.
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.
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10.8.
Appendix 8: Study Schedule Supplement 
The schedule of study procedures and assessments is tabulated by visit in the SOA in 
Section 1.3. The descriptions of the procedures to be performed at each visit are provided below.
10.8.1.
Screening (Visit 1)
The Screening Period will occur 4 to 7 weeks before Randomization (Visit 3/Day 1) and last for 
14 to 28 days during which time study procedures will be reviewed with the 
parent/guardian/LAR, and caregiver; and parent/guardian/LAR and 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 (Sections 5.1 and 5.2).
At Screening (Visit 1) the following procedures will be performed:
!
Review inclusion and exclusion criteria
!
Complete modified Rome III assessment
!
Register participants in IWRS 
!
Obtain medical history and current medication status
!
Perform a 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. Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
!
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 dis-impaction 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). After the participant has received treatment for 
the impaction, the investigator must re-evaluate the participant for the presence of fecal 
impaction at Visit 2/Preintervention Visit. 
!
Obtain height, vital signs (weight, temperature (oral, rectal, or tympanic), and respiratory 
rate), and postural vital signs (supine systolic and diastolic BP and pulse rate) (Section 8.2.2)
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IWRS verification
!
Perform a fecal impaction assessment if fecal impaction was documented during screening 
(Section 10.8.1)
!
Obtain vital signs (weight, temperature (oral, rectal, or tympanic), and respiratory rate) and 
postural vital signs (supine systolic and diastolic BP and pulse rate) (Section 8.2.2)
!
Review any AEs occurring since the last visit
!
Review concomitant medications
!
Contact the IWRS, where applicable, for rescue medication to be dispensed to the participant.
!
Remind caregiver to bring the bottle(s) of the rescue medication to the next visit.
!
Instruct participants when to fast to ensure they have fasted for at least 2 hours before 
receiving the first dose of study intervention at the study site during the Randomization Visit; 
participants will be allowed to eat 30 minutes after dosing.
!
Provide caregivers with the eDiary along with instructions 
10.8.3.
Randomization (Visit 3, Day 1)
Participants' eligibility to enter the Study Intervention Period must be confirmed prior to 
randomization by review of inclusion and exclusion criteria, including a fecal impaction 
assessment, adherence to instructions regarding the use of rescue medication and prohibited 
medications, meeting eligibility criteria captured in the eDiary device, including full compliance 
with eDiary on at least 10 of the 14 days immediately preceding Visit 3 and with clinic eDiary on 
the day of Randomization. The study coordinator will obtain the eDiary eligibility report to 
determine eDiary-related eligibility to be randomized. Once the participant's randomization 
eligibility is confirmed based on the eDiary eligibility report and other inclusion and exclusion 
criteria, the IWRS will randomize the participant. Study personnel will review the study 
procedures with the caregivers and instruct them to continue completing the eDiary entries every 
evening. Subsequent study visits will be scheduled keeping in mind that the last dose of study 
intervention will occur at Visit 5 and should occur at approximately same time as the other doses 
of study intervention during double-blind Study Intervention Period.  
Randomization will occur on the first day of the Study Intervention Period. Based on 
randomization, participants will receive placebo or linaclotide. Participants will complete at least 
4 weeks of treatment during the double-blind Study Intervention Period (ie, Study Intervention 
Period).
During the Randomization Visit (Visit 3), the following procedures will be performed:
!
Review inclusion and exclusion criteria, including review of eDiary-related criteria
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!
IWRS verification
!
Perform a fecal impaction assessment prior to randomization and dosing. If fecal impaction is 
present, the participant will not be eligible for the study.
!
Obtain vital signs (weight, temperature (oral, rectal, or tympanic), and respiratory rate) and 
postural vital signs (supine systolic and diastolic BP and pulse rate) (Section 8.2.2)
!
Review any AEs occurring since the last visit
!
Review concomitant medications
!
Review eDiary completion, including the Clinic eDiary
!
Ensure participants have refrained from using rescue medicine on the prior calendar day and 
on the day of the Randomization (Visit 3) until the time of the clinic visit. 
!
Remind participants not to use rescue medicine for the remainder of the day and on the next 
calendar day after the Randomization Visit
!
Run the eDiary Eligibility Report to confirm that the participant can be randomized.
!
Review use of protocol-permitted rescue medication dispensed in IWRS where applicable. 
Participants may choose a different protocol-permitted rescue medication at any visit, where 
available. Additional protocol-permitted rescue medications may be dispensed as needed at 
any visit
!
Prior to dosing, the investigator or appropriate site staff member will assess Rome IV criteria 
for childhood FC. Assessment result will be captured in the eCRF. Eligibility for the study is 
not based on this assessment
!
Contact the IWRS to obtain the study intervention (bottle number) to be dispensed to the 
participant based on randomization and PK sample assignment.
!
