Clinical trial NCT04026113
Conditions: Functional Constipation Irritable Bowel Syndrome With Constipation
Keywords: Functional constipation in children Irritable Bowel Syndrome with Constipation LINZESS
Sponsor: AbbVie
Start date: 2019-10-01; Completion date: 2024-05-29
Enrollment: 438 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of LIN-MD-64 is to evaluate the safety and efficacy of 12 weeks of linaclotide therapy (72 μg daily) in comparison with placebo in pediatric participants, 6 to 17 years of age, who fulfill modified Rome III Criteria for child/adolescent FC. The objective of LIN-MD-64 is to evaluate the safety and efficacy of 12 weeks of linaclotide therapy (145 μg or 290 μg daily) 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.

Detailed description:

Arms: arm 1: Placebo single dose, once daily at approximately the same time each day, 30 minutes before any meal. arm 2: Linaclotide 72 μg single dose, once daily at approximately the same time each day, 30 minutes before any meal. arm 3: Linaclotide 145 μg single dose, once daily at approximately the same time each day, 30 minutes before any meal. arm 4: Linaclotide 290 μg single dose, once daily at approximately the same time each day, 30 minutes before any meal
Interventions: intervention 1: Linaclotide intervention 2: Placebo
Intervention descriptions: intervention 1: Oral capsule (For participants who do not wish to take the dose as a capsule, a sprinkled dose may be prepared) intervention 2: Matching placebo

Protocol documents:
Prot_000.pdf: 




CONFIDENTIAL
Protocol LIN-MD-64, Amendment 1
Linaclotide
3
GRD-CLN-T-01-01 v2.0
Protocol Section(s)
Description of Changes
Rationale for Changes
Title Page

Updated title to include IBS-C participants.

Added the EudraCT number.

To align with changes in the 
protocol

To reflect current information
Section 1.1 Synopsis

All relevant changes made below in subsequent sections in the body of the protocol 
have been carried up to the synopsis.

To align with the body of the 
protocol
Section 1.3 Schedule of 
Activities (SoA)

Table 1-1 was edited to include IBS-C participants.

An assessment of Rome III criteria at EOT was added for all participants.

The following text was added to footnote ‘e’: ‘Prior to dosing, the investigator or 
appropriate site staff member will assess if Rome IV criteria for Child/Adolescent 
FC (FC and IBS-C participants) or Rome IV criteria for Child/Adolescent 
IBS (IBS-C participants) was met and record the outcome in the eCRF.’

A fecal impaction assessment at Randomization (Visit 3) was added for all 
participants. The footnotes have been updated accordingly.

Footnote ‘l’ has been updated for clarity.

Footnote ‘u’ has been added: ‘Additional unscheduled visits may be allowed at the 
discretion of the investigator with approval from the sponsor’.

For clarification and update to 
include IBS-C participants in 
the study

To assess participants for 
fulfilling Rome criteria at both 
screening and at end of 
treatment as an ‘other’
efficacy endpoint.

To update to include IBS-C 
participants in the study

To ensure participants didn’t 
have fecal impaction prior to 
receiving study intervention

For clarification

To allow additional visits for 
participants if needed
Section 2 Introduction

Text added to include the pediatric Phase 2 study LIN-MD-63 results in the 
introduction.

To reflect current information
Section 2.1 Study Rationale

Text added to describe the IBS disease and prevalence and the lack of any 
approved therapy for IBS-C in pediatric patients.

Added a summary of results for Phase 2 dose ranging study LIN-MD-63 
evaluating linaclotide in pediatric IBS-C participants.

Added the primary objective of LIN-MD-64 for IBS-C participants.

Updated to include IBS-C 
participants in the study
Approval Date: 05-Jun-2020 15:39:03 (GMT)


CONFIDENTIAL
Protocol LIN-MD-64, Amendment 1
Linaclotide
4
GRD-CLN-T-01-01 v2.0
Protocol Section(s)
Description of Changes
Rationale for Changes
Section 2.2.1 Adult Linaclotide 
Program

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 2.3 Benefit/Risk

Text added to include the IBS-C population.

Updated to include IBS-C 
participants in the study
Section 3 Objectives and 
Endpoints

Added the objective and primary and secondary endpoints for IBS-C participants.

Updated to include IBS-C 
participants in the study
Section 4.1 Overall Design

Added the study design for IBS-C participants.

Added text regarding the addition of an optional interim analysis for futility in FC 
participants.

Updated to include IBS-C 
participants in the study

To address potential 
enrollment issues with the 
pediatric FC population
Section 4.1.1 Clinical 
Hypotheses

Added a clinical hypothesis for treatment of IBS-C participants with linaclotide.

Updated to include IBS-C 
participants in the study
Section 4.2 Scientific Rationale 
for Study Design

Added a scientific rationale for the study design for IBS-C participants.

Updated to include IBS-C 
participants in the study
Section 4.3 Justification for 
Dose

Added a justification for the doses chosen for IBS-C participants.

Updated to include IBS-C 
participants in the study
Sections 5.1 Inclusion Criteria

Edits were made to inclusion criteria 1.01, 1.02, 2.01, and 4.02 to add IBS-C 
participants and/or to add clarity. 

Inclusion criteria 2.011 and 2.012 for IBS-C participants were added.

For clarification and to 
include IBS-C participants

Updated to include IBS-C 
participants in the study
Approval Date: 05-Jun-2020 15:39:03 (GMT)


CONFIDENTIAL
Protocol LIN-MD-64, Amendment 1
Linaclotide
5
GRD-CLN-T-01-01 v2.0
Protocol Section(s)
Description of Changes
Rationale for Changes
Section 5.2 Exclusion Criteria

Edits were made to exclusion criteria 1.01, 1.05, and 1.11 to add IBS-C 
participants and/or to add clarity. 

Exclusion criterion 1.04 was revised to add a fecal impaction assessment at Visit 3.

‘Vital sign assessment’ was included in exclusion criteria 1.07.

Criterion 1.13 was removed.

For clarification and to 
include IBS-C participants

To ensure participants didn’t 
have fecal impaction prior to 
dosing

For clarification

Updated eligibility criteria to 
be more inclusive for 
enrollment
Section 5.3 Lifestyle 
Considerations

Added lifestyle considerations for IBS-C participants.

Reorganized habits by all participants, FC participants, and IBS-C participants.

For clarification and update to 
include IBS-C participants in 
the study
Section 6 Study Intervention

Added text on the randomization and dosing of IBS-C participants.

Updated to include IBS-C 
participants in the study
Section 6.1 Study Intervention 
Administered

Added text on the study intervention administered to IBS-C participants.

Updated to include IBS-C 
participants in the study
Section 6.3 Measures to 
Minimize Bias: Randomization 
and Blinding

Added text on the randomization of FC and IBS-C participants being carried out 
separately.

Revised the study number from 301 to 364.

Revised the site number from 00001-99999 to 10001-19999.

Update to include IBS-C 
participants in the study 

To reflect what’s being used 
in the study
Section 6.3.1.2 Unblinding

Added text on the separate database locks and unblinding procedures for FC and 
IBS-C participants.

Updated to include IBS-C 
participants in the study
Section 6.5.1 Prohibited 
Interventions

Added linaclotide to the list of prohibited medicines with a 14-day washout period.

To provide additional clarity
Section 6.5.2 Rescue Medication

Added a statement clarifying the use of rescue medication with regard to Visit 3 
(Randomization Visit).

For clarification
Section 6.6 Dose Modification

Added the dose modifications permitted for IBS-C participants.

Updated to include IBS-C 
participants
Approval Date: 05-Jun-2020 15:39:03 (GMT)


CONFIDENTIAL
Protocol LIN-MD-64, Amendment 1
Linaclotide
6
GRD-CLN-T-01-01 v2.0
Protocol Section(s)
Description of Changes
Rationale for Changes
Section 7.1.1 Removal of 
Individual Participants from 
Therapy or Assessment

Two criteria have been moved from ‘participant may be discontinued’ to 
‘participant must be discontinued’.

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 further ensure participant 
safety

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 11.’

To add a reference to newly 
added Appendix 11
Section 8.1 Efficacy 
Assessments

Information regarding the efficacy assessments for IBS-C participants has been 
added and changes made to clarify what pertains to FC participants versus IBS-C 
participants.

The following text was deleted: ‘The relationship of the caregiver to the participant 
should be recorded in the eCRF.’

For clarification and update to 
include IBS-C participants in 
the study

To reflect current information
Section 8.1.1 Efficacy 
Assessments in FC Participants

Replaced ‘parameter’ with ‘endpoint’ as needed.

For clarification
Section 8.1.1.2 Secondary 
Efficacy Assessment

Revised text to reflect the text in the current eDiary. 

To align with the current 
eDiary
Section 8.1.1.3 Additional 
Efficacy Assessments

Added an assessment of modified Rome III criteria at the end of the study 
intervention period.

To assess FC participants for 
fulfilling modified Rome III
criteria at both screening and 
at end of treatment as an 
‘other’ efficacy endpoint
Section 8.1.2 Efficacy 
Assessments in IBS-C 
Participants

Added the efficacy assessments that will be performed for IBS-C participants.

Updated to include IBS-C 
participants.
Section 8.2.1 Physical 
Examinations

The following text was removed: A complete physical examination will be done at 
screening and at the 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.

Added a fecal impaction assessment at randomization (Visit 3) prior to dosing for 
all participants.

To align with current Allergan 
template 

To ensure participants don’t 
have fecal impaction prior to 
receiving study intervention
Section 8.2.2 Vital Signs

Removed bullet 2 from the procedure for obtaining vital signs.

For clarification
Approval Date: 05-Jun-2020 15:39:03 (GMT)


CONFIDENTIAL
Protocol LIN-MD-64, Amendment 1
Linaclotide
7
GRD-CLN-T-01-01 v2.0
Protocol Section(s)
Description of Changes
Rationale for Changes
Section 8.2.3 
Electrocardiograms

Revised text to clarify method for recording ECGs.

To reflect current information
Section 8.3.4 Follow-up of AEs, 
SAEs, and AESIs

Inserted ‘etiology’ in the following sentence: All AE/ SAE and non-serious AESIs 
will be followed until resolution, stabilization, the event’s etiology is otherwise 
explained, or the participant is lost to follow-up.

Deleted the following text as this information is presented in Appendix 3: Adverse 
Events:
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 .

For clarification

To align with current Allergan 
template
Section 8.3.6 Pregnancy

Added text regarding genetic abnormalities.

To align with current 
Allergan template
Section 8.3.7 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 Statistical 
Considerations

Text added to indicate that this study involves two independent parallel parts, one 
for FC participants and one for IBS-C participants, and that database locks will be 
performed separately for FC and IBS-C participants.

Section numbers were updated throughout to delineate statistical sections for each 
disease population, and corresponding section references were updated 
accordingly.

Text added throughout Section 9 to clarify what information corresponds to FC 
participants versus IBS-C participants.

For clarification and update to 
include IBS-C participants in 
the study
Section 9.1.3 Sample Size 
Determination - FC Participants

A brief description was added of the sample size to be targeted for FC participants 
if an optional interim analysis for futility is performed.

To provide information 
regarding sample size for the 
optional interim analysis
Section 9.1.5.1.1 Efficacy 
Analysis Endpoints

The other efficacy endpoint of ‘Time to the first SBM after the first dose of study 
intervention’ has been changed to ‘Time to the first report of SBM after the first 
dose of study intervention’ to more accurately reflect the endpoint.

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.’

For clarification

To assess whether 
participants meet Rome III 
criteria at the end of the 12-
week study intervention 
period. 
Approval Date: 05-Jun-2020 15:39:03 (GMT)


CONFIDENTIAL
Protocol LIN-MD-64, Amendment 1
Linaclotide
8
GRD-CLN-T-01-01 v2.0
Protocol Section(s)
Description of Changes
Rationale for Changes
Section 9.1.5.2.2 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
Section 9.2 Statistical 
Considerations for IBS-C 
Participants

Added information regarding the statistical analyses that will be performed for 
efficacy and safety data for IBS-C participants.

Updated to include IBS-C 
participants
Section 9.3 Interim Analyses

Details of the optional interim analysis strategy for FC participants were added.

Updated to include an 
optional interim analysis for 
FC participants
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.

Footnote ‘b’ was moved from Routine Urinalysis to the second bullet under Other
Screening Tests.

To reflect what’s being 
assessed in the study

To align with the liver 
appendix template 

For clarification
Section 10.3 Appendix 3: 
Adverse Events

Text regarding reporting of potential Hy’s Law cases was moved to newly added 
Appendix 9: Liver Safety: Suggested Actions and Follow-up Assessments.

A section title was revised from ‘SAE Reporting’ to ‘SAE Reporting to Sponsor 
or Designee Within 24 Hours’.

For clarity and to align with 
the liver appendix template
Section 10.4 Appendix 4: 
Abbreviations

Updated to align with new abbreviations used in the body of the protocol.

To align with changes in the 
protocol
Section 10.6 Appendix 6: Study 
Tabular Summary

Updated the study tabular summary to include information regarding IBS-C 
participants in the study.

Updated to include IBS-C 
participants
Section 10.7 Appendix 7: 
Contraceptive Guidance and 
Collection of Pregnancy 
Information

The description of the pregnancy testing sensitivity was revised as shown below:
‘Pregnancy testing with a sensitivity of 5, 10, ≤25 mIU/mL will be performed’.

For clarification and to reflect 
the sensitivity of the assay 
currently being used in the 
study
Approval Date: 05-Jun-2020 15:39:03 (GMT)


CONFIDENTIAL
Protocol LIN-MD-64, Amendment 1
Linaclotide
9
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. With the addition of the new Appendix 9, the subsequent Appendix has 
been moved to Appendix 10 and all section numbering and references have been
changed accordingly.

To provide liver safety 
information in a consolidated
location and to align with the 
liver appendix template
Section 10.10.1 Screening 
Period (Visit 1)

The following procedure was added to the Screening Visit: ‘Complete Rome III 
assessment’.

Lumbosacral was added to the physical exam.

Information regarding lifestyle modifications was updated to include IBS-C 
participants and clarify the modifications for each population.

To assess participants for 
fulfilling Rome III criteria at 
screening

For clarification

For clarification and update to 
include IBS-C participants in 
the study
Section 10.10.2 Preintervention 
Period (Visit 2)

The following text was removed: ‘If fecal impaction is documented during an 
optional repeat physical examination, the Study Physician must be notified’.

Text regarding the use of rescue medication was added.

For clarification
Section 10.10.3 Randomization 
(Visit 3, Day 1)

A fecal impaction assessment was added to the randomization visit (Visit 3) as 
shown below:
‘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 10.10.7 Week 12/EOT 
Visit (Visit 7)

Lumbosacral was added to the physical exam.

The following procedure was added to the EOT Visit: ‘Complete Rome III 
assessment.’

For clarification

To assess participants for 
fulfilling ROME III criteria at 
the end of treatment as an 
‘other’ efficacy endpoint.
Section 10.11 Appendix 11: 
Study Conduct During the Novel 
Coronavirus Pandemic

Appendix 11: Study Conduct During the Novel Coronavirus Pandemic was added.

To provide information on 
study conduct during the 
novel coronavirus pandemic
Section 10.12 Supporting 
Information from the Adult 
Linaclotide Program

Results from recently completed study MCP-103-312 were added to Table 10-3.

To reflect current information
Section 11 References

References for IBS and statistical analyses for the interim analysis were added.

To reflect current information
Approval Date: 05-Jun-2020 15:39:03 (GMT)






















CONFIDENTIAL
Protocol LIN-MD-64, Amendment 1
Linaclotide
20
GRD-CLN-T-01-01 v2.0
1.3.
Schedule of Activities (SoA)
Table 1–1
Schedule of Activities for FC and IBS-C Participants
Study Periods (Duration)
Screening (14-28 
Days)
Preintervention
(14-21 Days)
Study Intervention Period
(12 weeks)
Postintervention
(1 week)
Study Visitu
Screening
Preintervention
Randomization
Week 2
Week 4
Week 8
Week 12 Visit/
End of Treatment
(EOT)a
End of Study
(EOS) Visit b
Visit Number
1
2
3
4
5
6
7
8
Study Day 
-49 to -22
-21 to -14
1
15 (± 2)
29 (± 2)
57 (± 2)
85 (+3)c
EOT +7 (+7)
Parent/Caregiver Consent/Assentd
X
Inclusion and Exclusion Criteria
X
X
X
Rome III Assessment
X
X
Assess Rome IV statuse
X
IWRS 
X
X
Xf
X
X
X
Medical History
X
Lifestyle Modification Information 
Given to Participant/Caregiverg
X
Physical Examinationh
X
X
Fecal Impaction Assessmenti
X
Xj
Xk
Height
X
X
Vital Signs and Postural Vital Signsl
X
X
X
X
X
X
X
X
ECG
X
X
Clinical Laboratory Testsm
X
X
X
Serum Pregnancy Testsn
X
Urine Pregnancy Testso
X
X
X 
X
Urine Drug Screenp
X
AE Evaluation
X
X
X
X
X
X
X
X
Prior and Concomitant Medications
X
X
X
X
X
X
X
X
Rescue Medication Dispensedq
X
X
X
X
X
X
Approval Date: 05-Jun-2020 15:39:03 (GMT)


CONFIDENTIAL
Protocol LIN-MD-64, Amendment 1
Linaclotide
21
GRD-CLN-T-01-01 v2.0
Study Periods (Duration)
Screening (14-28 
Days)
Preintervention
(14-21 Days)
Study Intervention Period
(12 weeks)
Postintervention
(1 week)
Study Visitu
Screening
Preintervention
Randomization
Week 2
Week 4
Week 8
Week 12 Visit/
End of Treatment
(EOT)a
End of Study
(EOS) Visit b
Visit Number
1
2
3
4
5
6
7
8
Study Day 
-49 to -22
-21 to -14
1
15 (± 2)
29 (± 2)
57 (± 2)
85 (+3)c
EOT +7 (+7)
eDiary and Instructions Given to 
Participant/Caregiverr
X
eDiary Compliancer
X
X
X
X
X
X
eDiary Eligibility Reportf
X
Study Intervention Administered on 
Sites
X
Study Intervention Dispensed
X
X
X
Study Intervention and Rescue 
Medication Compliance and 
Accountability
Xs
X
X
X
X
Xt
AE = adverse event; ECG = electrocardiogram; eDiary = electronic diary: refers to the participant- or interviewer-administered version of the PRO diary on a handheld electronic 
device; IWRS = interactive Web response system; PRO = patient reported outcome.
a
Study procedures for screening in LIN-MD-66 can be combined with End of Treatment (EOT)/Week 12 Visit (Visit 7) for Study LIN-MD-64.
b
Participants who rollover to the long-term safety study, LIN-MD-66, before the EOS Visit (Visit 8) are not required to have this visit.
c
Participants must complete at least 12 weeks (84 days) of study intervention before arriving at the study site for the EOT/Week 12 Visit (Visit 7). All randomized participants 
who prematurely discontinue from the study intervention, regardless of cause, should complete assessments at this EOT/Week 12 Visit (Visit 7). 
d
The parent/guardian/legally authorized representative must provide written informed consent and the participant must provide assent 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.
e
Prior to dosing, the investigator or appropriate site staff member will assess if Rome IV criteria for Child/Adolescent FC (FC and IBS-C participants) or Rome IV criteria for 
Child/Adolescent IBS (IBS-C participants) was met and record the outcome in the eCRF. Eligibility for the study is not based on this assessment.
f
Eligibility report must be run prior to randomization.
g
During the Screening Period, participants and their caregivers will receive information regarding lifestyle modifications (refer to Section 5.3 for details). 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.
h
Physical examinations will be performed by medically qualified site personnel and may be repeated at the investigator’s discretion. If fecal impaction (as defined in footnote i) 
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.
j
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) (as defined in footnote i above), 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. 
Approval Date: 05-Jun-2020 15:39:03 (GMT)


CONFIDENTIAL
Protocol LIN-MD-64, Amendment 1
Linaclotide
22
GRD-CLN-T-01-01 v2.0
k
A fecal impaction assessment is performed at the Randomization Visit (Visit 3) after eDiary eligibility is confirmed and prior to randomization. If there is no fecal impaction 
at the Randomization Visit (Visit 3) (as defined in footnote i above), the participant is eligible for randomization. If fecal impaction is present upon examination, the 
participant will not be eligible for the study.
l
Vital signs include temperature, respiratory rate, and weight. Postural vital signs (supine and standing) include pulse rate and systolic and diastolic blood pressure. At all 
visits, postural vital signs must be obtained after participants have been in a supine position for at least 2 to 3 minutes, followed by a standing position for at least 1 minute. 
Temperature may be recorded as oral, rectal or tympanic (ear). If possible, temperature should be obtained using the same method at each visit.
m
Clinical laboratory tests consist of clinical chemistry, hematology, and urinalysis. All laboratory tests requiring blood draws should be collected at the same time.
n
Serum pregnancy test will be obtained for female participants of childbearing potential. 
o
Urine pregnancy test will be obtained for female participants of childbearing potential. A negative urine pregnancy test is required prior to dosing at the Randomization Visit 
(Visit 3) and prior to study intervention dispensing at Week 4 (Visit 5) and Week 8 (Visit 6). 
p
A urine drug screen will be obtained at Screening (Visit 1) for all participants 12 to 17 years of age and only if deemed necessary by the investigator for participants 6 to 
11 years of age. Urine drug screens may be repeated at the investigator’s discretion at any time during the study.
q
Protocol-permitted rescue medication will be dispensed in IWRS where applicable. Participants 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 visit, where available.
r
At the Preintervention Visit (Visit 2), participants and parents/caregivers will be trained on the use of the eDiary device and instructed to complete both morning and evening 
assessments daily. At subsequent visits, study site staff will verify participant compliance with the eDiary device and remind participants to complete their morning and 
evening 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 beginning at Randomization through End-of-Study.
s
Study intervention will be administered at the study site during the Randomization Visit (Visit 3) after running the Eligibility report and confirming the participant has fasted 
for at least 2 hours. 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). 
t
Protocol-permitted rescue medications only.
u
Additional unscheduled visits may be allowed at the discretion of the investigator with approval from the sponsor.
Approval Date: 05-Jun-2020 15:39:03 (GMT)


























































































































































































































CONFIDENTIAL
Protocol LIN-MD-64, Amendment 1
Linaclotide
131
GRD-CLN-T-01-01 v2.0
10.12.
Supporting Information from the Adult Linaclotide Program
Table 10-3
Summary of Studies in the Linaclotide Adult Program Conducted in North America
Study Number
Study Design/Study Population
Major Conclusions
MCP-103-312
Phase 3b, randomized, double-blind, 
placebo-controlled, parallel-group trial 
of linaclotide 290 μg administered orally 
for 12 weeks followed by a 4-week 
randomized withdrawal period in 
patients with irritable bowel syndrome 
with constipation

Linaclotide showed a statistically significant improvement in Overall Change from
Baseline in Abdominal Score Throughout the Treatment Period compared with 
placebo for the primary analysis of the primary endpoint (p<0.0001), as well as for 
the secondary time-course analysis of the primary endpoint (p<0.0005 at all weeks).