Prepare and administer the first dose of study intervention after completion of all Visit 3 
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
!
Dispense assigned study intervention for this study after the first dose has been administered. 
Provide study intervention reconstitution instructions for sprinkles to caregivers 
(Section 10.7).
!
Record the date and time the first dose was administered
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!
Remind caregiver to bring the bottle(s) of the study intervention and rescue medication to the 
next visit
!
Encourage caregivers to schedule Visit 5 (Week 4) as the participants will need to take 
linaclotide in a fasted state.
10.8.4.
Week 2 (Visit 4)
During Week 2 (Visit 4), the following procedures will be performed:
!
Obtain vital signs (weight, temperature (oral, rectal, or tympanic), and respiratory rate) and 
postural vital signs (supine systolic and diastolic BP and pulse rate) (Section 8.2.2)
!
Review any AEs occurring since the last visit
!
Review concomitant medications
!
Review use of protocol-permitted rescue medication dispensed in IWRS where applicable. 
Participants may choose a different protocol-permitted rescue medication at any visit, where 
available. Additional protocol-permitted rescue medications may be dispensed as needed at 
any visit
!
Review study intervention and rescue medication compliance and accountability
!
Review eDiary completion
!
Remind participant and caregiver to bring the bottle(s) of the study intervention and rescue 
medication to the next visit
!
Remind caregivers to have the participant fast for at least 2 hours before receiving their last 
dose of study intervention at the study site during the Week 4 (Visit 5) Visit.
10.8.5.
Week 4/EOT (Visit 5)
Participants will arrive in a fasted state for this visit after completing at least 28 days of study 
intervention to receive their last dose of study intervention before or after PK sample. All 
randomized participants who prematurely discontinue from the study, regardless of cause, are 
required to be seen for the assessments completed at EOT (Visit 5, Week 4), except for PK 
sample collection. This visit should be scheduled at approximately the same time as when 
participants take their daily dose. During Week 4 (Visit 5), the following procedures will be 
performed:
!
IWRS verification
!
Perform a physical examination, including general appearance, skin, HEENT (head, ears, 
eyes, nose, and throat), neck, thorax/lungs, cardiovascular, abdomen, musculoskeletal, lymph
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nodes, neurologic (including mental status), and visual inspection of the lumbosacral and 
perianal region.
!
Complete modified Rome III assessment
!
Obtain vital signs (weight, temperature (oral, rectal, or tympanic), and respiratory rate) and 
postural vital signs (supine 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
!
Review any AEs occurring since the last visit
!
Review concomitant medications
!
PK sample will be obtained in participants who will be completing the study intervention at 
this visit. 
!
Pre-dose or post-dose PK sampling should be obtained at the same time as clinical lab tests 
described above to avoid an extra needle stick. 
!
Pre-dose sample will be obtained from participants assigned to this group at the clinic before 
the administration of the last dose of study intervention. Post-dose PK sample will be 
obtained 1-8 hours after the last dose of study intervention in participants assigned to the 
post-dose PK group. The last dose of study intervention should be administered after 
confirming the participant has fasted for at least 2 hours. Participants may resume eating 30 
minutes after receiving their last dose of study intervention at the study site.
!
Obtain date and time of the dose of study intervention prior to PK sample collection
!
Obtain standard 12-lead ECG (supine)
!
Review use of protocol-permitted rescue medication dispensed in IWRS where applicable. 
Participants may choose a different protocol-permitted rescue medication at any visit, where 
available. Additional protocol-permitted rescue medications may be dispensed as needed at 
any visit
!
Review study intervention and protocol-permitted rescue medication use and accountability
!
Review eDiary completion
!
Remind caregiver to bring the bottle(s) of the rescue medication to the next visit
!
Return study intervention
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10.8.6.
End of Study Visit /Postintervention Follow-up (1 week)
During EOS Visit (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 systolic and diastolic BP, and pulse rate) (Section 8.2.2) 
!
Review any AEs occurring since the last visit
!
Review concomitant medications
!
Review use of protocol-permitted rescue medication dispensed in IWRS where applicable. 
!
Review rescue medication compliance, accountability 
!
Return rescue medication
!
Review eDiary completion and return eDiary device
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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.
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
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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 
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. 
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10.10.
Appendix 10: Study Conduct During the Novel Coronavirus 
Pandemic: Pre-randomization
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.
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.
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10.11.
Appendix 11: Supporting Information from the Adult Linaclotide 
Program
Figure 10–1
Change from Baseline over the First 4 Weeks in Observed SBM/Week 
by Dose in μg/kg: ITT Population of Phase 2 and 3 Adult CIC 
Population
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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.
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;94:367-73.
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.
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.
Lewis SJ, and Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J
Gastroenterol 1997;32:920-924.
Approval Date: 04-May-2020 21:25:29 (GMT)

SAP_001.pdf: 
NCT04110145