Linaclotide showed statistically significant improvements compared with placebo for
the secondary endpoints of Change from Baseline in 12-week Abdominal Score 
(comparison of cumulative distribution function curves) and 6/12 Week Abdominal 
Score Responder (both p<0.0001).

Statistically significant improvement in abdominal score with linaclotide versus 
placebo was observed within the first week of dosing and was sustained over the 12-
week Treatment Period.

Diarrhea was the most commonly reported TEAE during the trial. During the 
treatment period, 4.6% of linaclotide patients reported at least 1 episode of diarrhea, 
compared with 1.6% of placebo patients; this represented a lower diarrhea rate than 
previously observed in linaclotide trials.
LIN-MD-31
Phase 3 study multicenter, randomized, 
double-blind, placebo-controlled, 
parallel-group study in adults with IBS-
C comparing one dose (266 μg) of 
linaclotide with placebo. Included a 4-
week double blind, randomized 
withdrawal period immediately 
following the 12-week treatment period 
to assess the potential for rebound 
worsening of bowel or abdominal 
symptoms

Linaclotide showed a statistically significant improvement versus placebo for all 4 
primary efficacy parameters controlling for multiplicity: 9/12 Week APC 3+1 
responder (p = 0.0004), 9/12 Week CSBM 3+1 responder (p < 0.0001), 9/12 Week 
abdominal pain responder (p = 0.0262), and 6/12 Week APC +1 responder 
(p = < 0.0001).

Linaclotide showed a statistically significant improvement versus placebo for each of 
the 10 secondary efficacy parameters (all p-values statistically significant controlling 
for multiplicity). The results were observed within the first week of dosing and were 
sustained over the 12-week treatment period.

There was no evidence of a rebound effect when linaclotide treatment was withdrawn.

Diarrhea was the most frequently reported TEAE during the trial. In the treatment 
period, 79 (19.5%) of 406 patients treated with linaclotide reported at least 1 episode 
of diarrhea compared to 14 (3.5%) of 396 patients treated with placebo.
Approval Date: 05-Jun-2020 15:39:03 (GMT)


CONFIDENTIAL
Protocol LIN-MD-64, Amendment 1
Linaclotide
132
GRD-CLN-T-01-01 v2.0
Study Number
Study Design/Study Population
Major Conclusions
MCP-103-302
Phase 3 randomized, double blind, 
placebo-controlled, parallel-group study 
of linaclotide administered orally for 26 
weeks in adults with IBS-C

Safety and efficacy of linaclotide 290 µg administered as a solid oral capsule for 12 or 
26 weeks: Results showed improvement in abdominal and bowel symptoms at 12 
weeks that was maintained throughout 26 weeks of treatment. Diarrhea was the most 
frequently reported TEAE during the study.

Linaclotide showed a statistically significant difference from placebo for each of the 4 
primary efficacy parameters (p < 0.0001 for all 4 parameters): 9/12 week APC 3+1 
Responder, 9/12 week CSBM 3+1 Responder, 9/12 week Abdominal Pain Responder, 
and 6/12 week APC +1 Responder, all of which were statistically significant 
controlling for multiplicity.

Differences in linaclotide versus placebo were observed within the first week of 
dosing and were sustained over the 26-week Treatment Period.

Diarrhea was the most common TEAE reported during the trial. During the Treatment 
Period, 79 (19.7%) of 402 linaclotide patients reported at least 1 episode of diarrhea, 
compared to 10 (2.5%) of 403 placebo patients.
Approval Date: 05-Jun-2020 15:39:03 (GMT)


CONFIDENTIAL
Protocol LIN-MD-64, Amendment 1
Linaclotide
133
GRD-CLN-T-01-01 v2.0
Study Number
Study Design/Study Population
Major Conclusions
LIN-MD-01
Phase 3 multicenter, randomized, double-
blind, placebo-controlled, parallel-group, 
multiple-dose, 12-week trial comparing 2 
doses of linaclotide with placebo in adults 
with CIC

Linaclotide showed a statistically significant improvement compared with placebo for 
the primary efficacy parameter, 12-week CSBM overall responder, at both the 266-
and 133-μg/day doses (p = 0.0012 and p < 0.0001, respectively, statistically 
significant after controlling for multiplicity).

The odds of linaclotide patients being 12-week CSBM overall responders are 
approximately 3 to 4 times those of patients receiving placebo.

Linaclotide showed a statistically significant improvement compared with placebo for 
each of the secondary efficacy parameters at both the 266- and 133-μg/day doses (all 
p-values statistically significant after controlling for multiplicity).

For most parameters, improvements versus placebo were observed for both doses of 
linaclotide within the first week, often on the first day of dosing, and were sustained 
over the 12-week treatment period.

None of the patients tested had quantifiable serum levels of linaclotide or its primary 
metabolite (MM-419447), supporting previous clinical studies that demonstrated that 
linaclotide is minimally absorbed.

Diarrhea was the most frequently reported TEAE during the trial. In the treatment 
period, 72 (17.2%) of 418 linaclotide patients reported at least 1 episode of diarrhea 
compared with 6 (2.8%) of 215 placebo patients. Diarrhea incidence was not dose 
related; 42 (19.7%) and 30 (14.6%) patients in the 133- and 266-μg/day linaclotide 
groups, respectively, experienced TEAEs of diarrhea. 

There were no clinically meaningful differences between placebo and linaclotide 
groups in the mean or change from baseline QT interval (corrected by either Bazett’s 
or Fridericia’s formula). Overall the data indicated that linaclotide does not adversely 
affect the ECG of linaclotide-treated adult participants.
Approval Date: 05-Jun-2020 15:39:03 (GMT)


CONFIDENTIAL
Protocol LIN-MD-64, Amendment 1
Linaclotide
134
GRD-CLN-T-01-01 v2.0
Study Number
Study Design/Study Population
Major Conclusions
MCP-103-303
Phase 3, Randomized, Double-blind, 
Placebo-controlled, Parallel-group, Trial 
of Linaclotide Administered Orally for 12 
Weeks Followed by a 4-Week 
Randomized Withdrawal Period in 
adults with CIC

Linaclotide showed a statistically significant improvement from placebo for the 
primary efficacy parameter, 12-week CSBM Overall Responder, at both the 133 and 
266 µg doses. The odds of being a 12-week CSBM Overall Responder are 
approximately 7 times higher in patients on linaclotide than in patients on placebo.

Linaclotide showed a statistically significant improvement from placebo for each of 
the secondary efficacy parameters at both the 266 and 133 µg doses (all p-values 
statistically significant after controlling for multiplicity).

The results were robust and consistent across the primary and secondary efficacy 
parameters.

No patient had quantifiable plasma levels of linaclotide or its primary metabolite 
(MM-419447), supporting previous clinical studies that demonstrated that linaclotide 
is minimally absorbed.

Diarrhea was the most common TEAE reported during the study. In the Treatment 
Period, diarrhea was reported by 27 (12.4%) and 30 (13.8%) patients in the 133 and 
266 µg linaclotide groups, respectively, compared to 14 (6.7%) placebo patients.

No rebound of constipation symptoms was observed and there was no evidence of 
withdrawal symptoms in the RW Period.
LIN-MD-02
Multicenter, open-label study examining 
the long-term (78-week) safety of 
linaclotide in adult participants with 
CIC and IBS-C who completed 1 of the 
linaclotide Phase 2 or 3 studies or the 
Pretreatment Period of 1 of the Phase 3 
double-blind studies, but failed to meet 
specific inclusion or exclusion criteria to 
be randomized

As observed in previous studies with linaclotide, diarrhea was the most frequently
reported TEAE during the study, with 524 (33.7%) of 1554 patients reporting at least 
1 episode of diarrhea. Most of the TEAEs were reported as mild or moderate and 
unrelated to linaclotide.

The incidence of SAEs was low for both the CC Safety and IBS-C Safety Populations 
(with 5.9% and 5.5% of patients, respectively) reporting 1 or more SAEs over the 
duration of the 18 month study)
MCP-103-305
Multicenter, open-label, long-term safety 
study of oral linaclotide in adult 
participants with CIC and IBS-C who 
completed 1 of the linaclotide Phase 2 or 
3 studies or the Pretreatment Period of 1 
of the Phase 3 double-blind studies, but 
failed to meet specific inclusion or 
exclusion criteria to be randomized

As observed in previous studies with linaclotide, diarrhea was the most common 
TEAE.

Reduction in linaclotide dose from 290 µg to 145 µg seemed to enable patients to 
remain in the study when they might otherwise have withdrawn

The incidence of SAEs was low for both the CC Safety and IBS-C Safety Populations 
(with 6.8% and 5.0% of patients, respectively reporting one or more SAEs over the 
duration of the 18 month study). The nature of the SAEs did not raise any safety 
concerns regarding treatment with linaclotide.
Approval Date: 05-Jun-2020 15:39:03 (GMT)


CONFIDENTIAL
Protocol LIN-MD-64, Amendment 1
Linaclotide
135
GRD-CLN-T-01-01 v2.0
Study Number
Study Design/Study Population
Major Conclusions
LIN-MD-04
Randomized, double-blind, placebo 
controlled, parallel-group, study of 
linaclotide at doses of 145 µg/day and 
290 µg /day, administered orally for 12 
weeks to adult participants with CIC 
and prominent abdominal bloating at 
baseline (ie, bloating ≥ 5.0 on an 11-point 
numerical rating scale)

Patients treated with linaclotide 145 μg/day met the primary efficacy endpoint of 3 or 
more CSBMs per week and an increase of 1 or more CSBMs per week from baseline 
for at least 9 of 12 weeks compared with placebo-treated patients. 

The odds of being a 9/12-week CSBM 3 + 1 responder were approximately 2.2 times 
higher for patients treated with linaclotide 145-μg/day than for patients who were 
treated with placebo.

Patients with prominent abdominal bloating at baseline experienced improvement in 
their bloating symptoms within the first week of treatment with linaclotide 145- and 
290-μg/day relative to placebo treatment and the improvement was sustained for the 
duration of treatment.

Diarrhea was the most common TEAE reported among linaclotide-treated patients in 
this study; however, none of the observed TEAEs of diarrhea had serious sequelae.
MCP-103-309
Phase 3 randomized, double-blind, 
placebo-controlled, parallel-group study 
of linaclotide at doses of 72 µg/day and 
145 µg/day was administered orally for 
12 weeks in adults with CIC at baseline.

Overall, once-daily linaclotide 72 µg showed statistically significant improvement in 
CIC symptoms compared with placebo during the Treatment Period, with treatment 
effects that were similar to the linaclotide 145 µg dose.

Consistent with the established linaclotide AE profile, diarrhea was the most common
TEAE reported during the study and was experienced by 19.2% and 22.1% of patients 
in the linaclotide 72 µg and 145 µg groups, respectively, compared with 7.0% in the 
placebo group. Diarrhea was mostly mild to moderate in severity
Approval Date: 05-Jun-2020 15:39:03 (GMT)



SAP_001.pdf: 
CONFIDENTIAL
Linaclotide
Protocol LIN MD 64
1
LIN MD 64 Statistical Analysis Plan for IBS C Participants (Amendment #2)
20 February 2024
1
Title Page
LIN-MD-64
A Phase 3, Multicenter, Randomized, Double-blind, Parallel-group, Safety and Efficacy 
Study of Linaclotide in Pediatric Participants, Ages 6 to 17 Years, With Irritable Bowel 
Syndrome with Constipation (IBS-C) and of Linaclotide versus Placebo in Pediatric 
Participants with Functional Constipation (FC)
STATISTICAL ANALYSIS PLAN - Clinical Study Report
FOR IBS-C PARTICIPANTS
Final:
Amendment #1:
Amendment #2: 20 February 2024
Confidentiality Statement
This document is the property of Allergan, plc and may not
in full or part
be passed on, 
reproduced, published, distributed to any person, or submitted to any regulatory authority 
without the express written permission of Allergan, plc.
NCT04026113


CONFIDENTIAL  
 
Linaclotide 
Protocol LIN MD 64 
2 
LIN MD 64 Statistical Analysis Plan for IBS C Participants (Amendment #2) 
20 February 2024 
2 
Table of Contents 
1 
Title Page .............................................................................................................................1 
2 
Table of Contents .................................................................................................................2 
2.1 
List of Tables .............................................................................................................4 
2.2 
List of Figures............................................................................................................4 
3 
List of Abbreviations............................................................................................................5 
4 
Introduction .........................................................................................................................7 
5 
Objectives .......................................................................................................................... 12 
6 
Participant Populations ...................................................................................................... 13 
6.1 
Screened Population ................................................................................................ 13 
6.2 
Randomized Population ........................................................................................... 13 
6.3 
Modified Intent-to-Treat Population ......................................................................... 13 
6.4 
Safety Population ..................................................................................................... 13 
7 
Participant Disposition ....................................................................................................... 15 
8 
Demographics and Other Baseline Characteristics.............................................................. 16 
9 
Extent of Exposure and Study Intervention Compliance ..................................................... 18 
9.1 
Extent of Exposure .................................................................................................. 18 
9.2 
Measurement of Treatment Compliance ................................................................... 18 
9.3 
eDiary Compliance .................................................................................................. 18 
10 Efficacy Analyses .............................................................................................................. 20 
10.1 Primary Efficacy Endpoint ....................................................................................... 20 
10.1.1 Main Analysis Approach ............................................................................... 21 
10.1.2 Supplemental Analysis .................................................................................. 23 
10.1.3 Estimand Framework .................................................................................... 25 
10.2 Secondary Efficacy Endpoints ................................................................................. 26 
10.2.1 Main Analysis Approach ............................................................................... 27 
10.2.2 Supplemental Analysis .................................................................................. 28 
10.3 Other Efficacy Endpoints ......................................................................................... 29 
10.4 Subgroup Analysis for Efficacy endpoints ................................................................ 32 
11 Safety Analyses.................................................................................................................. 33 
 
 
 


CONFIDENTIAL  
 
Linaclotide 
Protocol LIN MD 64 
3 
LIN MD 64 Statistical Analysis Plan for IBS C Participants (Amendment #2) 
20 February 2024 
11.1 Adverse Events ........................................................................................................ 33 
11.2 Clinical Laboratory Parameters ................................................................................ 34 
11.3 Vital Signs ............................................................................................................... 37 
11.4 Electrocardiogram.................................................................................................... 39 
11.5 Other Safety Parameters........................................................................................... 40 
11.5.1 Potential Hy’s Law ........................................................................................ 40 
12 Health Outcomes Analyses ................................................................................................. 41 
13 Interim Analysis ................................................................................................................. 42 
14 Determination of Sample Size ............................................................................................ 43 
15 Statistical Software ............................................................................................................ 45 
16 Data Handling Conventions ............................................................................................... 46 
16.1 Visit Time Windows for Safety Analyses ................................................................. 46 
16.2 Visit Time Windows for Efficacy Analyses .............................................................. 46 
16.3 Derived Variables..................................................................................................... 48 
16.3.1 Missing or Incomplete Morning/Evening eDiary Assessments ....................... 48 
16.3.2 Incomplete Morning/Evening eDiary Assessments ........................................ 49 
16.3.3 Incomplete Clinic Diary on Randomization Visit (If Present) ........................ 49 
16.3.4 Stool Frequency ............................................................................................ 49 
16.3.5 Abdominal Pain ............................................................................................. 52 
16.3.6 Stool Consistency .......................................................................................... 53 
16.3.7 Straining ....................................................................................................... 54 
16.3.8 Abdominal Bloating ...................................................................................... 54 
16.3.9 Rome III Criteria ........................................................................................... 56 
16.3.10 Participant-completed Global Items ............................................................. 56 
16.3.11 Observer-completed Global Items................................................................ 58 
16.4 Repeated or Unscheduled Assessments of Safety Parameters ................................... 59 
16.5 Missing Date of the Last Dose of Study Intervention ............................................... 59 
16.6 Missing Severity Assessment for Adverse Events ..................................................... 59 
16.7 Missing Causal Relationship to Study Drug for Adverse Events ............................... 59 
16.8 Missing Date Information for Adverse Events .......................................................... 59 
16.9 Missing Date Information for Prior or Concomitant Medications ............................. 61 
16.9.1 Incomplete Start Date .................................................................................... 61 
16.9.2 Incomplete Stop Date .................................................................................... 62 
 
 
 


CONFIDENTIAL  
 
Linaclotide 
Protocol LIN MD 64 
4 
LIN MD 64 Statistical Analysis Plan for IBS C Participants (Amendment #2) 
20 February 2024 
16.10 Character Values of Clinical Laboratory Parameters ................................................. 62 
17 Changes To Analyses Specified In Protocol ........................................................................ 64 
18 References ......................................................................................................................... 65 
19 Appendix 1: Simulation Codes for Bayesian Power Estimates By Sample Size and Effective 
Sample Size ....................................................................................................................... 66 
 
2.1 
List of Tables 
Table 4-1. 
Schedule of Evaluations: Study LIN-MD-64 (IBS-C Participants) ..................9 
Table 11-1. 
Criteria for Potentially Clinically Significant Laboratory Results.................. 36 
Table 11-2. 
Criteria for Potentially Clinically Significant Vital Signs .............................. 38 
Table 11-3. 
Criteria for Potentially Clinically Significant Electrocardiograms ................. 39 
Table 14-1. 
Bayesian Power Estimates by Sample Size and ESS (vs. the Responder Rate 
of the Adult Placebo Response, 0.16*).......................................................... 44 
Table 14-2. 
Bayesian Power Estimates by Sample Size and ESS (vs. the Upper Limit of 
the 95% CI (2-sided) of the Adult Placebo Response, 0.18*) ........................ 44 
Table 16-1. 
Visit Time Windows ..................................................................................... 46 
Table 16-2. 
Analysis Time Windows for Efficacy Analysis - Daily Questions ................. 47 
Table 16-3. 
Analysis Time Windows for Efficacy Analysis - Weekly Questions .............. 48 
Table 16-4. 
Examples of Coding Special Character Values for Clinical Laboratory 
Parameters.................................................................................................... 63 
 
2.2 
List of Figures 
Figure 4-1. 
LIN-MD-64 Study Schema.............................................................................8 
 
 
 
 


CONFIDENTIAL  
 
Linaclotide 
Protocol LIN MD 64 
5 
LIN MD 64 Statistical Analysis Plan for IBS C Participants (Amendment #2) 
20 February 2024 
3 
List of Abbreviations 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase  
AST 
aspartate aminotransferase 
BM 
bowel movement  
BP 
blood pressure  
CI 
confidence interval  
CSBM 
complete spontaneous bowel movement 
eCRF 
electronic case report form  
eDiary 
electronic diary 
ECG 
electrocardiogram, electrocardiographic  
EOS 
End- of- Study  
EOT 
End- of- Treatment  
ESS 
effective sample size 
FC 
functional constipation  
IBS 
irritable bowel syndrome 
IBS-C 
irritable bowel syndrome with constipation 
IWRS 
interactive web response system 
LLN 
lower limit of normal 
mITT 
modified intent-to-treat  
OC 
observed cases 
p-BSFS  
pediatric Bristol Stool Form Scale  
PCS 
potentially clinically significant 
PID 
participant identification 
QTc 
QT interval corrected for heart rate 
QTcB 
QT interval corrected for heart rate using the Bazett formula (QTcB = QT/(RR)½) 
QTcF 
QT interval corrected for heart rate using the Fridericia formula (QTcF = QT/(RR)⅓) 
RM 
rescue medication 
 
 
 


CONFIDENTIAL  
 
Linaclotide 
Protocol LIN MD 64 
6 
LIN MD 64 Statistical Analysis Plan for IBS C Participants (Amendment #2) 
20 February 2024 
SAE 
serious adverse event  
SAP 
statistical analysis plan 
SBM 
spontaneous bowel movement  
SD 
standard deviation 
SI 
Le Système International d’Unités (International System of Units)  
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
ULN 
upper limit of normal 
 
 
 
 


CONFIDENTIAL  
 
Linaclotide 
Protocol LIN MD 64 
7 
LIN MD 64 Statistical Analysis Plan for IBS C Participants (Amendment #2) 
20 February 2024 
4 
Introduction 
This statistical analysis plan (SAP) provides a more technical and detailed elaboration of the 
statistical analyses of the efficacy and safety data as outlined and/or specified in the amended 
protocol of Study LIN-MD-64 (version dated Jun-2020) for irritable bowel syndrome with 
constipation (IBS-C) participants only. Specifications of tables, figures, and data listings for 
IBS-C participants are contained in a separate document.  
The statistical analyses of the efficacy and safety for functional constipation (FC) participants as 
specified in amended protocol of LIN-MD-64 (version dated Jun-2020) are documented in a 
separate statistical analysis plan.  
The design elements that are only for IBS-C participants in study LIN-MD-64 are discussed in 
this SAP. The IBS-C portion of Study LIN-MD-64 is a Phase 3 multicenter, randomized, double-
blind, parallel-group, confirmatory safety and efficacy study of linaclotide therapy (145 µg or 
290 µg daily) in pediatric participants, 7 to 17 years of age, with a diagnosis of irritable bowel 
syndrome with constipation (IBS-C) [ie, who fulfill the Rome III criteria for child/adolescent 
IBS and modified Rome III criteria for child/adolescent functional constipation (FC)]. A total of 
at least 100 IBS-C participants are planned to be randomized in a 1:1 ratio to receive either 
145 µg or 290 µg linaclotide. Randomization of IBS-C participants will be stratified by age 
group only (7 to 11 years of age versus 12 to 17 years of age) with a minimum of 40% of 
participants within each age group. 
The study will include a total of 8 visits and will be up to 20 weeks in duration: a 2-to 4-week 
Screening Period, a 2- to 3-week Preintervention Period, followed by a 12-week double-blind 
Study Intervention Period and 1-week Postintervention Period. The raw datasets of study 
LIN-MD-64 capture Preintervention Period as Pretreatment Period, Study Intervention Period as 
Treatment Period, and Postintervention Period as Posttreatment Period. Participants will not 
receive study intervention (i.e. study treatment) during the Screening/Preintervention Period and 
the Postintervention Period. 
Participants who enter into the long-term safety study, LIN-MD-66, before the End-of-Study 
(EOS) Visit are not required to have the EOS visit in LIN-MD-64.  
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, with the exception of the first dose at 
Day 1 (Randomization Visit) when participants will receive linaclotide in the clinic. 
 
 
 


CONFIDENTIAL  
 
Linaclotide 
Protocol LIN MD 64 
8 
LIN MD 64 Statistical Analysis Plan for IBS C Participants (Amendment #2) 
20 February 2024 
Approximately 140 sites from the United States of America, Canada, and the Europe and Middle 
East are expected to participate in the study to enroll FC participants. Only study sites in North 
America will randomize IBS-C participants. 
Figure 4-1 is the schematic of the study design. 
Figure 4-1. 
LIN-MD-64 Study Schema 
 
* 
Participants who rollover to the long term safety study, LIN MD 66, before the EOS Visit are not required to have this visit. 
 
The schedule of evaluations for Study LIN-MD-64 IBS-C participants is presented in Table 4-1. 
Screening 
Visit
(Day -49 to Day -21)
14 to 28 days
14 to 21 days
12 weeks
Screening Period
Preintervention
Period
Double-blind Study 
Intervention Period
Preintervention 
Visit
(Day -21 to Day -14)
Randomization Visit
(Day 1)
End of 
Treatment
Period; Week 
12 Visit
(Day 85+3)
Week 2 Visit
(Day 15±2)
Week 4 Visit
(Day 29±2)
Week 8 Visit
(Day 57±2)
Post-
intervention 
Period
1 week
End of Study 
(EOS)*   
EOT+7(+7) 
-
  
 
 


C O N FI D E N TI A L   
 
Li nacl oti de  
Pr ot oc ol LI N M D
6 4  
9  
LI N M D
6 4 St atisti cal A nal ysis Pla n f or I B S C Parti ci pa nts ( A me n d me nt # 2 ) 
2 0 Fe br uar y 2 0 2 4  
T a ble  4 -1 . 
Sc he d ule of E v al u ati o ns: St u d y LI N -M D -6 4 (I B S -C P artici p a nts)  
St u d y P eri o ds 
( D ur ati o n) 
Scree ni n g 
( 1 4-2 8 
D a ys)  
P rei nt er ve nti o n 
( 1 4-2 1 D a ys)  
St u d y I nt er ve nti o n P eri o d  
( 1 2 wee ks) 
P osti nt er ve nti o n 
( 1 wee k)  
St u d y Visit  
Scree ni n g  P rei nt er ve nti o n  R a n d o mi z ati o n  Wee k 2  Wee k 4  Wee k 8  
Wee k 1 2 
Visit/  
E n d of 
Tre at me nt 
( E O T)a 
E n d of St u d y 
( E O S) Visit b  
Visit N u m ber  
1  
2  
3  
4  
5  
6  
7  
8  
St u d y D a y  
-4 9 t o -2 2  
-2 1 t o -1 4  
1  
1 5 ( ± 2)  2 9 ( ± 2)  5 7 ( ± 2)  
8 5 ( + 3) c 
E O T + 7 ( + 7)  
Par e nt/ Car e gi ver 
C o nse nt/ Asse nt d  
X  
 
 
 
 
 
 
 
I n cl usi o n a n d 
E xcl usi o n Criteri a  
X  
X  
X  
 
 
 
 
 
R o me III Assess me nt  
X  
 
 
 
 
 
X  
 
Assess R o me I V 
st at use 
 
 
X  
 
 
 
 
 
I W R S  
X  
X  
X f 
 
X  
X  
X  
 
Me di cal Hist or y  
X  
 
 
 
 
 
 
 
Lifest yl e M o difi cati o n 
I nf or mati o n Gi ve n t o 
Parti ci pa nt/ Car e gi ver g 
X  
 
 
 
 
 
 
 
P h ysi cal E xa mi nati o n h  
X  
 
 
 
 
 
X  
 
Fecal I m pacti o n 
Assess me nt i 
X  
X j 
X k 
 
 
 
 
 
Hei g ht  
X  
 
 
 
 
 
X  
 
Vit al Si g ns a n d 
P ost ural Vit al Si g ns l 
X  
X  
X  
X  
X  
X  
X  
X  
E C G  
X  
 
 
 
 
 
X  
 
Cli ni cal La b or at or y 
Tests m  
X  
 
X  
 
 
 
X  
 
Ser u m Pre g na nc y 
Testi n g n  
X  
 
 
 
 
 
 
 
Uri ne Pr e g na nc y 
Testi n g o  
 
 
X  
 
X  
X  
X  
 
Uri ne Dr u g Scr ee n p  
X  
 
 
 
 
 
 
 
A E E val uati o n  
X  
X  
X  
X  
X  
X  
X  
X  
Pri or a n d C o nc o mit a nt 
Me di cati o ns  
X  
X  
X  
X  
X  
X  
X  
X  
Resc ue Me di cati o n 
Dis pe nse d q  
 
X  
X  
X  
X  
X  
X  
 
e Di ar y a n d I nstr ucti o ns 
Gi ve n t o 
Parti ci pa nt/ Car e gi ver r 
 
X  
 
 
 
 
 
 


C O N FI D E N TI A L   
 
Li nacl oti de  
Pr ot oc ol LI N M D
6 4  
1 0  
LI N M D
6 4 St atisti cal A nal ysis Pla n f or I B S C Parti ci pa nts ( A me n d me nt # 2 ) 
2 0 Fe br uar y 2 0 2 4  
St u d y P eri o ds 
( D ur ati o n) 
Scree ni n g 
( 1 4-2 8 
D a ys)  
P rei nt er ve nti o n 
( 1 4-2 1 D a ys)  
St u d y I nt er ve nti o n P eri o d  
( 1 2 wee ks) 
P osti nt er ve nti o n 
( 1 wee k)  
St u d y Visit  
Scree ni n g  P rei nt er ve nti o n  R a n d o mi z ati o n  Wee k 2  Wee k 4  Wee k 8  
Wee k 1 2 
Visit/  
E n d of 
Tre at me nt 
( E O T)a 
E n d of St u d y 
( E O S) Visit b  
Visit N u m ber  
1  
2  
3  
4  
5  
6  
7  
8  
St u d y D a y  
-4 9 t o -2 2  
-2 1 t o -1 4  
1  
1 5 ( ± 2)  2 9 ( ± 2)  5 7 ( ± 2)  
8 5 ( + 3) c 
E O T + 7 ( + 7)  
e Di ar y C o m pli a nce r 
 
 
X  
X  
X  
X  
X  
X  
e Di ar y Eli gi bilit y 
Re p ort f 
 
 
X  
 
 
 
 
 
St u d y I nt er ve nti o n 
A d mi nistere d o n Sit e s 
 
 
X  
 
 
 
 
 
St u d y I nt er ve nti o n 
Dis pe nse d  
 
 
X  
 
X  
X  
 
 
St u d y I nt er ve nti o n a n d 
Resc ue Me di cati o n 
C o m pli a nce a n d 
Acc o u nt a bilit y  
 
 
X s 
X  
X  
X  
X  
X t 
A E  a d verse e ve nt; E C G  electr ocar di o gr a m; e Di ar y  el ectr o ni c di ar y:  r efers t o t he parti ci pa nt  or i nter vi e wer a d mi nist ere d 
versi o n of t he patie nt re p orte d o ut c o me (P R O ) di ar y o n a ha n d hel d el ectr o ni c de vi ce; I W R S  i nt er acti ve We b res p o nse s yst e m.  
a. 
St u d y pr oce d ur es f or scr ee ni n g i n LI N M D
6 6 ca n be c o m bi ne d wit h E n d of T r eat me nt ( E O T)/ Wee k 1 2 Visit ( Visit 7) f or 
St u d y LI N M D
6 4.  
b . 
Parti ci pa nts w h o r oll o ver t o t he l o n g t er m safet y st u d y, LI N M D
6 6, bef or e t he E O S Visit ( Visit 8) are n ot re q uire d t o ha ve 
t his visit. 
c. 
T he parti ci pa nt m ust c o m pl et e at l east 1 2 wee ks ( 8 4 da ys) of st u d y i nt er ve nti o n bef or e arri vi n g at t he st u d y sit e f or t he 
E O T/ Wee k 1 2 Visit ( Visit 7). All ra n d o mi ze d parti ci pa nts w h o pr e mat ur el y disc o nti n ue fr o m t he st u d y i nter ve nti o n, 
r e gar dl ess of ca use, s h o ul d c o m pl et e assess me nts at t his E O T/ Wee k 1 2 Visit ( Visit 7).  
d.  
T he pare nt/ g uar dia n/le gall y a ut h ori ze d re prese ntati ve m ust pr o vi de writte n i nf or me d c o nse nt a n d t he parti ci pa nt m ust 
pr o vi de asse nt bef or e t he parti ci pa nt’s e nr oll me nt i n t he st u d y. If a  par e nt or l e gal g uar dia n is als o t he parti ci pa nt’s 
car e gi ver, he or s he will be as ke d t o si g n  a c o m bi ne d pare nt a n d care gi ver writt e n i nf or me d c o nse nt . Care gi vers ot her t ha n 
par e nt or l e gal g uar dia n m ust pr o vi de writt e n i nf or me d c o nse nt.  
e. 
Pri or t o d osi n g, t he i n vesti gat or or a p pr o priat e sit e st aff me m ber will assess if R o me I V crit eri a f or C hil d/ A d ol esce nt F C  or 
R o me I V criteri a f or C hil d/ A d ol esce nt I B S (I B S C parti ci pa nts) was met a n d rec or d t he o ut c o me i n t he e C R F. Eli gi bilit y f or 
t he st u d y is n ot based o n t his assess me nt.  
f. 
Eli gi bilit y r e p ort m ust be r u n pri or t o r a n d o mi zati o n.  
g.  
D uri n g t he Scree ni n g Peri o d, parti ci pa nts a n d t heir car e gi vers will recei ve i nf or mati o n r e gar di n g lifest yl e m o difi cati o ns. 
T here s h o ul d be at least a 2 wee k i nter val bet wee n  disc ussi n g t he lifest yl e m o difi cati o ns d uri n g t he Scree ni n g Peri o d a n d t he 
parti ci pa nt’s e ntr y i nt o t he Pr ei nter ve nti o n Peri o d.  
h.  
P h ysi cal e xa mi nati o ns will be perf or me d b y me di call y q ualifie d site pers o n nel a n d ma y be r e peat e d at t he i n vesti gat or’s 
disc r eti o n. If fecal i m pacti o n ( as defi ne d i n f o ot n ot e i) is d oc u me nte d d uri n g a n o pti o nal r e peat p h ysi cal e xa mi nati o n, t he 
St u d y P h ysi ci a n m ust be n otifi e d.  
i. 
Fecal i m pacti o n is defi ne d as a har d mass i n t he l o wer a b d o me n i de ntifi e d o n p h ysi cal e xa mi nati o n o r a dil at e d rect u m fill e d 
wit h a l ar ge a m o u nt of st o ol o n r ect al e xa mi nati o n. If a r ect al e xa mi nati o n is perf or me d, t he me di call y q ualifie d site 
pers o n nel s h o ul d assess f or a n d d oc u me nt t he prese nce of a nal wi n k a n d n or mal a nal t o ne.  


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j. 
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) (as defined in footnote i above), 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.  
k. 
A fecal impaction assessment is performed at the Randomization Visit (Visit 3) after eDiary eligibility is confirmed and 
prior to randomization. If there is no fecal impaction at the Randomization Visit (Visit 3) (as defined in footnote i above), 
the participant is eligible for randomization. If fecal impaction is present upon examination, the participant will not be 
eligible for the study. 
l. 
Vital signs include temperature, respiratory rate, and weight. Postural vital signs (supine and standing) include pulse rate and 
systolic and diastolic blood pressure. At all visits, postural vital signs must be obtained after participants have been in a 
supine position for at least 2 to 3 minutes, followed by a standing position for at least 1 minute. Temperature may be 
recorded as oral, rectal or tympanic (ear). If possible, temperature should be obtained using the same method at each visit. 
m. Clinical laboratory tests consist of clinical chemistry, hematology, and urinalysis. All laboratory tests requiring blood draws 
should be collected at the same time. 
n. 
Serum pregnancy test will be obtained for female participants of childbearing potential.  
o. 
Urine pregnancy test will be obtained for female participants of childbearing potential. A negative urine pregnancy test is 
required prior to dosing at the Randomization Visit (Visit 3) and prior to study intervention dispensing at Week 4 (Visit 5) 
and Week 8 (Visit 6).  
p. 
A urine drug screen will be obtained at Screening (Visit 1) for all participants 12 to 17 years of age and only if deemed 
necessary by the investigator for participants 6 to 11 years of age. Urine drug screens may be repeated at the investigator’s 
discretion at any time during the study. 
q. 
Protocol permitted rescue medication will be dispensed in IWRS where applicable. Participants 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 visit, where available. 
r. 
At the Preintervention Visit (Visit 2), participants and parents/caregivers will be trained on the use of the eDiary device and 
instructed to complete both morning and evening assessments daily. At subsequent visits, study site staff will verify 
participant compliance with the eDiary device and remind participants to complete their morning and evening 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 beginning at Randomization through End of Study. 
s. 
Study intervention will be administered at the study site during the Randomization Visit (Visit 3) after running the 
Eligibility report and confirming the participant has fasted for at least 2 hours. 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).  
t. 
Protocol permitted rescue medications only.  
u. 
Additional unscheduled visits may be allowed at the discretion of the investigator with approval from the sponsor.  
 
 
 
 


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5 
Objectives 
For IBS-C participants, the objective of LIN-MD-64 is to evaluate the safety and efficacy of 
12 weeks of linaclotide therapy (145 µg or 290 µg daily) 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. 
 
 
 


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6 
Participant Populations 
6.1 
Screened Population 
Screened Population will consist of all participants with IBS-C who undergo the Screening Visit 
(Visit 1) and receive a participant identification (PID) number. 
6.2 
Randomized Population 
Randomized Population will consist of all participants in the Screened Population who are 
randomized to a study intervention group. 
6.3 
Modified Intent-to-Treat Population 
The Modified Intent-to-Treat (mITT) Population will consist of all participants in the 
Randomized Population who receive at least 1 dose of double-blind study intervention. 
Participants will be summarized according to the randomized study intervention for all efficacy 
analysis variables/endpoints. 
Significant non-compliance was identified at an investigational site (Site ID 10049). As a result 
of this finding, efficacy data for the participants randomized at this investigational site will be 
excluded from the statistical analyses. Safety data for these participants will be included in the 
statistical analyses. There were 3 participants that were randomized at this site, who will be 
excluded from mITT population. 
An issue was discovered in July 2021 during the implementation of adding IBS-C participants in 
this study by the eDiary vendor, where the inclusion criterion (#2.012) related to abdominal pain 
was not displayed in the eligibility report. Because of this, 8 IBS-C participants (including the 3 
participants at the above site 10049) were incorrectly randomized without meeting the abdominal 
pain criterion. As a result of this finding, these participants will be excluded from mITT 
population and efficacy data for these participants will be excluded from the statistical analyses. 
Safety data for these participants will be included in the statistical analyses. 
6.4 
Safety Population 
The Safety Population will consist of 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 received for all 
safety analysis variables/endpoints. If a participant received study intervention other than 
 
 
 


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randomized study intervention, actual study intervention received will be determined based on 
the study intervention received for the majority of the double-blind Study Intervention Period. If 
there is a tie, the higher dose will be considered the actual study intervention for that participant. 
This is also relevant for subjects who require dose de-escalation, which is allowed once per 
participant to ensure safety and tolerability for study subjects.  The actual study intervention will 
be listed for the participants in the listing related to study intervention dosing information. 
 
 
 


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7 
Participant Disposition 
The number and percentage of participants in 3 study populations (Randomized, mITT, and 
Safety) will be summarized overall, by study intervention group, country, and study center; the 
number of participants screened will be summarized overall, only by country, and study center. 
Screen-failure participants (ie, participants who are screened but do not enter into the 
Preintervention Period), participants ineligible for randomization (ie, participants who enter into 
the Preintervention Period but are not randomized at Visit 3, also labeled as preintervention 
failures), and the associated reasons for failure as recorded in the electronic case report forms 
(eCRF) will be tabulated overall for all screened participants. 
The number and percentage of participants who complete the study, complete the double-blind 
Study Intervention Period, complete the Postintervention Period, prematurely discontinue the 
study, prematurely discontinue the double-blind Study Intervention Period, and prematurely 
discontinue the Postintervention Period will be presented for each study intervention group and 
pooled across study intervention groups for the Randomized Population. The reasons for 
premature discontinuation from the double-blind Study Intervention Period and the 
Postintervention Period as recorded in the eCRF will be summarized (number and percentage) by 
study intervention group for the Randomized Population. All participants who prematurely 
discontinue during the Study Intervention Period or Postintervention period will be listed by 
discontinuation reason for the Randomized Population. 
Please note that a participant is considered to have completed the study if he/she has completed 
12 weeks of double-blind study intervention, End-of-Treatment visit, and the EOS visit. 
Participants who rollover to the long-term safety study, LIN-MD-66, before the EOS Visit will 
be considered to have completed the study if he/she has completed 12 weeks of study 
intervention and the End-of-Treatment Visit. 
 
 
 


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8 
Demographics and Other Baseline Characteristics 
Demographic parameters (age; age group [7-11 and 12-17 years (inclusive)]; race; ethnicity; sex) 
and baseline characteristics (weight; height; and body mass index, calculated as weight 
[kg]/(height [m])2) will be summarized descriptively by study intervention group for the mITT, 
and Safety Populations. The above demographics parameters will also be summarized by age 
group (7-11 and 12-17 years (inclusive)) within the Safety Population. 
Other baseline characteristics (including efficacy parameters related to the bowel habits and 
symptoms as discussed in Section 10) will be summarized descriptively by study intervention 
group for the mITT Population. 
Continuous variables will be summarized by number of participants, mean, standard deviation 
(SD), median, minimum, and maximum values. Categorical variables will be summarized by 
number and percentage of participants. 
Abnormalities in participants’ medical and surgical histories will be coded using the Medical 
Dictionary for Regulatory Activities, version 23.0 or newer. The number and percentage of 
participants with abnormalities in medical and surgical histories in each system organ class and 
preferred term will be summarized by study intervention group for the Safety Population. 
Prior medication is defined as any medication 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 prior medications stopped more than 30 days before the 
date of the first dose of study intervention and any concomitant medications started after the date 
of the last dose of study intervention will not be presented in the summary tables but will be 
included in the participant data listings. 
Both prior and concomitant medications will be coded by drug name and therapeutic class. The 
use of prior and concomitant medications will be summarized by the number and percentage of 
participants in each study intervention group for the Safety Population. If a participant took a 
specific medication multiple times or took multiple medications within a specific therapeutic 
class, that participant would be counted only once for the coded drug name or therapeutic class. 
The World Health Organization (WHO) Drug Dictionary, version Global B3 March 2020 or 
newer, will be used to classify prior and concomitant medications by therapeutic class and drug 
name. 
 
 
 


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Unique participants reporting significant protocol deviations will be summarized in total and by 
study intervention group for the Randomized Population. 
 
 
 


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9 
Extent of Exposure and Study Intervention Compliance 
9.1 
Extent of Exposure 
Exposure to the study intervention for the Safety Population during the double-blind Study 
Intervention Period will be summarized for study intervention duration, calculated as the number 
of days from the date of the first dose of study intervention to the date of the last dose of study 
intervention, inclusive. Descriptive statistics (number of participants, mean, SD, median, 
minimum, and maximum) will be presented by study intervention group. 
Patient-years, defined as exposure to the study intervention in years, will be summarized by 
study intervention for the Safety Population. 
9.2 
Measurement of Treatment Compliance 
Dosing compliance for the double-blind Intervention Period is defined as number of capsules 
actually taken by a participant during that period divided by the number of capsules prescribed 
for that period multiplied by 100. This information will be obtained from the study intervention 
record of the participant’s eCRF. 
The number of capsules expected to be taken for the double-blind Intervention Period will be 
calculated by multiplying the number of days in that period by the number of capsules to be 
taken per day. Descriptive statistics for treatment compliance will be presented by study 
intervention group between 2 consecutive visits, as well as for the whole double-blind 
Intervention Period for the Safety Population. 
9.3 
eDiary Compliance 
Participants will complete the electronic diary (eDiary) twice daily, once in the morning and 
once in the evening. Participant’s eDiary compliance will be assessed based on the number of 
days with fully completed morning and evening assessments in a specific period. Morning or 
evening assessments will be considered fully completed if the participant responded to each 
question in the corresponding eDiary. eDiary compliance will be summarized for the 
Preintervention Period, double-blind Intervention Period, Postintervention Period, and for each 
week within each period based on the mITT Population. 
 
 
 


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Compliance for each participant/interval will be calculated using the following formula: 
%Compliance = 100 * # of days with completed morning and evening assessments within the interval 
# of expected days within the interval 
On randomization day, the morning diary and/or clinic diary will be included in Preintervention 
Period and the evening diary will be included in the double-blind Intervention Period. On the day 
after last dose date, the morning diary will be included in the double-blind Intervention Period 
and the evening diary will be included in the Postintervention Period. 


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10 
Efficacy Analyses 
The efficacy analyses will be based on the mITT Population. All efficacy assessments will be 
determined by responses entered in the eDiary (morning eDiary, evening eDiary, or weekly 
eDiary) and eCRF (as appropriate). 
Baseline values for efficacy endpoints related to daily eDiary responses will be derived from the 
eDiary in the Preintervention Period, specifically the time period from 14 days before 
randomization up to the time of randomization. 
An SBM is a BM that occurs in the absence of laxative, suppository, or enema use on the 
calendar day of the BM or the calendar day before the BM. A complete spontaneous bowel 
movement (CSBM) is an SBM that is associated with a sense of complete evacuation. 
The baseline SBM and CSBM weekly rates, stool consistency, straining, and abdominal 
symptoms (abdominal pain and bloating) will be derived as discussed in Section 16.3.5 from 
14 days prior to randomization and up to randomization (as appropriate). A participant’s baseline 
stool consistency and straining cannot be assessed if the participant does not have at least 1 SBM 
during the Preintervention Period. For participants who report no SBMs during a study period, 
the stool consistency and straining assessments will be considered missing for that study period 
in the analyses. Participants with missing baseline stool consistency and straining will be 
excluded from the respective stool consistency and straining analyses that involve change from 
baseline. 
Baseline values for the participant-completed global change and severity items, and observer 
completed global change and severity items, will be based on the last non-missing assessment on 
or before the date of first dose of study intervention. 
An observed cases (OC) approach to missing postbaseline data will be applied. Efficacy 
responses following onset of dose de-escalation will not be included for primary analyses. 
Supplemental summaries will be provided for primary and secondary endpoints by study 
intervention dose sequence incorporating the responses following the onset of dose de-escalation. 
No statistical testing will be performed to compare linaclotide doses. No multiplicity adjustment 
will be applied in this study for IBS-C participants. 
10.1 Primary Efficacy Endpoint 
The primary efficacy endpoint for IBS-C pediatric participants is 6/12 weeks APS (abdominal 
pain and SBM) + 2 responder. A 6/12 weeks APS + 2 responder is a participant that meets the 
 
 
 


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weekly APS + 2 responder criteria for at least 6 out of the 12 weeks of the intervention period. A 
weekly APS +2 responder is a participant who has an increase of at least 2 in the SBM weekly 
rate from baseline, AND a decrease of at least 30% in the mean abdominal pain score 
(combination daytime and nighttime) from baseline, during that study intervention week. Details 
on the derivations of SBM rate and abdominal pain score are provided in Section 16.3.4 and 
Section 16.3.5, respectively. 
10.1.1 Main Analysis Approach 
The primary efficacy endpoint will be summarized by counts and percentages by study 
intervention group for the mITT population. 
Based on the review that the IBS-C disorder and the patient response to linaclotide treatment 
being similar between the adult and pediatric subjects, the primary statistical analysis is 
comprised of a partial extrapolation approach utilizing a Bayesian method. Following this 
approach, information is borrowed from the adult IBS-C population in Phase 2b study 
MCP-103-202 and Phase 3 registration studies LIN-MD-31 and MCP-103-302 
(Carlin and Louis 2009). To enable this approach, the proposed IBS-C pediatric portion of study 
LIN-MD-64 will utilize the primary efficacy endpoint, 6/12 weeks APS + 2 responder to align 
with the adult registration studies where APC (abdominal pain and complete SBM) +1 responder 
is one of the primary efficacy endpoints. 
The assumptions and details of the proposed Bayesian analysis are discussed below. 
1. META-ANALYSIS of PLACEBO EFFECT in ADULTS: Utilizing the three adult studies, 
MCP-103-202, MCP-103-302, and LIN-MD-31, a meta-analysis was conducted to obtain an 
estimate for adult placebo effect related to 6/12 weeks APS + 2 responder rate The estimated 
6/12 Weeks APS + 2 responder rate for placebo was 0.16 and upper bound of 95% 
confidence interval (CI) of the placebo responder rate was 0.18. 
2. PRIOR for LINACLOTIDE TREATMENT: Utilizing the three adult studies, MCP-103-202, 
MCP-103-302, and LIN-MD-31, a meta-analysis of the adult studies was conducted to obtain 
an adult prior distribution for linaclotide 290 ug responder rate. All subjects administered 
266 ug to 300 ug in these contributing studies were included and considered for linaclotide 
290 ug. Since this responder rate is bounded between [0,1], the prior distribution of 
linaclotide responder rate (θ) can be approximated by the Beta distribution. In this case, 
α  (aggregate number of adult responders) and β  (aggregate number of adult non-
responders 
 
θ ~ Beta(α, β),  
 
 
 
 


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where α  340 and β  550 based on meta-analysis of 3 adult contributing studies  
(MCP-103-202, LIN-MD-31 and MCP-103-302).  
 
In this Bayesian analysis, this distribution forms the prior for the pediatric responder rate in 
linaclotide treated subjects for each linaclotide arm (145 ug and 290 ug). 
 
3. LIKELIHOOD FUNCTION: Let N be the sample size of IBS-C participants in LIN-MD-64 
and for each θ  Pr(Pediatric subject is a responder), let X be the observed number of 
pediatric patients who are responders in LIN-MD-64.   Then, given θ, X will have a 
binomial likelihood function, which can also be simply expressed as follows: 
 
X θ ~ Binomial(N, θ) 
 
4. DOWNWEIGHT PRIOR:  Due to the large number of adult subjects, a down weighting 
factor, w, bounded (0,1), is prespecified, such that the prior in step 2 becomes   
θ ~ Beta(w*α, w*β) 
Down-weighting in this manner will allow each adult patient to be ’worth’ the fraction w of a 
new pediatric patient. An alternative way of expressing this ’worth’ and describing the impact 
of the weights would be to describe an effective sample size (ESS). ESS is calculated as 
(α + β)*w and is interpreted as the amount of new samples that the adult data will be 
equivalent to in an analysis. 
5. POSTERIOR for TREATMENT EFFECT: The posterior distribution for linaclotide 
responder rate utilizing IBS-C pediatrics data in Step 3 is also a Beta distribution with down-
weighted prior in Step 4: 
 
Θ|X ~ Beta(X + w*α, N - X + w*β) 
6. For each linaclotide dose arm, calculate the Bayesian probabilities (Bayesian powers) of the 
pediatric posterior (i.e., pediatric responder rate based on pediatric posterior distribution in 
Step 5) in two ways as below:  
(a) demonstrating superiority to the adult placebo effect, based on the 2.5 percentile of the 
posterior distribution exceeding the upper bound 0.18 of 95% CI of the adult placebo 
effect calculated in Step 1 
(b) demonstrating superiority to the adult placebo effect, based on the 2.5 percentile of the 
posterior distribution exceeding the adult pooled placebo estimate of 0.16 as calculated in 
Step 1. 
 
 
 


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7. Repeat Steps 4 to 6 for a range of values of “w”; plot Bayesian probability as function of 
“w” as specified in Step 6. Range of w is prespecified as (0.0067, 0.0200), corresponding 
to an ESS for adult data providing the informational equivalent of approximately 6 to 20 
pediatric subjects. 
 
10.1.2 Supplemental Analysis 
The following supplemental and sensitivity analyses on the primary endpoint will be performed: 
• The primary efficacy endpoint will be summarized by counts and percentages and 95% 
Exact binomial CI by study intervention group for the mITT population. 
• The proportion of responders will be compared to 0.18 (the upper bound of the 95% CI of 
the adult placebo rate from the meta-analysis) based on a one-sample proportion exact 
test, and the corresponding p-value will be provided for the pooled linaclotide dose 
groups and for each individual linaclotide dose group. 
• Bayesian probabilities of the pediatric posterior in Step 6 (Section 10.1.1) will also be 
calculated with a non-informative prior (i.e., Beta(1, 1)) for linaclotide treatment. 
• The primary efficacy endpoint will also be summarized by counts and percentages by 
study intervention incorporating all efficacy responses including the responses following 
onset of dose-de-escalation. 
 
Weekly responder rates (counts and percentages) will be provided for APS+2 responders by 
study intervention group. The 95% Exact binomial CI for weekly responder rate at week 12 will 
be presented. 
 
 
 


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Additional Sensitivity Analyses with Different Missing Data Handling Methods 
For any postbaseline analysis week, if participant has less than 4 completed diary days (i.e., 
completed both morning and evening diaries) in an analysis week, participant’s corresponding 
week’s analysis value for SBM or abdominal pain (AP) combination score will be considered 
missing and the postbaseline missing week during the intervention period will be imputed as 
follows. 
• Missing weekly SBM or AP combination scores will be imputed using multiple 
imputation (MI) assuming missing at random. Subjects with missing weekly values will 
be characterized as responders or non-responders based on the derived weekly SBM or 
AP combination scores from MI datasets. The imputed endpoints will be analyzed using 
each of the 30 datasets. SAS PROC MIANALYZE will be used to generate the final 
percentages and 95% CI for the responder rate based on normal approximation using 
Rubin's rule. 
 
The following tipping-point analysis will be performed assuming missing-not-at-random as 
another sensitivity analysis to evaluate the impact of missingness assumption for the analysis 
result. 
• The achievement of the primary efficacy endpoint requires a participant to meet the 
weekly APS + 2 responder criteria for at least 6 out of the 12 weeks of the intervention 
period. For participants with missing data on weekly SBM or AP combination scores, the 
missingness may or may not affect the responder status in the primary endpoint. For 
example, if a participant already met the weekly APS + 2 responder criteria for 6 weeks 
and had missing data for 3 weeks, the participant would achieve the primary endpoint, 
regardless of the missing data. On the other hand, if a participant met the weekly APS + 2 
responder criteria for 2 weeks, did not meet the weekly APS + 2 responder criteria for 
7 weeks, and had missing data for the other 3 weeks, the participant would not achieve 
the primary endpoint, regardless of the missing data. In this analysis, the participants with 
missing data that potentially impacts the responder status will be sequentially imputed as 
responders (i.e., from 0 to the total number of participants with missing data that 
potentially impacts the responder status) and the series of 95% Exact binomial CI will be 
presented. 
 


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10.1.3 Estimand Framework 
Population 
The target population is participants with IBS-C, ages 7-17 years old, satisfying the inclusion and 
exclusion criteria as specified in Sections 5.1 and 5.2 of the protocol (Version June-2020), 
respectively.  
The analysis population is mITT as discussed in Section 6.3. 
Variable 
The variable is the primary efficacy endpoint defined in Section 10.1, which is 6/12 weeks APS 
(abdominal pain and SBM) + 2 responder as derived from twice daily responses in eDiary 
(morning and evening). SBM is derived based on responses for BM and rescue medication in the 
eDiary twice daily (morning and evening). Abdominal pain score is also derived based on 
responses in the eDiary twice daily for abdominal pain. 
Accounting for Intercurrent Events in the Primary Efficacy Analyses 
The following intercurrent events are considered for the primary efficacy analyses. All the 
intercurrent events are handled based on the composite strategy. 
• The BMs for the participants who took a laxative, enema, or suppository on the calendar 
day of the BM or the calendar day before the BM will not be considered as SBMs for the 
analysis. 
• Participants who discontinue prematurely during but prior to the completion of the 
double-blind Study Intervention Period will have their eDiary data included up to the 
morning diary following the last dose date for primary endpoint. The early discontinued 
participants will be considered non-responders for the following weeks for primary 
endpoint. 
• eDiary responses following the onset of dose de-escalation will not be included. The 
participants with dose de-escalation will be considered non-responders for the subsequent 
study intervention weeks (after the onset of dose de-escalation) for the primary endpoint 
based on the randomized study intervention group. 
• A participant has to have at least 4 completed diary days per study intervention week to 
be considered a responder for that week and otherwise, the participant will be considered 
non-responder for that week. A completed diary day is a day in which both morning and 
evening eDiary entries are filled out by a study participant. 
 
 
 
 


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Population-level Summary 
The population-level summary for the primary endpoint is the proportion of participants 
satisfying the APS + 2 responder criteria for at least 6 out of 12 weeks during the study 
intervention period for each linaclotide dose. 
A Bayesian analysis will be performed for the primary efficacy endpoint using adult IBS-C data 
(borrowed from studies MCP-103-202, MCP-103-303, and LIN-MD-31) to inform the prior 
distribution of response in pediatric IBS-C patients. The 2.5 percentile of posterior distribution 
for the APS + 2 responder rate for linaclotide 145 μg or 290 μg will be compared separately with 
the pooled placebo APS + 2 responder rate and with the upper limit of 95% CI of the pooled 
placebo responder rate from contributing adult studies as discussed in Section 10.1.1. 
10.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints are as follows: 
• Change from baseline in 12-week SBM frequency rate (SBMs/week) during the study 
intervention period 
• Change from baseline in 12-week abdominal pain during the study intervention period 
• Change from baseline in 12-week stool consistency during the study intervention period 
• 6/12 weeks SBM + 2 responder 
• 6/12 weeks abdominal pain responder 
 
Change From Baseline in 12-Week SBM Frequency Rate During the Study Intervention 
Period 
Assessments of BM characteristics that determine occurrences of SBM (ie, BM frequency and 
RM use) will be measured by using the eDiary completed twice daily (morning and evening) on 
the eDiary device. 
The 12-week SBM frequency rate (SBMs/week) during the study intervention period will be 
derived based on total number of SBMs a participant reported during this period in the morning 
and evening assessments on the eDiary. The details of the derivation of SBM frequency rate are 
provided in Section 16.3.4. 
Change From Baseline in 12-Week Abdominal Pain During the Study Intervention Period 
Abdominal pain will be measured twice daily, once in the morning and once in the evening 
eDiary, using a 5-point scale. The 12-week abdominal pain score during the study intervention 


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period will be derived for each participant based on the reported abdominal pain scores in 
morning and evening eDiary assessments during this period. The details of the derivation of 
abdominal pain score are provided in Section 16.3.5. 
Change From Baseline in 12-Week Stool Consistency During the Study Intervention Period 
Stool consistency will be measured twice daily, once in the morning and once in the evening 
eDiary, using the 7-point ordinal p-BSFS for each BM. The 12-week stool consistency score 
during the study intervention period will be derived based on the responses in morning and 
evening eDiary assessments during this period.  If the participant has no SBM during the 
baseline period, the stool consistency (p-BSFS score) during the baseline period will be missing 
and the participant will be excluded from the change from baseline analysis for this secondary 
endpoint. The details of the derivation of stool consistency are provided in Section 16.3.6. 
6/12 Weeks SBM + 2 Responder 
A 6/12 weeks SBM + 2 responder is a participant who meets the weekly SBM + 2 responder 
criteria for at least 6 out of the 12 weeks of the study intervention period. A weekly SBM + 2 
responder is a participant who had an increase of at least 2 in the SBM weekly rate from baseline 
during that study intervention week. A participant has to have at least 4 completed diary days in 
analysis week to be considered as responder for that week and otherwise, will be considered as 
non-responder for that analysis week. 
6/12 Weeks Abdominal Pain Responder 
A 6/12 weeks abdominal pain responder is a participant who meets the weekly abdominal pain 
responder criteria for at least 6 out of the 12 weeks of the study intervention period. A weekly 
abdominal pain responder is a participant who had a decrease of at least 30% in the mean 
abdominal pain score from baseline during that study intervention week. A participant has to 
have at least 4 completed diary days in analysis week to be considered as responder for that week 
and otherwise, will be considered as non-responder for that analysis week. 
10.2.1  
Main Analysis Approach 
Descriptive statistics for continuous secondary endpoints in terms of mean, median, standard 
deviation, standard error of mean, minimum, and maximum will be provided by study 
intervention group. For responder endpoints, counts and percentages will be provided by study 
intervention group. 


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10.2.2  
Supplemental Analysis 
Weekly responder rates (counts and percentages) will be provided separately for abdominal pain 
weekly responders and SBM+2 weekly responders by study intervention group. By-week 
summary (mean, median, SD, standard error of mean, minimum, and maximum) will be 
provided for change from baseline in SBM frequency rate, abdominal pain, and stool consistency 
separately. 
The descriptive statistics (mean, median, SD, standard error of mean, minimum, and maximum 
for continuous endpoints and counts and percentages for responder endpoints) will also be 
provided by study intervention sequence incorporating efficacy responses following onset of 
dose-de-escalation for secondary efficacy endpoints. 
 
 
 


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10.3 Other Efficacy Endpoints 
The other efficacy endpoints are as follows: 
• 6/12 weeks APS + 1 responder 
• 9/12 weeks SBM + 2 responder 
• 9/12 weeks abdominal pain (combined daytime and nighttime symptoms) responder 
• 9/12 weeks APS + 2 responder 
• Proportion of participants with SBMs within 24 hours of first dose of study intervention 
• Change from baseline in 12-week straining during the study intervention period 
• Change from baseline in 12-week abdominal pain (daytime symptoms and nighttime 
symptoms separately) during the study intervention period 
• Change from baseline in 12-week percent of abdominal pain (combined daytime and 
nighttime symptoms)-free days during the study intervention period 
• Change from baseline in 12-week bloating (daytime, nighttime, and combined symptoms) 
during the study intervention period 
• Change from baseline in 12-week CSBM frequency rate (CSBMs/week) during the study 
intervention period 
• Proportion of participants who no longer fulfill Rome III criteria for IBS-C at the end of 
the study intervention period 
• Proportion of participants with each individual item score for the participant-completed 
global change items (pooping problems, tummy problems, and tummy pain) and global 
severity items (pooping problems, tummy problems, and tummy pain) at each week 
during the study intervention period 
• Proportion of participants with each individual item score for the observer-completed 
global change item and the global severity item at each week during the study 
intervention period (collected for age group of 7-11 years only) 
 
6/12 Weeks APS + 1 Responder 
A 6/12 weeks APS + 1 responder is a participant that meets the weekly APS + 1 responder 
criteria for at least 6 out of the 12 weeks of the intervention period. A weekly APS +1 responder 
is a participant who has an increase of at least 1 in the SBM weekly rate from baseline, AND a 
decrease of at least 30% in the mean abdominal pain score (combination daytime and nighttime) 
from baseline, during that study intervention week. This responder endpoint will be derived 
similar to the primary endpoint as discussed in Section 10.1. The proportion of participants 
 
 
 


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satisfying responder criteria for at least 6 out of 12 weeks during the study intervention period 
will be presented by study intervention group. 
9/12 Weeks SBM + 2 Responder 
A 9/12 weeks SBM + 2 responder is a participant that meets the weekly SBM + 2 responder 
criteria for at least 9 out of the 12 weeks of the intervention period. A weekly SBM +2 responder 
is a participant who has an increase of at least 2 in the SBM weekly rate from baseline during 
that study intervention week. A participant has to have at least 4 completed diary days in analysis 
week to be considered as responder for that week and otherwise, will be considered as non-
responder for that analysis week. 
The proportion of participants satisfying responder criteria for at least 9 out of 12 weeks during 
the study intervention period will be presented by study intervention group. 
9/12 Weeks Abdominal Pain (Combined Daytime and Nighttime Symptoms) Responder 
A 9/12 weeks abdominal pain responder is a participant who meets the weekly abdominal pain 
responder criteria for at least 9 out of the 12 weeks of the study intervention period. A weekly 
abdominal pain responder is a participant who had a decrease of at least 30% in the mean 
abdominal pain score from baseline during that study intervention week. A participant has to 
have at least 4 completed diary days in analysis week to be considered as responder for that week 
and otherwise, will be considered as non-responder for that analysis week. 
The proportion of participants satisfying responder criteria for at least 9 out of 12 weeks during 
the study intervention period will be presented by study intervention group. 
9/12 Weeks APS + 2 Responder 
A 9/12 weeks APS + 2 responder is a participant that meets the weekly APS + 2 responder 
criteria for at least 9 out of the 12 weeks of the intervention period. A weekly APS +2 responder 
is a participant who has an increase of at least 2 in the SBM weekly rate from baseline, AND a 
decrease of at least 30% in the mean abdominal pain score (combination daytime and nighttime) 
from baseline, during that study intervention week. This responder endpoint will be derived 
similar to the primary endpoint as discussed in Section 10.1. The proportion of participants 
satisfying responder criteria for at least 9 out of 12 weeks during the study intervention period 
will be presented by study intervention group. 


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Proportion of Participants with an SBM within 24 Hours of First Dose of Study 
Intervention 
A participant is a 24-hour responder if the participant has at least 1 SBM within 24 hours of first 
dosing of study intervention. Any SBM reported in the evening diary on randomization day and 
in the morning diary at the day after first dose date (i.e., Day 2) will be considered a SBM within 
24 hours. The proportion of participants satisfying responder criteria will be presented by study 
intervention group. 
Change From Baseline in Other Efficacy Endpoints Related to Bowel Habits and 
Abdominal Symptoms 
The derivations of straining, abdominal pain (daytime and nighttime), bloating (daytime, 
nighttime, and combined daytime and nighttime symptoms), and CSBM frequency rates 
(CSBMs/week) during the Study Intervention Period are discussed in Section 16.3.7, 
Section 16.3.5, Section 16.3.8, and Section 16.3.4, respectively. 
Descriptive statistics (mean, median, SD, standard error of mean, minimum, and maximum) will 
be presented by study intervention group. 
Change from Baseline in 12-week Percent of Abdominal Pain (Combined Daytime and 
Nighttime Symptoms)-Free Days During Study Intervention Period  
The percent of abdominal pain-free days during the analysis period will be derived as the number 
of days with abdominal pain (combined daytime and nighttime symptoms) scores of 0 divided by 
the total number of days with non-missing abdominal pain scores in the period (baseline or study 
intervention period) multiplied by 100. If a participant has reported abdominal pain score (any 
non-zero value from 1 to 4) in at least one eDiary (morning or evening) on a specific day during 
the analysis period, that day will not be counted as abdominal pain-free day during that analysis 
period.  
Descriptive statistics (mean, median, SD, standard error of mean, minimum, and maximum) will 
be presented by study intervention group. 
Proportion of Participants Who No Longer Fulfill Rome III Criteria for IBS-C at the End 
of the Study Intervention Period 
The details of the derivation of this endpoint are discussed in Section 16.3.9. The proportion of 
participants who no longer fulfill Rome III criteria for IBS-C at the end of the study intervention 
period will be presented by study intervention group. 


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Participant-Completed Global Change Items and Global Severity Items at Each Week 
During Study Intervention Period 
The details of participant-completed global change item scores and global severity item scores 
are discussed in Section 16.3.10. For each of the participant-completed global change items 
(pooping problems, tummy problems, and tummy pain) and global severity items (pooping 
problems, tummy problems, and tummy pain), counts and percentages for each category within 
each individual item will be provided by study intervention group at each week during the study 
intervention period. 
Observer-Completed Global Change Item and Global Severity Item at Each Week During 
Study Intervention Period 
The observer-completed global change item and global severity item will be assessed on a 
weekly basis in the eDiary, for the 7 - 11 years of age group only as discussed in Section 16.3.11. 
Counts and percentages of the global change item and the global severity item will be provided 
by study intervention group at each week during the study intervention period. 
10.4 Subgroup Analysis for Efficacy endpoints 
Primary and secondary efficacy endpoints will be summarized in a similar way as discussed for 
main analysis approach for the following subgroups (within each subgroup category) based on 
the mITT Population. Subgroups will be interpreted with caution due to possible limited sample 
size within each subgroup category. 
• Age group (7-11 years group, 12-17 years group)  
• Race (white, non-white)  
• Gender (male, female) 
 


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11 
Safety Analyses 
The safety analysis will be performed using the Safety Population. The safety parameters will 
include adverse events (AEs) and clinical laboratory parameters, vital sign (including postural), 
electrocardiographic (ECG) parameters, height, and weight. For each safety parameter of the 
clinical laboratory, vital signs, height, weight, and ECG parameters, the last non-missing safety 
assessment before the first dose of study intervention will be used as the baseline for all analyses 
of that safety parameter. Continuous variables will be summarized by number of participants and 
mean, SD, median, minimum, and maximum values. Categorical variables will be summarized 
by number and percentage of participants. The safety summaries will be provided by study 
intervention group.  
11.1 Adverse Events 
Adverse events will be coded by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities, version 23.0 or newer. 
An AE will be considered a treatment-emergent adverse event (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 30 days after the last dose of study intervention will not be counted 
as a TEAE.   
An AE will be considered a treatment-emergent serious adverse event (TESAE) if it is a TEAE 
that additionally meets any SAE criterion.  
The number and percentage of participants reporting TEAEs in each study intervention group 
will be tabulated by descending percentage in any group, by system organ class and preferred 
term, and further categorized by severity and causal relationship to the study intervention. 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 greatest severity and strictest causality for 
the summarization by severity and causal relationship. The above summaries of TEAEs, further 
categorized by severity and causal relationship will also be provided within each age group. If 
there are 5 or less participants with severe or related TEAEs in any study intervention group, the 
 
 
 


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corresponding age group summaries for TEAEs by severity or causal relationship will not be 
provided. 
The incidence of common (≥ 5% of participants in any study intervention group) TEAEs will be 
summarized by system organ class, preferred term, and study intervention group. 
Summary tables will be provided for participants with TESAEs, AEs of special interest, and 
participants with AEs leading to discontinuation. 
For all screened participants, separate listings will be presented for participants who died, 
participants with SAEs, participants with AEs leading to premature discontinuation, and 
participants with AEs of special interest (AESI). AEs during the Postintervention Period will also 
be included in the listings. A listing of all AEs will also be presented. 
11.2 Clinical Laboratory Parameters 
Descriptive statistics for clinical laboratory values (in International System of Units [SI] units) 
and changes from the baseline values at each assessment time point will be presented by study 
intervention group for the following laboratory parameters:  
Hematology: 
Absolute and differential white blood cell count, erythrocyte count, 
hemoglobin, hematocrit, platelet count, red blood cell count, and red blood 
cell indices (mean corpuscular volume, mean corpuscular hemoglobin, and 
mean corpuscular hemoglobin concentration) 
Chemistry: 
Sodium, potassium, calcium, chloride, bicarbonate, magnesium, phosphate, 
glucose, blood urea nitrogen, creatinine, total protein, alkaline phosphatase 
(ALP), albumin, total bilirubin (TBL), alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), total cholesterol 
Urinalysis: 
Specific gravity and pH 
Clinical laboratory test values will be considered potentially clinically significant (PCS) if they 
meet either the lower-limit or higher-limit PCS criteria listed in Table 11-1. The number and 
percentage of participants who have PCS postbaseline clinical laboratory values will be tabulated 
by study intervention for the double-blind Intervention Period. The percentages will be 
calculated relative to the number of participants with available non-PCS baseline values and at 
least 1 postbaseline assessment for the double-blind Intervention Period. The numerator will be 
the total number of participants with available non-PCS baseline values and at least 1 PCS 
postbaseline value for the double-blind Intervention Period. A supportive tabular display of 
participants with PCS postbaseline values will be provided, including the PID number, baseline 
 
 
 


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and all postbaseline (including non-PCS) values. In this listing, any participant with PCS value 
(if any) during the Post-intervention period will also be included. 
In addition, a tabular display showing all AEs that occurred in participants who had PCS 
postbaseline clinical laboratory values will be provided. 
Shift tables from baseline to the end of double-blind Intervention Period for clinical laboratory 
parameters listed above will be presented by study intervention group for the following 
categories: low, normal, and high, which are provided by lab vendor.  
 
 
 


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Table 11-1. 
Criteria for Potentially Clinically Significant Laboratory Results 
Parameter 
SI Unit 
Lower Limit 
Higher Limit 
CHEMISTRY 
Albumin 
g/L 
< 0.9 × LLN 
> 1.1 × ULN 
Alanine aminotransferase (ALT) 
U/L 
— 
≥ 3 × ULN 
Alkaline phosphatase 
U/L 
— 
≥1.2 x ULN: 6-12 (inclusive), 
male & female; 
13-15 (inclusive), male 
≥ 3 × ULN:13-15 (inclusive), 
female; 16- 17 
(inclusive), male & female 
Aspartate aminotransferase (AST) 
U/L 
— 
≥ 3 × ULN 
Bicarbonate 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Bilirubin, total 
μmol/L 
— 
> 1.5 × ULN 
Calcium 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Chloride 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Cholesterol, Total 
mmol/L 
— 
> 1.6× ULN 
Creatinine 
μmol/L 
— 
> 1.3 × ULN 
Glucose, random, serum 
mmol/L 
< 0.8 × LLN 
> 1.4 × ULN 
Potassium 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Protein, total  
g/L 
< 0.9 × LLN 
> 1.1 × ULN 
Sodium 
mmol/L 
< 0.9 × LLN 
> 1.1 × ULN 
Urea Nitrogen (BUN) 
mmol/L 
— 
> 1.2 × ULN 
HEMATOLOGY 
Basophils, absolute cell count 
109/L 
— 
> 3 × ULN 
Eosinophils absolute cell count 
109/L 
— 
> 3 × ULN 
Lymphocytes absolute cell count 
109/L 
< 0.7 × LLN 
> 1.3 × ULN 
Monocytes, absolute cell count 
109/L 
< 0.5 × LLN 
> 2.0 × ULN 
Neutrophils, absolute cell count 
109/L 
< 0.8 × LLN 
> 1.5 × ULN 
Hematocrit 
Ratio 
< 0.9 × LLN 
> 1.1 × ULN 
Hemoglobin 
g/L 
< 0.9 × LLN 
> 1.1 × ULN 
Platelet count 
109/L 
< 0.5 × LLN 
> 1.5 × ULN 
Red blood cell count 
1012/L 
< 0.9 × LLN 
> 1.1 × ULN 
White blood cell count 
109/L 
< 0.7 × LLN 
> 1.5 × ULN 
URINALYSIS 
pH 
— 
< 0.9 × LLN 
> 1.1 × ULN 
Specific gravity 
— 
— 
> 1.1 × ULN 
LLN  lower limit of normal value provided by the laboratory; SI  Le Système International d’Unités (International System of 
Units); ULN  upper limit of normal value provided by the laboratory. 
 
 
 
 


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11.3 Vital Signs 
Descriptive statistics for height, vital signs (ie, temperature, body weight, respiratory rate, and 
supine pulse rate, supine systolic and diastolic BP) and changes from baseline values at each 
assessment time point will be presented by study intervention group. 
Vital sign values will be considered PCS if they meet both the observed-value criteria and the 
change-from-baseline criteria listed in Table 11-2. The number and percentage of participants 
with PCS postbaseline values will be tabulated by study intervention group for the double-blind 
Intervention Period and Postintervention Period separately. The percentages will be calculated 
relative to the number of participants with available non-PCS baseline values and at least 1 
postbaseline assessment in the specific period. The numerator will be the total number of 
participants with available non-PCS baseline values and at least 1 PCS postbaseline value during 
the specific period. A supportive tabular display of participants with PCS postbaseline values will 
be provided, including the PID number, baseline and all postbaseline (including non-PCS) 
values. 
In addition, a tabular display showing all AEs that occurred in participants who had PCS 
postbaseline vital sign values will be provided. 
 
 
 


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Table 11-2. 
Criteria for Potentially Clinically Significant Vital Signs 
Parameter 
Flag 
Criteriaa 
Observed Value 
Change From Baseline 
Systolic Blood 
Pressure, mmHg - 
Postural Vital Signs 
(Supine and Standing) 
 
Decrease in systolic blood 
pressure of 20 mmHg or 
more from supine to standing 
[*Change from supine 
SBP <= -20] 
Decrease in systolic blood pressure from 
supine to standing at observed time point is at 
least 10 mmHg greater than the decrease in 
systolic blood pressure from supine to 
standing at baseline 
[Postbaseline change from supine SBP – 
baseline change from supine SBP <= -10] 
Diastolic Blood 
Pressure, mmHg 
Postural Vital Signs 
(Supine and Standing) 
 
Decrease in diastolic blood 
pressure of 10 mmHg or 
more from supine to standing 
[Change from supine 
DBP <= -10] 
Decrease in diastolic blood pressure from 
supine to standing at observed time point is at 
least 10 mmHg greater than the decrease in 
diastolic blood pressure from supine to 
standing at baseline 
[Postbaseline change from supine DBP – 
baseline change from supine DBP <= -10]  
Pulse Rate, bpm - 
Postural Vital Signs 
(Supine and Standing) 
 
Increase in heart rate of 
20 beats per minute or more 
from supine to standing 
[Change from supine pulse 
rate >= 20] 
Increase in heart rate from supine to standing 
at observed time point is at least 10 beats per 
minute greater than the increase in heart rate 
from supine to standing at baseline  
[Postbaseline change from supine pulse rate – 
baseline change from supine pulse rate >= 10] 
Systolic Blood 
Pressure, mm Hg 
(Supine) 
High 
Age 6-11 (inclusive): ≥ 140 
Age 12-17 (inclusive): ≥ 155 
Increase of ≥ 20 
Low 
Age 6-11 (inclusive): ≤ 80 
Age 12-17 (inclusive): ≤ 90 
Decrease of ≥ 20 
Diastolic Blood 
Pressure, mm Hg 
(Supine) 
High 
Age 6-11 (inclusive): ≥ 95 
Age 12-17(inclusive): ≥ 105 
Increase of ≥ 15 
Low 
Age 6-11 (inclusive): ≤40 
Age 12-17 (inclusive): ≤ 45 
Decrease of ≥ 15 
Pulse Rate, bpm 
(Supine) 
High 
Age 6-11 (inclusive): ≥ 140 
Age 12-17 (inclusive): ≥ 120 
Increase of ≥ 15 
Low 
Age 6-11 (inclusive): ≤ 50 
Age 12-17 (inclusive): ≤ 40 
Decrease of ≥ 15 
Weight, kg 
High 
— 
Increase of ≥ 5% 
Low 
— 
Decrease of ≥ 5% 
a. 
A postbaseline value is considered potentially clinically significant if it meets both the observed value and the 
change from baseline criteria. 
bpm  beats per minute; DBP  diastolic blood pressure; SBP  systolic blood pressure. 
* 
Change from supine value  standing value  supine value 
 


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11.4 Electrocardiogram 
Descriptive statistics for ECG parameters (ventricular heart rate, RR interval, PR interval, QRS 
interval, QT interval, and QTc) and changes from baseline values at each assessment time point 
will be presented by study intervention group. The QTc will be calculated using both the Bazett 
and Fridericia corrections. 
Electrocardiographic parameter values are considered PCS if they meet or exceed the higher-
limit PCS criteria listed in Table 11-3. The number and percentage of participants with PCS 
postbaseline ECG values will be tabulated by study intervention group for the double-blind 
invention period. The percentages will be calculated relative to the number of participants with 
available non-PCS baseline values and at least 1 postbaseline assessment for the double-blind 
Intervention Period. The numerator is the total number of participants with available non-PCS 
baseline values and at least 1 PCS postbaseline value for the double-blind Intervention Period. A 
supportive tabular display of participants with PCS postbaseline values will be provided, 
including the PID number, baseline, all postbaseline (including non-PCS) values, and change 
from baseline. In this listing, any participant with PCS value (if any) during Postintervention 
Period will also be included. 
In addition, a tabular display showing all AEs that occurred in participants who had postbaseline 
PCS ECG values will be provided. 
A shift table from baseline to the end of double-blind Intervention Period in the Investigator’s 
overall interpretation of the ECG will be presented by study intervention group for the following 
categories: normal; abnormal, not clinically significant; abnormal, clinically significant. A 
tabular display showing participants with postbaseline clinically significant ECG abnormalities 
according to the Investigator’s overall interpretation will be provided. 
Table 11-3. 
Criteria for Potentially Clinically Significant Electrocardiograms 
Parameter 
Unit 
Higher Limit 
QRS interval 
msec 
QRS >= 115 msec (6-7 (inclusive) years) 
QRS >= 125 msec (8-15 (inclusive) years) 
QRS >= 150 msec (16-17 (inclusive) years) 
PR interval 
msec 
PR > 225 msec (6-7 (inclusive) years) 
PR > 250 msec (8-17 (inclusive) years)  
QTc(F)  
msec 
>480 
QTc(F)  QT Corrected by Fridericia’s formula 
 


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11.5 Other Safety Parameters 
11.5.1 Potential Hy’s Law 
Potential Hy’s Law criteria within a 24-hour window is defined by a post baseline elevation of 
ALT or AST ≥ 3x ULN, along with TBL ≥ 2x ULN and a non-elevated ALP < 2x ULN, all based 
on blood draws collected within a 24-hour period. 
Participants who meet the potential Hy’s Law criteria from the first dose of study drug to within 
30 days after the last dose of study intervention will be summarized. Supportive tabular displays 
will also be provided. 
 
 
 


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Health Outcomes Analyses 
Not applicable. 
 
 
 


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Interim Analysis 
For IBS-C participants in this study, no interim analysis is planned. 
 
 
 


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Determination of Sample Size 
The sample size of at least 50 randomized participants per arm (at least 100 randomized 
participants in total) for IBS-C participants in this study was planned to inform the prescriber 
regarding the safe and efficacious use of linaclotide doses in this patient population. The planned 
sample size is not driven by any statistical consideration. This section provides the estimated 
Bayesian powers for the primary analysis of the primary endpoint in IBS-C portion of this study 
for the planned sample size. 
Extrapolation from IBS-C adult studies (MCP-103-202 [Phase 2b], LIN-MD-31 [Phase 3], and 
MCP-103-302 [Phase 3]) was performed using Bayesian methodology with the primary efficacy 
endpoint of 6/12 week APS + 2 responder endpoint (as defined in Section 10.1). APS + 2 
responder rates for treated individuals from the adult IBS-C population in Phase 2b study 
MCP-103-202 and Phase 3 pivotal studies LIN-MD-31 and MCP-103-302 were used to form a 
prior probability distribution for the pediatric APS + 2 response rate. This prior was down-
weighted. Responder data from LIN-MD-64 were simulated using the down-weighted prior and 
the lower 2.5 percentile of posterior samples compared separately against the pooled placebo rate 
and the upper limit of 95% CI (2-sided) of pooled placebo rate from the adult contributing 
studies. The probabilities (Bayesian powers) that the lower 2.5 percentile of the linaclotide 
responder rate being greater than the pooled placebo rate from contributing adult studies, for 
different sample sizes and effective sample sizes (with associated down-weight factors) are 
provided in Table 14-1. Similarly the probabilities (Bayesian powers) that the lower 2.5 
percentile of the linaclotide responder rate being greater than the upper limit of the 95% 
confidence interval of the placebo responder rate from contributing adult studies are also 
provided in Table 14-2. 
With the consideration of a modest weight of 0.017 on the prior (equivalent to 15 new subjects 
from the adult IBS-C studies), the planned sample size of 50 IBS-C participants per arm should 
sufficiently describe the efficacy in pediatrics when contextualized using the pooled placebo rate 
from adult contributing studies. 
The details of simulation codes to generate Bayesian powers in Table 14-1 and Table 14-2 are 
provided in Appendix 1. 
 
 
 


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Table 14-1. 
Bayesian Power Estimates by Sample Size and ESS (vs. the Responder 
Rate of the Adult Placebo Response, 0.16*) 
 
N/Arm=30 
N/Arm=40 
N/Arm=50 
ESS=12 (w = 0.0135) 
0.763 
0.808 
0.836 
ESS=15 (w = 0.017)  
0.865 
0.873 
0.854 
ESS=18 (w = 0.020)  
0.865 
0.903 
0.904 
ESS=24 (w = 0.027)  
0.943 
0.954 
0.964 
ESS (Effective Sample Size) is calculated as the number of subjects used to derive the prior distribution multiplied by the down
weight (w). 
* 
Based on pooled adult placebo data from Phase 2b study MCP 103 202 and Phase 3 pivotal studies LIN MD 31 and 
MCP 103 302. 
 
Table 14-2. 
Bayesian Power Estimates by Sample Size and ESS (vs. the Upper Limit 
of the 95% CI (2-sided) of the Adult Placebo Response, 0.18*) 
 
N/Arm=30 
N/Arm=40 
N/Arm=50 
ESS=12 (w = 0.0135) 
0.674 
0.762 
0.741 
ESS=15 (w = 0.017)  
0.809 
0.769 
0.809 
ESS=18 (w = 0.020)  
0.800 
0.855 
0.828 
ESS=24 (w = 0.027)  
0.895 
0.925 
0.895 
ESS (Effective Sample Size) is calculated as the number of subjects used to derive the prior distribution multiplied by the down
weight (w). 
* 
Based on pooled adult placebo data from Phase 2b study MCP 103 202 and Phase 3 pivotal studies LIN MD 31 and 
MCP 103 302. 
 


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Statistical Software 
Statistical analyses will be performed using version 9.4 (or newer) of SAS on a Linux operating 
system. 
 
 
 


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Data Handling Conventions 
16.1 Visit Time Windows for Safety Analyses 
Table 16-1 presents the visits assigned for safety analyses and the corresponding range of study 
intervention days (window) during which an actual visit may occur. 
Table 16-1. 
Visit Time Windows 
Derived Visit 
Scheduled Visit Daya 
Window 
Baseline 
Day 1 
Days ≤ 1 
Week 2 Visit 
Day 15 
Days [2, 21] 
Week 4 Visit 
Day 29 
Days [22, 42] 
Week 8 Visit 
Day 57 
Days [43, 70] 
Week 12 Visit 
Day 85 
Days [Day 71, max (last dose day+1, Visit 7 date)] 
Post-intervention Visit 
Day 92 
Days >= max (last dose day+1, Visit 7 date)+1 
End of Double-Blind 
Intervention Periodb  
Final or Termination Visit during the double-blind Intervention Period 
a. 
Relative to the date of the first dose of double blind study intervention. Day 1  the date of the first dose of double blind 
study intervention. There is no Day 0 or Week 0. 
b. 
Presented in analysis tables for safety parameters, including but not limited to electrocardiograms, clinical laboratory values, 
and vital signs. 
 
Participants who rollover to the long-term safety study, LIN-MD-66, before the EOS visit (i.e. 
Visit 8, post-intervention visit) are not required to have this EOS visit or post-intervention visit. 
If the assessment date (if the assessment date is unavailable, use visit date instead) is on or after 
the date of the first dose of study intervention, the study day is calculated by assessment date  
date of the first dose of study intervention + 1. If the assessment date is before the date of the 
first dose of study intervention, the study day is calculated by assessment date  date of the first 
dose of study intervention. Therefore, a negative day indicates a day before the start of the study 
intervention. 
If a participant has 2 or more visits within the same window, the last visit with a non-missing 
value will be used for analysis. 
16.2 Visit Time Windows for Efficacy Analyses 
Table 16-2 below presents the analysis weeks assigned for the efficacy analysis of the participant 
daily diary data related to BM and/or abdominal symptom characteristics. These analysis weeks 


C O N FI D E N TI A L   
 
Li nacl oti de  
Pr ot oc ol LI N M D
6 4  
4 7  
LI N M D
6 4 St atisti cal A nal ysis Pla n f or I B S C Parti ci pa nts ( A me n d me nt # 2 ) 
2 0 Fe br uar y 2 0 2 4  
will be u s e d i n t he calc ulati o ns f or all wee k-bas e d e n d p oi nts (e g, S B M wee kl y fre q ue nc y rat e, 
et c.). 
T a ble  1 6 -2 . 
A n al ysis Ti me Wi n d o ws f o r Effic ac y A n al ysis - D ail y Q uesti o ns  
Pe ri o d  
A n al ysis Wee k  
Be gi ns a 
E n ds a 
Pr e i nt er ve nti o n 
( Baseli n eb)  
Wee k -2  
Da y -1 4  
Da y -8  
Wee k -1  
Da y -7  
Da y 1, ti me of ra n d o mizati o n  
I nt er ve nti o n 
Wee k 1  
Da y 1, ti me after ra n d o mizati o n  
Da y 7  
Wee k 2  
Da y 8  
Da y 1 4  
Wee k 3  
Da y 1 5  
Da y 2 1  
Wee k 4  
Da y 2 2  
Da y 2 8  
Wee k 5  
Da y 2 9  
Da y 3 5  
Wee k 6  
Da y 3 6  
Da y 4 2  
Wee k 7  
Da y 4 3  
Da y 4 9  
Wee k 8  
Da y 5 0  
Da y 5 6  
Wee k 9  
Da y 5 7  
Da y 6 3  
Wee k 1 0  
Da y 6 4  
Da y 7 0  
Wee k 1 1  
Da y 7 1  
Da y 7 7  
Wee k 1 2  
Da y 7 8  
Da y of last d ose + 1  
P ost -i nt er ve nti o n 
P ost -i nter ve nti o n 
Da y of last d ose + 1  
Da y of e n d of st u d y visit  
N ot e: O n r a n d o mi zati o n da y, if parti ci pa nt alr ea d y c o m pl et e d m or ni n g di ar y, at t he cli ni c visit, parti ci pa nts fill o ut a cli ni c diar y 
a n d t he assess me nts i n t he cli ni c diar y will be part of t he Pr e i nter ve nti o n Peri o d. M or ni n g diar y assess me nts o n r a n d o mi zati o n 
da y will als o be part of Pr ei nter ve nti o n Peri o d. e Di ar y assess me nts i n e ve ni n g diar y o n t he da y of r a n d o mi zati o n will be part of 
t he I nt er ve nti o n Peri o d. e Diar y assess me nts i n m or ni n g diar y at t he da y aft er t he l a st d ose da y will be c o nsi der e d as assess me nts 
i n t he I nt er ve nti o n Peri o d.  
a. 
Rel ati ve t o t he date of r a n d o mi zati o n; Da y 1  t he da y of r a n d o mi zati o n.  
b . 
Baseli ne val ues f or effi cac y par a meters will be deri ve d fr o m t he dail y m or ni n g a n d e ve ni n g e Diari es  a n d e C R F dat a 
c oll ect e d i n t he Pre i nt er ve nti o n Peri o d, s pecifi call y t he peri o d of ti me fr o m 1 4 da ys bef or e r a n d o mi zati o n u p t o t he ti me of 
r a n d o mi zati o n. 
 
F or t he I nt er ve nti o n Peri o d, dail y diar y da y is calc ulat e d as ( diar y dat e - dat e of 
ra n d o mizati o n +  1). F or t he Prei nt er ve nti o n Peri o d, dail y diar y da y is c alc ulat e d as ( diar y 
dat e  - dat e of ra n d o mizati o n). H o we ver, t he da y of ra n d o mizati o n is st u d y Da y 1 re gar dless. 
Partici p a nts will c o m plet e t heir diar y e ntries t wice per da y f or dail y diar y.  
If a partici pa nt wit h dra ws d uri n g t he I nt er ve nti o n Peri o d, t he partici pa nt’s m or ni n g diar y 
assess me nts of dail y e Diar y o n t he da y aft er last d ose da y will be ca pt ure d as assess me nts i n t he 
I nt er ve nti o n Peri o d. T he i m p act e d I nt er ve nti o n Peri o d wee k s hall be s h ort e ned t o t he e n d of t he 


C O N FI D E N TI A L   
 
Li nacl oti de  
Pr ot oc ol LI N M D
6 4  
4 8  
LI N M D
6 4 St atisti cal A nal ysis Pla n f or I B S C Parti ci pa nts ( A me n d me nt # 2 ) 
2 0 Fe br uar y 2 0 2 4  
wit h dra w n partici pa nt ’s I nt er ve nti o n Peri o d a n d all s u bs e q ue nt I nt er ve nti o n Peri o d wee ks will be 
missi n g f or t hat partici pa nt.  
Ta ble  1 6 -3  bel o w prese nts t he wee kl y p eri o ds assi g ne d f or t he efficac y a nal ysis of t he partici pa nt 
wee kl y diar y dat a relat e d t o gl o bal se verit y it e ms a n d gl o bal c ha n ge it e ms.  
T a ble  1 6 -3 . 
A n al ysis Ti me Wi n d o ws f o r Effic ac y A n al ysis - Wee kl y Q uesti o ns  
A n al ysis Wee k  
Be gi ns a 
E n ds a 
Wee k -2  
Visit 2 da y  
Visit 2 da y + 7  
Wee k -1 ( Baseli n e)  
Visit 2 da y + 8  
Da y 1  
Wee k 1  
Da y 2  
Da y 8  
Wee k 2  
Da y 9  
Da y 1 5  
Wee k 3  
Da y 1 6  
Da y 2 2  
Wee k 4  
Da y 2 3  
Da y 2 9  
Wee k 5  
Da y 3 0  
Da y 3 6  
Wee k 6  
Da y 3 7  
Da y 4 3  
Wee k 7  
Da y 4 4  
Da y 5 0  
Wee k 8  
Da y 5 1  
Da y 5 7  
Wee k 9  
Da y 5 8  
Da y 6 4  
Wee k 1 0  
Da y 6 5  
Da y 7 1  
Wee k 1 1  
Da y 7 2  
Da y 7 8  
Wee k 1 2  
Da y 7 9  
last d ose date + 1 
P ost -i nter ve nti o n 
Da y of last d ose date + 8  
Da y of e n d of st u d y visit 
a. 
Be gi n a n d e n d of eac h wee k fr o m Wee k 1 o n war ds are r el ati ve t o t he date of t he first d ose of d o u bl e
bli n d st u d y 
i nter ve nti o n. Da y 1  t he dat e of t he first d ose of d o u bl e bli n d st u d y i nt er ve nti o n. T here is n o Da y 0 or Wee k 0. E n d of 
Wee k  1 t o Wee k 1 2 will be da y of l ast d ose + 1 or c orr es p o n di n g e n d da y i n ta bl e w hi c he ver c o mes earlier.  
 
Partici p a nts w h o r oll o ver t o t he l o n g -t er m safet y st u d y, LI N-M D -6 6, bef ore t he E O S visit (i. e. 
Visit 8, p ost -i nt er ve nti o n visit) are n ot re q uire d t o ha ve t he E O S visit or p ost-i nt er ve nti o n visit. 
1 6. 3  Deri ve d Vari a bles  
1 6. 3. 1  Miss i n g or I nc o m plete M or ni n g/ E ve ni n g e Di ar y Ass ess me nts  
N o i m p ut ati o n or deri vati o n will be perf or me d f or miss e d m or ni n g/e ve ni n g assess me nts u nless 
ot her wise s pe cifie d.  


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16.3.2 Incomplete Morning/Evening eDiary Assessments 
Missing responses in incomplete morning and/or evening assessments will not be imputed for 
most of the parameters, with the exception of rescue medication (RM) use and BM frequency. 
If the answer to the RM use question is missing for any assessment (morning or evening), no RM 
usage will be considered during that diary period (morning or evening diary) in eDiary, with the 
exception that the missing RM will be considered “used” if the other available assessment during 
that diary period is “yes”. 
If the answer to the question related to BM frequency is missing in any assessment (morning or 
evening), BM frequency will be considered as zero for that diary period (morning or evening 
diary) in the eDiary. 
16.3.3 Incomplete Clinic Diary on Randomization Visit (If Present) 
Missing responses in an incomplete clinic diary on randomization day will be handled in a 
similar way as mentioned for incomplete daily morning/evening assessments. Clinic diary on 
randomization day will be considered as part of morning diary on randomization day. 
16.3.4 Stool Frequency 
The derivation of SBM and CSBM frequencies require the collection of data on bowel 
movement frequency and rescue medication use. Participants will report their BM frequency (the 
number of BMs) and use of rescue medication by responding to the following:  
Bowel Movement Frequency - Morning eDiary 
For this parameter, participants will record their BM frequency by responding to the following in 
the morning eDiary: 
• From bedtime last night until now, how many times did you poop (and poop came out)?  
• Enter number of times. 
 


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Bowel Movement Frequency - Evening eDiary 
For this parameter, participants will record their BM frequency by responding to the following in 
the evening eDiary: 
• From when you got up this morning until now, how many times did you poop (and poop 
came out)? 
• Enter number of times. 
 
Rescue Medication Use - Morning eDiary 
For this parameter, participants will record whether they took rescue medication by responding 
to the following in the morning eDiary: 
• From bedtime last night until now, did you take any medicine to help you poop, other 
than the study medicine?  
o Yes 
o No 
 
Rescue Medication Use - Evening eDiary 
For this parameter, participants will record whether they took rescue by responding to the 
following in the evening eDiary: 
• From when you got up this morning until now, did you take any medicine to help you 
poop, other than the study medicine? 
o Yes 
o No 
 
Spontaneous Bowel Movement (SBM) 
An SBM is a BM that occurs in the absence of rescue medication (laxative, suppository, or 
enema) use on the calendar day of the BM or the calendar day before the BM. 


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Complete Spontaneous Bowel Movement (CSBM)/Incomplete Evacuation 
A CSBM is an SBM that is associated with a sense of complete evacuation. Participants will 
record their assessment of the sensation of incomplete evacuation for each BM by responding to 
the following in the morning and evening eDiaries: 
• When you pooped, did it feel like there was more poop left inside that didn’t come out? 
o Yes 
o No 
 
Values of “No” correspond to a CSBM.  
Stool Frequency Rates  
The components for calculating a participant’s stool frequency rates (SBM/CSBM weekly rates) 
for a given period are as follows: 
• The number of BMs that occurred during that specific period 
• The number of those BMs that were SBMs 
• The number of those SBMs that were CSBMs 
• The number of days during that specific period: 
o Randomization day with evening diary will be considered a half day for the double-
blind Intervention Period. 
o Randomization day with morning and/or clinic diary will be considered a half day for 
the Preintervention Period. 
o The day after last dose will be considered a half day for the double-blind Intervention 
Period with morning diary and for the Postintervention Period with evening diary. 
 
Duration of an Analysis Week 
With respect to a participant’s scheduled analysis weeks, the term duration is used. In regard to 
the duration of a week, it is expected that 1 or more of a participant’s “weeks” may not be 
exactly 7 days in duration (eg, a participant may withdraw or discontinue early from the trial, 
may have half day data with diary entries, or may have missing diary day). Deviations from the 7 
days norm are structural in nature; and, as such, the calculations of the weekly rates of SBMs or 
CSBMs will incorporate the actual days contributed within the time period (week or specific 
phase). 
 
 
 


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Weekly Stool Frequency Rate Calculations 
The weekly frequency rate for SBMs (CSBMs) will be based on the total number of SBMs 
(CSBMs) occurring based on the diary entries during that time period, adjusting for differences 
in the length of the time period. Weekly stool frequency rates for each specific period will be 
calculated as follows: 
• Weekly Frequency Rate (Specific Period)  
Total number of events (SBMs or CSBMs) during the specific period 
Number of days during the specific analysis period
 X 7 
16.3.5 Abdominal Pain 
Abdominal pain scores will be collected twice daily in the eDiary (morning and evening).  
Abdominal Pain - Daytime 
For this parameter, participants will rate their abdominal pain during the daytime by responding 
to the following in the evening eDiary: 
• From when you got up this morning until now, did your tummy hurt at all? 
o Yes 
o No 
If “yes”, then participant answers the following question: 
• How much did your tummy hurt?  
1  a tiny bit 
2  a little  
3  some  
4  a lot 
Abdominal Pain - Nighttime 
For this parameter, participants will rate their abdominal pain during the nighttime by responding 
to the following in the morning eDiary: 
• From bedtime last night until now, did your tummy hurt at all? 
o Yes 
o No 
If “yes”, then the participant answers the following question: 


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• How much did your tummy hurt?  
1  a tiny bit 
2  a little  
3  some  
4  a lot 
 
Abdominal Pain - Combination (Total 24-hour Period) 
The Abdominal Pain Combination Score for a 24-hour period will be determined based on 
combined daytime symptoms of abdominal pain in evening eDiary assessments and nighttime 
symptoms of abdominal pain in morning eDiary assessments as follows: 
• Combination score  average of morning and evening assessments, if both morning and 
evening assessments are present 
• Combination score  morning or evening assessment, if either morning or evening 
assessment is present 
• Combination score  missing, if both morning and evening assessments are missing 
 
The participant’s abdominal pain score for a specific period based on evening assessments 
(daytime symptoms), morning assessments (nighttime symptoms), and combined morning and 
evening assessments will be derived as the mean of the non-missing abdominal pain scores 
within the corresponding diaries during the specific period. The abdominal pain scores of 0, 1, 2, 
3, and 4 will be used to calculate the average, where ‘0’ indicates no abdominal pain. 
16.3.6 Stool Consistency 
Participants will use the pediatric Bristol Stool Form Scale (p-BSFS), to rate their stool 
consistency for each BM: 
"Choose the poop that is most like the poop you had." 
Type 1  looks like small hard lumps or balls, like pebbles 
Type 2  looks like fat sausage shape but lumpy and hard 
Type 3  looks like a sausage but with cracks on it 
Type 4  looks like a sausage or snake, smooth and soft 
Type 5  looks like chicken nuggets, soft smooth blobs 
Type 6  looks like oatmeal, fluffy mushy pieces 
Type 7  looks like a milkshake, watery 
99 - I don’t know 


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"I don't know" is considered as a missing response. Stool consistency will be collected twice 
daily (morning and evening) in the eDiary and measured using the 7-point p-BSFS. Stool 
consistency (p-BSFS) score during a specific analysis period will be derived as mean of 
participant’s non-missing, SBM-associated p-BSFS scores during that specific period.  
16.3.7 Straining 
For every BM, participants will assess the degree of straining by responding to the following in 
the morning and evening eDiaries: 
• When you pooped, how hard did you push? 
0  not hard at all 
1  I pushed a tiny bit hard 
2  I pushed a little hard 
3  I pushed hard 
4  I pushed very hard 
 
Straining will be collected twice daily (morning and evening) in the eDiary and measured using a 
5-point scale. The participant’s straining score in a specific analysis period will be the mean of 
participant’s non-missing, SBM-associated straining scores during that specific period. 
16.3.8 Abdominal Bloating 
Abdominal bloating scores will be collected twice daily in the eDiary (morning and evening).  
Abdominal Bloating - Daytime 
For this parameter, participants will record their assessment of abdominal bloating during the day 
by responding to the following in the evening eDiary: 
• From when you got up this morning until now, did your tummy FEEL big and full?   
o Yes 
o No  
If “yes” then participant answers the following question: 
 
 
 


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How big and full did your tummy FEEL? 
1  a tiny bit 
2  a little  
3  medium  
4  very 
 
Abdominal Bloating - Nighttime 
For this parameter, participants will record their assessment of nighttime abdominal bloating by 
responding to the following in the morning eDiary: 
• From bedtime last night until now, did your tummy FEEL big and full? 
o Yes 
o No  
If “yes”, then the participant answers the following question: 
• How big and full did your tummy FEEL?  
1  a tiny bit 
2  a little  
3  medium  
4  very 
 
Abdominal Bloating - Combination (Total 24-hour Period) 
The Abdominal Bloating Combination Score for a 24-hour period will be determined based on 
combined daytime symptoms of abdominal bloating in evening assessments and nighttime 
symptoms of abdominal bloating in morning assessments as follows: 
• Combination score  average of morning and evening assessments, if both morning and 
evening assessments are present 
• Combination score  morning or evening assessment, if either morning or evening 
assessment is present 
• Combination score  missing, if both morning and evening assessments are missing 
 
The participant’s abdominal bloating score for a specific period based on evening assessments 
(daytime symptoms), morning assessments (nighttime symptoms), and combined morning and 
evening assessments will be derived as the mean of the non-missing abdominal bloating scores 


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within the corresponding diaries during the specific period. The abdominal bloating scores of 0, 
1, 2, 3, and 4 will be used to calculate the average, where ‘0’ indicates no bloating. 
16.3.9 Rome III Criteria 
Rome III criteria will be assessed by the investigator at the Screening Visit (Visit 1) and at the 
end of the study intervention period (EOT Visit [Visit 7]). A participant will be considered as 
fulfilling Rome III criteria if a “yes” response is recorded to the overall question of whether the 
participant meets Rome III criteria for IBS-C. For the EOT assessment, the criteria will be 
assessed over the last 4 weeks of the double-blind study intervention period. In the event a 
participant discontinues the study prematurely, these criteria will be assessed over the last 4 
weeks of double-blind study intervention, or over the duration of double-blind study intervention 
if less than 4 weeks. 
16.3.10 Participant-completed Global Items  
Participant-completed global change and global severity items were developed by the sponsors. 
The participant-completed global items consist of 6 items, 3 assessing global change in the 
participant’s symptoms and 3 assessing the global severity of the participant’s symptoms. All 
6 participant-completed global items have a 7-day recall period and will be completed weekly on 
the eDiary device. The global severity items will be completed beginning at the Preintervention 
Period through End-of-Study (EOS) and the global change items will be completed beginning at 
Randomization through EOS. 
Participant-completed Global Change Items 
The 3 participant-completed global change items assess self-reported change in the participant’s 
bowel symptoms (“pooping problems”) and abdominal symptoms (“tummy problems” and 
“tummy pain”) and are as follows: 
• Compared to 7 days ago, my pooping problems today are: 
0  a lot better    
1  a little better  
2  the same  
3  a little worse  
4  a lot worse  
 
 
 


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• Compared to 7 days ago, my tummy problems today are: 
0  a lot better 
1  a little better  
2  the same  
3  a little worse  
4  a lot worse  
• Compared to 7 days ago, my tummy pain today is: 
0  a lot better    
1  a little better  
2  the same  
3  a little worse  
4  a lot worse  
 
Global Severity Items 
The 3 participant-completed global severity items assess self-reported severity of the 
participant’s constipation using the same child-friendly terminology as detailed for the global 
change items above and are as follows: 
• How bad have your pooping problems been over the past 7 days: 
0  I have not had pooping problems  
1  a little bad 
2  bad 
3  very bad 
• How bad have your tummy problems been over the past 7 days: 
0  I have not had tummy problems  
1  a little bad  
2  bad  
3  very bad   
• How bad has your tummy pain been over the past 7 days: 
0  I have not had tummy pain in the past 7 days  
1  a little bad  
2  bad  
3  very bad 
 
 
 
 


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16.3.11 Observer-completed Global Items 
The observer-completed (parents/caregivers) 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 observer-completed global items will be completed weekly on the eDiary device. The 
global severity item will be completed beginning at the Preintervention Period through the EOS 
and the global change item will be completed beginning at Randomization through the EOS. 
Only parents/caregivers of participants 7 to 11 years of age will complete these items. 
Observer-completed Global Change Item 
The observer-completed global change item assesses the change in the child’s IBS-C symptoms 
(1 item) as follows: 
• Compared to 7 days ago, how would you rate your child’s IBS with constipation 
symptoms today? 
o completely relieved 
o considerably relieved 
o somewhat relieved 
o unchanged 
o somewhat worse 
o considerably worse 
o as bad as I can imagine 
 
Observer-completed Global Severity Item 
The observer-completed global severity item assesses the severity of the child’s constipation 
symptoms (1 item) as follows: 
• How would you rate the severity of your child’s IBS with constipation over the past 7 
days? 
o none 
o mild 
o moderate 
o severe 
o very severe 
 
 
 


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16.4 Repeated or Unscheduled Assessments of Safety Parameters 
If a participant has repeated assessments before the start of the first study intervention, the results 
from the final non-missing assessment made prior to the start of the study intervention will be 
used as baseline. If end-of-study assessments are repeated or if unscheduled visits occur, the last 
non-missing postbaseline assessment will be used as the end-of-study assessment for generating 
summary statistics. However, all postbaseline assessments will be used for PCS value 
determinations, and all assessments will be presented in the data listings. 
16.5 Missing Date of the Last Dose of Study Intervention 
When the date of the last dose of study intervention is missing for a participant in the Safety 
Population, all efforts should be made to obtain the date from the Investigator. If after all efforts 
are made it is still missing, the Visit 7 date (if available) -1 will be set as last dose date. In 
absence of the Visit 7 date, the double-blind disposition status date -1 will be set as last dose 
date. 
16.6 Missing Severity Assessment for Adverse Events 
If severity is missing for an AE that started before the date of the first dose of study intervention, 
an intensity of mild will be assigned. If severity is missing for an AE that started on or after the 
date of the first dose of study intervention, an intensity of severe will be assigned. The imputed 
values for severity assessment will be used for the incidence summary; the values will be shown 
as missing in the data listings. 
16.7 Missing Causal Relationship to Study Drug for Adverse Events 
If the causal relationship to the study intervention is missing for an AE that started on or after the 
date of the first dose of study intervention, a causality of yes will be assigned. The imputed 
values for causal relationship to study intervention will be used for the incidence summary; the 
values will be shown as missing in the data listings. 
16.8 Missing Date Information for Adverse Events 
The following imputation rules only apply to cases in which the start date for AEs is incomplete 
(ie, partly missing). 
 
 
 


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Missing month and day 
• If the year of the incomplete start date is the same as the year of the first dose of study 
intervention, the month and day of the first dose of study intervention will be assigned to 
the missing fields 
• If the year of the incomplete start date is before the year of the first dose of study 
intervention, December 31 will be assigned to the missing fields 
• If the year of the incomplete start date is after the year of the first dose of study 
intervention, January 1 will be assigned to the missing fields 
Missing month only 
• If only the month is missing, the day will be treated as missing and both the month and 
the day will be replaced according to the above procedure 
Missing day only 
• If the month and year of the incomplete start date are the same as the month and year of 
the first dose of study intervention, the day of the first dose of study intervention will be 
assigned to the missing day 
• If either the year of the incomplete start date is before the year of the date of the first dose 
of study intervention or if both years are the same but the month of the incomplete start 
date is before the month of the date of the first dose of study intervention, the last day of 
the month will be assigned to the missing day 
• If either the year of the incomplete start date is after the year of the date of the first dose 
of study intervention or if both years are the same but the month of the incomplete start 
date is after the month of the date of the first dose of study intervention, the first day of 
the month will be assigned to the missing day 
 
If the stop date is complete and the imputed start date as above is after the stop date, the start 
date will be imputed by the stop date. 
If the start date is completely missing and the stop date is complete, the following algorithm will 
be used to impute the start date: 
• If the stop date is after the date of the first dose of study intervention, the date of the first 
dose of study intervention will be assigned to the missing start date 
• If the stop date is before the date of the first dose of study intervention, the stop date will 
be assigned to the missing start date 
 
 
 
 


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16.9 Missing Date Information for Prior or Concomitant Medications 
For prior or concomitant medications, including rescue medications, incomplete (ie, partly 
missing) start dates and/or stop dates will be imputed. When the start date and the stop date are 
both incomplete for a participant, the start date will be imputed first. 
16.9.1 Incomplete Start Date 
The following rules will be applied to impute the missing numeric fields for an incomplete prior 
or concomitant medication start date. If the stop date is complete (or imputed) and the imputed 
start date is after the stop date, the start date will be imputed using the stop date. 
Missing month and day 
• If the year of the incomplete start date is the same as the year of the first dose of study 
intervention, the month and day of the first dose of study intervention will be assigned to 
the missing fields 
• If the year of the incomplete start date is before the year of the first dose of study 
intervention, December 31 will be assigned to the missing fields 
• If the year of the incomplete start date is after the year of the first dose of study 
intervention, January 1 will be assigned to the missing fields 
Missing month only 
• If only the month is missing, the day will be treated as missing and both the month and 
the day will be replaced according to the above procedure 
Missing day only 
• If the month and year of the incomplete start date are the same as the month and year of 
the first dose of study intervention, the day of the first dose of study intervention will be 
assigned to the missing day 
• If either the year of the incomplete start date is before the year of the date of the first dose 
of study intervention or if both years are the same but the month of the incomplete start 
date is before the month of the date of the first dose of study intervention, the last day of 
the month will be assigned to the missing day. 
• If either the year of the incomplete start date is after the year of the date of the first dose 
of study intervention or if both years are the same but the month of the incomplete start 
date is after the month of the date of the first dose of study intervention, the first day of 
the month will be assigned to the missing day 
 
 
 
 


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16.9.2 Incomplete Stop Date 
The following rules will be applied to impute the missing numeric fields for an incomplete prior 
or concomitant medication stop date. If the date of the last dose of study intervention is missing, 
impute it as descripted in Section 16.5. If the imputed stop date is before the start date (imputed 
or nonimputed start date), the imputed stop date will be equal to the start date. 
Missing month and day 
• If the year of the incomplete stop date is the same as the year of the last dose of study 
intervention, the month and day of the last dose of study intervention will be assigned to 
the missing fields 
• If the year of the incomplete stop date is before the year of the last dose of study 
intervention, December 31 will be assigned to the missing fields 
• If the year of the incomplete stop date is after the year of the last dose of study 
intervention, January 1 will be assigned to the missing fields 
Missing month only 
• If only the month is missing, the day will be treated as missing and both the month and 
the day will be replaced according to the above procedure 
Missing day only 
• If the month and year of the incomplete stop date are the same as the month and year of 
the last dose of study intervention, the day of the last dose of study intervention will be 
assigned to the missing day 
• If either the year of the incomplete stop date is before the year of the date of the last dose 
of study intervention or if both years are the same but the month of the incomplete stop 
date is before the month of the date of the last dose of study intervention, the last day of 
the month will be assigned to the missing day 
• If either the year of the incomplete stop date is after the year of the date of the last dose of 
study intervention or if both years are the same but the month of the incomplete stop date 
is after the month of the date of the last dose of study intervention, the first day of the 
month will be assigned to the missing day 
 
16.10 Character Values of Clinical Laboratory Parameters 
If the reported value of a clinical laboratory parameter cannot be used in a statistical summary 
table because, for example, a character string is reported for a parameter of the numeric type, a 
 
 
 


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coded value must be appropriately determined for use in the statistical analyses. The actual 
values, however, as reported in the database will be presented in the data listings. 
Table 16-4 shows examples of how some possible laboratory results should be coded for the 
analysis. 
Table 16-4. 
Examples of Coding Special Character Values for Clinical Laboratory 
Parameters 
Laboratory Test, SI Unit 
Possible Laboratory Results 
Coded Value for Analysis 
CHEMISTRY 
ALT, U/L 
< 5 
5 
AST, U/L 
< 5 
5 
Bilirubin, total, μmol/L 
< 2 
2 
URINALYSIS 
Glucose, mmol/L 
= OR > 55, ≥ 55, > 0 
Positive 
≤ 0, negative 
Negative 
pH 
> 8.0, ≥ 8.0 
8.0 
≥ 8.5 
8.5 
Protein 
= OR > 3.0, ≥ 3.0, > 0 
Positive 
≤ 0 
Negative 
ALT  alanine aminotransferase; AST  aspartate aminotransferase; SI  Le Système International d’Unités (International 
System of Units). 
 
 


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17 
Changes To Analyses Specified In Protocol 
The following major changes were made in SAP Amendment #1 to the analyses specified in the 
protocol (version dated June-2020). 
• The frequentist 95% exact binomial CI for the primary endpoint will be presented. 
• A Bayesian 95% credible interval derived from a non-informative prior (a uniform prior) 
distribution will be provided. 
• Added supplemental analyses for the primary endpoint to handle missing data for weekly 
SBM or AP scores. 
• Participants from a non-compliant site will be excluded from the mITT population. 
 
The following major changes have been made in this SAP Amendment #2: 
• Section 6.3: Participants who were incorrectly randomized due to an implementation 
error for adding IBS-C participants in this study by the eDiary vendor will be excluded 
from the mITT population.  
• Section 10.1.2: Added a supplemental analysis to compare the proportion of responders to 
0.18 (the upper bound of the 95% CI of the adult placebo rate) based on a one-sample 
proportion exact test. 
• Section 10.1.2: Removed “Exact binomial” from the sensitivity analysis of multiple 
imputation as the 95% CI will be based on the synthesized results from the 30 imputed 
datasets. 
• Section 11.1: Modified TEAE definition to include any AE that occurs within 30 days 
(instead of 1 day) after the last dose of study intervention.  
 
 
 
 


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18 
References 
Carlin BP and Louis TA. Bayesian Methods for Data Analysis. 2009. Bayesian Design. Chapman 
and Hall/CRC. 
 
 
 


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19 
Appendix 1: Simulation Codes for Bayesian Power Estimates By Sample 
Size and Effective Sample Size 
The specifics of this approach are as follows: 
1. Use the 6/12 weeks APS+2 responder rates from the treated adult subjects to form a prior 
distribution for the pediatric 6/12 weeks APS+2 responder rate. Since this responder rate is 
bounded between [0,1] the prior distribution of responder rate can be approximated by the 
Beta distribution. In this case, 
 
α  (aggregate number of adult responders) and  
 
β  (aggregate number of adult non-responders) 
 
θ~ Beta(α, β) .....................................(1) 
2. Suppose N subjects in LIN-MD-64 and for each θ  Pr(Pediatric subject is a responder), and 
let X be the number of pediatric patients who are responders in LIN-MD-64 then: 
 
X|θ ~ Bi(N, θ)............................... (2)  
3. The posterior distribution is also a Beta distribution: 
 
θ |X ~ Beta(X + α, N  X + β) ........................(3)  
4. Randomly select θj from the prior, and X j from the binomial likelihood for j 1 to M 
simulated trials.  
5. Tally the number of times the 2.5th percentile of the simulated posterior is greater than C, 
where C includes the Placebo responder rate observed in the Adult trials and upper bound of 
95% CI of the Placebo responder rate in the Adult trials. 
6. The proportion, tally/M, is the predictive probability (Bayesian Power) to exceed a rate of C 
with a trial of size N. 
7. To investigate how sensitive the results are to the selection of the prior, we will down-weight 
the prior by multiplying α and β from our prior distribution by w, where (0≤w≤1). This will 
have the effect of allowing the prior to have the same center, but will have heavier tails or 
decreased confidence in the prior distribution. Down-weighting in this manner will allow each 
adult patient to be ‘worth’ the fraction w of a new pediatric patient. An alternative way of 
 
 
 


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expressing this ‘worth’ and describing the impact of the weights would be to describe an 
effective sample size. Effective Sample Size (ESS) is 
calculated as (α + β)*w and is interpreted as the amount of new samples that the adult data will 
be equivalent to in an analysis. 
8. A suitable sample size should have a sufficiently high Bayesian power across a range of 
weights for the prior distribution.  
Here the priors are all of the "weighted" form, ie Beta((adult responder)*w,(adult non-
responder)*w), 0 < w < 1. 
Keep seed as 99; w as 0.017 first and c as 0.16 and 0.18 to generate output as provided in  
Table 14-1 and Table 14-2. 
R-code for Bayesian power estimates: 
 set.seed(99)                     #Seed for reproducibility 
 w <- c(.017)                    #w are the weights, this program can only do one weight per  
                                         #run; run for other ws in Table 14-1 and Table 14-2 
                                         #(w 0.0135, 0.020, 0.027) 
 N <- seq(20,100,10)       #N are your sample sizes in this case from 20 to 100 by 10 
 C<- seq(0.16, 0.18,0.02)         #C is the cut point for determining success 0.16 is the  
                                                  #pooled placebo rate in adult; 0.18 95%UCL of placebo  
                                                  #rate in adult 
Nrep <- 1000                   #Nrep is the number of replicates 
library(tidyr) 
pct <- matrix(0,length(C),length(w)*length(N)+1);  pct[,1] <- C 
#  The adult responder rate DATA: 
no.resp <- 550; resp <- 340 
#  NOW START MAIN SIMULATION LOOPS: 
for(j in 1:length(w)){ 
  alpha <- resp*w[j]                        
  beta <- no.resp*w[j] 
  cb.prior <- rbeta(Nrep,alpha,beta) 
   
 
 
 


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  for(k in 1:length(N)){ 
    cb.x <- rbinom(Nrep,N[k],cb.prior) 
#  HERE IS THE CALCULATION OF THE 2.5TH PERCENTILE OF THE #POSTERIOR: 
    cb.post <- rep(NA,Nrep) 
    cb.post <- qbeta(0.025,cb.x + alpha,N[k] - cb.x + beta) 
     
    cat(paste("\n N  ", N[k], "   w  ", w[j])) 
    for(i in 1:length(C)){ 
      pct[i,1+(j-1)*length(N)+k] <- sum((cb.post > C[i])
T)/Nrep 
      cat(paste("\n Percent of lower .025 points >",C[i]," is",        
                round(pct[i,1+(j-1)*length(N)+k],3))) 
    } 
  }  # end of N[k] loop 
}  # end of w[j] (prior) loop 
#Data manipulations to create the dataframe  
colnames(pct)<-c("Placebo",paste(N[1],"-",w[1]),paste(N[2],"-",w[1]),paste(N[3],"-
",w[1]),paste(N[4],"-",w[1]), 
                 paste(N[5],"-",w[1]),paste(N[6],"-",w[1]),paste(N[7],"-",w[1]),paste(N[8],"-
",w[1]),paste(N[9],"-",w[1])) 
rownames(pct)<-C 
df<-as.data.frame(as.table(pct)) 
# tabulate<-filter(df, Var2 !  "Placebo") 
tabulate<-dplyr::filter(df, Var2 !  "Placebo") 
p<- tabulate %>% separate(Var2, c("SampleSize", "Weight"),sep "-") 
p$SampleSize<-as.factor(p$SampleSize) 
p$SampleSize<- ordered(p$SampleSize, levels  c("20 ", "30 ", "40 ","50 ","60 ","70 ","80 ","90 
","100 ")) 
p$Weight<-as.factor(p$Weight) 
p<- tabulate %>% separate(Var2, c("SampleSize", "Weight"),sep "-") 
p$SampleSize<-as.factor(p$SampleSize) 
p$Weight<-as.factor(p$Weight) 
 
 
 


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LIN-MD-64 Statistical Analysis Plan for FC Participants (Amendment #1)
1.0
TITLE PAGE
LIN-MD-64
A Phase 3, Multicenter, Randomized, Double-blind, Parallel-group, Safety and Efficacy 
Study of Linaclotide in Pediatric Participants, Ages 6 to 17 Years, With Irritable Bowel
Syndrome with Constipation (IBS-C) and of Linaclotide versus Placebo in Pediatric
Participants with Functional Constipation (FC)
STATISTICAL ANALYSIS PLAN - Clinical Study Report
FOR FC PARTICIPANTS
Final:
Amendment #1: 
Confidentiality Statement
This document is the property of Allergan, plc and may notin full or partbe passed on, 
reproduced, published, distributed to any person, or submitted to any regulatory authority 
without the express written permission of Allergan, plc.
  
 
 
 


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2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ........................................................................................................................................... 1
2.0
TABLE OF CONTENTS.......................................................................................................................... 2
2.1
List of Tables.............................................................................................................................. 3
2.2
List of Figures............................................................................................................................. 4
3.0
LIST OF ABBREVIATIONS ................................................................................................................... 5
4.0
INTRODUCTION.................................................................................................................................... 7
5.0
OBJECTIVES ........................................................................................................................................ 11
6.0
PARTICIPANT POPULATIONS ........................................................................................................... 12
6.1
Screened Population.................................................................................................................. 12
6.2
Randomized Population ............................................................................................................ 12
6.3
Modified Intent-to-Treat Population .......................................................................................... 12
6.4
Safety Population...................................................................................................................... 12
7.0
PARTICIPANT DISPOSITION.............................................................................................................. 13
8.0
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ................................................... 14
9.0
EXTENT OF EXPOSURE AND Study Intervention COMPLIANCE...................................................... 15
9.1
Extent of Exposure.................................................................................................................... 15
9.2
Measurement of Study Intervention Compliance........................................................................ 15
9.3
eDiary Compliance ................................................................................................................... 15
10.0
EFFICACY ANALYSES........................................................................................................................ 16
10.1
Primary Efficacy Endpoint........................................................................................................ 17
10.1.1
Main Analysis Approach ............................................................................................. 17
10.1.2
Sensitivity Analysis..................................................................................................... 18
10.1.3
Exploratory Analysis ................................................................................................... 19
10.1.4
Estimand Framework................................................................................................... 19
10.2
Secondary Efficacy Endpoints................................................................................................... 22
10.2.1
Main Analysis Approach ............................................................................................. 22
10.2.2
Sensitivity Analysis..................................................................................................... 22
10.2.3
Exploratory Analysis ................................................................................................... 22
10.2.4
Estimand Framework................................................................................................... 22
10.3
Other Efficacy Endpoints .......................................................................................................... 23
10.4
Subgroup Analysis for Efficacy endpoints ................................................................................. 28
11.0
SAFETY ANALYSES............................................................................................................................ 29
11.1
Adverse Events......................................................................................................................... 29
11.2
Clinical Laboratory Parameters ................................................................................................. 30
11.3
Vital Signs................................................................................................................................ 31
11.4
Electrocardiogram..................................................................................................................... 33
11.5
OTHER SAFETY PARAMETERS........................................................................................... 33
11.5.1
Potential Hy’s Law...................................................................................................... 33
12.0
HEALTH OUTCOMES ANALYSES..................................................................................................... 35
13.0
INTERIM ANALYSIS ........................................................................................................................... 36


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14.0
DETERMINATION OF SAMPLE SIZE................................................................................................. 39
15.0
STATISTICAL SOFTWARE ................................................................................................................. 40
16.0
DATA HANDLING CONVENTIONS ................................................................................................... 41
16.1
Visit Time Windows for Safety Analyses .................................................................................. 41
16.2
Visit Time Windows for Efficacy Analyses ............................................................................... 41
16.3
Derived Variables ..................................................................................................................... 43
16.3.1
Missed Morning/Evening eDiary Assessments............................................................. 43
16.3.2
Incomplete Morning/Evening eDiary Assessments....................................................... 43
16.3.3
Incomplete Clinic Diary on Randomization Visit (If Present) ....................................... 44
16.3.4
Stool frequency ........................................................................................................... 44
16.3.5
Stool Consistency........................................................................................................ 45
16.3.6
Straining ..................................................................................................................... 45
16.3.7
Abdominal Bloating .................................................................................................... 46
16.3.8
Abdominal Pain........................................................................................................... 47
16.3.9
Fecal Incontinence - Daytime ...................................................................................... 48
16.3.10 Participant-completed Global Items ............................................................................. 48
16.3.11 Observer-completed Global Items................................................................................ 49
16.3.12 Modified Rome III Criteria.......................................................................................... 50
16.4
Repeated or Unscheduled Assessments of Safety Parameters ..................................................... 50
16.5
Missing Date of the Last Dose of STudy Intervention ................................................................ 50
16.6
Missing Severity Assessment for Adverse Events ...................................................................... 51
16.7
Missing Causal Relationship to stuDy drug for Adverse Events ................................................. 51
16.8
Missing Date Information for Adverse Events ........................................................................... 51
16.9
Missing Date Information for Prior or Concomitant Medications ............................................... 52
16.9.1
Incomplete Start Date.................................................................................................. 52
16.9.2
Incomplete Stop Date .................................................................................................. 53
16.10
Character Values of Clinical Laboratory Parameters .................................................................. 54
17.0
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL .................................................................... 55
18.0
HISTORY OF CHANGES...................................................................................................................... 56
19.0
REFERENCES....................................................................................................................................... 57
2.1
LIST OF TABLES
Table 4-1
Schedule of Evaluations: Study LIN-MD-64 (FC Participants).............................................. 9
Table 10-1
Sequential Testing Procedure.............................................................................................. 17
Table 11-1
Criteria for Potentially Clinically Significant Laboratory Results......................................... 31
Table 11-2
Criteria for Potentially Clinically Significant Vital Signs..................................................... 32
Table 11-3
Criteria for Potentially Clinically Significant Electrocardiograms........................................ 33
Table 13-1
Summary of Interim Analysis Strategy for FC Participants.................................................. 36
Table 13-2
Different Interim Analysis Scenarios .................................................................................. 38
Table 14-1
Sample Size Assumptions for the Primary Efficacy Endpoint.............................................. 39
Table 16-1
Visit Time Windows .......................................................................................................... 41
Table 16-2
Analysis Time Windows for Efficacy Analysis - Daily Questions........................................ 42
Table 16-3
Analysis Time Windows for Efficacy Analysis - Weekly Questions.................................... 43
Table 16-4
Examples of Coding Special Character Values for Clinical Laboratory Parameters.............. 54


CONFIDENTIAL
Protocol LIN-MD-64
Linaclotide
4
LIN-MD-64 Statistical Analysis Plan for FC Participants (Amendment #1)
2.2
LIST OF FIGURES
Figure 4-1
LIN-MD-64 Study Schema................................................................................................... 8
Figure 13-1
Plot of Type II Error Spending Functiona............................................................................ 37


CONFIDENTIAL
Protocol LIN-MD-64
Linaclotide
5
LIN-MD-64 Statistical Analysis Plan for FC Participants (Amendment #1)
3.0
LIST OF ABBREVIATIONS
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase 
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BM
bowel movement 
CMH
Cochran-Mantel-Haenszel
CP
conditional power
CSBM
complete spontaneous bowel movement
DSMB
Data Safety Monitoring Borad
eCRF
electronic case report form
eDiary
electronic diary
ECG
electrocardiogram, electrocardiographic
EMEA
Europe, the Middle East, and Africa
EOS
End- of- Study
EU
European Union
FC
functional constipation
IA
interim analysis
IBS-C
irritable bowel syndrome with constipation
LLN
lower limit of normal
LSM
least squares mean
MAR
missing at random 
MCMC
Markov Chain Monte Carlo
mITT
modified intent-to-treat 
MMRM
mixed-effects model for repeated measures
NMAR
not missing at random
OC
observed cases
p-BSFS 
pediatric Bristol Stool Form Scale 
PCS
potentially clinically significant
PID
participant identification
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using the Bazett formula (QTcB = QT/(RR)½)
QTcF
QT interval corrected for heart rate using the Fridericia formula (QTcF = QT/(RR)⅓)
RM
rescue medication
SAE
serious adverse event
SAP
statistical analysis plan


CONFIDENTIAL
Protocol LIN-MD-64
Linaclotide
6
LIN-MD-64 Statistical Analysis Plan for FC Participants (Amendment #1)
SBM
spontaneous bowel movement 
SD
standard deviation
SI
Le Système International d’Unités (International System of Units)
TBL
total bilirubin
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
ULN
upper limit of normal


CONFIDENTIAL
Protocol LIN-MD-64
Linaclotide
7
LIN-MD-64 Statistical Analysis Plan for FC Participants (Amendment #1)
4.0
INTRODUCTION
This statistical analysis plan (SAP) provides a more technical and detailed elaboration of the 
statistical analyses of the efficacy and safety data as outlined and/or specified in the final 
protocol of Study LIN-MD-64 (version dated Jun-2020) for functional constipation (FC) 
participants only. Specifications of tables, figures, and data listings for FC participants are 
contained in a separate document.
The statistical analyses of the efficacy and safety for irritable bowel syndrome with constipation 
(IBS-C) participants as specified in amended protocol of LIN-MD-64 (version dated Jun-2020) 
are documented in a separate statistical analysis plan.
The design elements that are only for FC participants in study LIN-MD-64 are discussed in this 
SAP. The FC portion of study LIN-MD-64 is a Phase 3 multicenter, randomized, double-blind, 
placebo-controlled, parallel-group, confirmatory safety and efficacy study comparing linaclotide 
at 72 µg and placebo in pediatric participants, 6 to 17 years of age, with a diagnosis of FC based 
on modified Rome III Child/Adolescent Criteria (ie, who fulfill modified Rome III criteria for 
child/adolescent FC). 
A total of 326 participants with FC are targeted to be randomized in a 1:1 ratio to receive either 
linaclotide 72 µg (163 participants) or placebo (163 participants). The targeted FC participant 
population will include male and female participants. Randomization will be stratified by age 
group only (6 to 11 years of age versus 12 to 17 years of age) with a minimum of 40% of 
participants within each age group. The study aims to enroll approximately 1/3 of the 
participants in the European Union (EU). An optional interim analysis (IA) for futility in the FC 
population may be considered based on the enrollment of FC participants in this study (ie, if the 
rate of enrollment is below expectations). The details related to the planned sample size with the
optional IA are provided in Section 13.0 and Section 14.0.
The study will include a total of 8 visits and will be up to 20 weeks in duration: a 2-to 4-week 
Screening Period, a 2- to 3-week Preintervention Period, followed by a 12-week double-blind 
Study Intervention Period and 1-week Postintervention Period. The raw datasets of study
LIN-MD-64 capture Preintervention Period as Pretreatment Period, Study Intervention Period as
Treatment Period, and Postintervention Period as Posttreatment Period. Participants will not
receive study intervention (i.e. study treatment) during the Screening/Preintervention Period and
the Postintervention Period.
Participants who enter into the open-label long-term safety study, LIN-MD-66, before the 
End-of-Study (EOS) Visit are not required to have the EOS visit in LIN-MD-64.
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, with the exception of the first dose at 
Day 1 (Randomization Visit) when participants will receive linaclotide or placebo in the clinic.
Approximately 140 sites from the United States of America, Canada, Europe, and Middle East 
are expected to participate in the study to enroll FC participants.
Figure 4-1 is the schematic of the study design.




CONFIDENTIAL
Protocol LIN-MD-64
Linaclotide
9
LIN-MD-64 Statistical Analysis Plan for FC Participants (Amendment #1)
Table 4-1
Schedule of Evaluations: Study LIN-MD-64 (FC Participants)
Study Periods 
(Duration)
Screening 
(14-28 
Days)
Preintervention 
(14-21 Days)
Study Intervention Period
(12 weeks)
Postintervention 
(1 week)
Study Visitu
Screening Preintervention
Randomization Week 
2
Week 
4
Week 
8
Week 12 Visit/
End of 
Treatment 
(EOT)a
End of Study 
(EOS) Visit b
Visit Number 
1
2
3
4
5
6
7
8
Study Day 
-49 to -22
-21 to -14
1
15 (± 
2)
29 (± 
2)
57 (± 
2)
85 (+3)c
EOT +7 (+7)
Parent/Caregiver 
Consent/Assentd
X
Inclusion and Exclusion 
Criteria
X
X
X
Rome III Assessment
X
X
Assess Rome IV statuse
X
IWRS 
X
X
Xf
X
X
X
Medical History
X
Lifestyle Modification 
Information Given to 
Participant/Caregiverg
X
Physical Examinationh
X
X
Fecal Impaction 
Assessmenti
X
Xj
Xk
Height
X
X
Vital Signs and Postural 
Vital Signsl
X
X
X
X
X
X
X
X
ECG
X
X
Clinical Laboratory 
Testsm
X
X
X
Serum Pregnancy Testsn
X
Urine Pregnancy Testso
X
X
X 
X
Urine Drug Screenp
X
AE Evaluation
X
X
X
X
X
X
X
X
Prior and Concomitant 
Medications
X
X
X
X
X
X
X
X
Rescue Medication 
Dispensedq
X
X
X
X
X
X
eDiary and Instructions 
Given to 
Participant/Caregiverr
X
eDiary Compliancer
X
X
X
X
X
X
eDiary Eligibility Reportf
X
Study Intervention 
Administered on Sites
X
Study Intervention 
Dispensed
X
X
X
Study Intervention and 
Rescue Medication 
Compliance and 
Accountability
Xs
X
X
X
X
Xt


CONFIDENTIAL
Protocol LIN-MD-64
Linaclotide
10
LIN-MD-64 Statistical Analysis Plan for FC Participants (Amendment #1)
AE = adverse event; ECG = electrocardiogram; eDiary = electronic diary: refers to the participant- or interviewer-administered 
version of the PRO diary on a handheld electronic device; IWRS = interactive Web response system; PRO = patient reported 
outcome.
a.
Study procedures for screening in LIN-MD-66 can be combined with End of Treatment (EOT)/Week 12 Visit (Visit 7) for 
Study LIN-MD-64.
b
Participants who rollover to the long-term safety study, LIN-MD-66, before the EOS Visit (Visit 8) are not required to have 
this visit.
c
Participants must complete at least 12 weeks (84 days) of study intervention before arriving at the study site for the 
EOT/Week 12 Visit (Visit 7). All randomized participants who prematurely discontinue from the study intervention, 
regardless of cause, should complete assessments at this EOT/Week 12 Visit (Visit 7). 
d.
The parent/guardian/legally authorized representative must provide written informed consent and the participant must 
provide assent 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.
e.
Prior to dosing, the investigator or appropriate site staff member will assess if Rome IV criteria for Child/Adolescent FC 
(FC and IBS-C participants) or Rome IV criteria for Child/Adolescent IBS (IBS-C participants) was met and record the 
outcome in the eCRF. Eligibility for the study is not based on this assessment. 
f.
Eligibility report must be run prior to randomization.
g
During the Screening Period, participants and their caregivers will receive information regarding lifestyle modifications 
(refer to Section 5.3 of the protocol. for details). 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.
h.
Physical examinations will be performed by medically qualified site personnel and may be repeated at the investigator’s 
discretion. If fecal impaction (as defined in footnote i) 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.
j
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) (as defined in footnote i above), 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. 
k.
A fecal impaction assessment is performed at the Randomization Visit (Visit 3) after eDiary eligibility is confirmed and 
prior to randomization. If there is no fecal impaction at the Randomization Visit (Visit 3) (as defined in footnote i above), 
the participant is eligible for randomization. If fecal impaction is present upon examination, the participant will not be 
eligible for the study.
l
Vital signs include temperature, respiratory rate, and weight. Postural vital signs (supine and standing) include pulse rate and 
systolic and diastolic blood pressure. At all visits, postural vital signs must be obtained after participants have been in a
supine position for at least 2 to 3 minutes, followed by a standing position for at least 1 minute. Temperature may be 
recorded as oral, rectal or tympanic (ear). If possible, temperature should be obtained using the same method at each visit.
m.
Clinical laboratory tests consist of clinical chemistry, hematology, and urinalysis. All laboratory tests requiring blood draws 
should be collected at the same time.
n.
Serum pregnancy test will be obtained for female participants of childbearing potential. 
o
Urine pregnancy test will be obtained for female participants of childbearing potential. A negative urine pregnancy test is 
required prior to dosing at the Randomization Visit (Visit 3) and prior to study intervention dispensing at Week 4 (Visit 5) 
and Week 8 (Visit 6). 
p
A urine drug screen will be obtained at Screening (Visit 1) for all participants 12 to 17 years of age and only if deemed 
necessary by the investigator for participants 6 to 11 years of age. Urine drug screens may be repeated at the investigator’s 
discretion at any time during the study.
q
Protocol-permitted rescue medication will be dispensed in IWRS where applicable. Participants 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 visit, where available.
r
At the Preintervention Visit (Visit 2), participants and parents/caregivers will be trained on the use of the eDiary device and 
instructed to complete both morning and evening assessments daily. At subsequent visits, study site staff will verify 
participant compliance with the eDiary device and remind participants to complete their morning and evening 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 beginning at Randomization through End-of-Study.
s
Study intervention will be administered at the study site during the Randomization Visit (Visit 3) after running the 
Eligibility report and confirming the participant has fasted for at least 2 hours. 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). 
t.
Protocol-permitted rescue medications only.
u
Additional unscheduled visits may be allowed at the discretion of the investigator with approval from the sponsor. 


CONFIDENTIAL
Protocol LIN-MD-64
Linaclotide
11
LIN-MD-64 Statistical Analysis Plan for FC Participants (Amendment #1)
5.0
OBJECTIVES
For FC participant population, the objective of LIN-MD-64 is to evaluate the safety and efficacy 
of 12 weeks of linaclotide therapy in comparison with placebo in pediatric participants aged 6 to 
17 years who fulfill modified Rome III Criteria for Child/Adolescent FC.


CONFIDENTIAL
Protocol LIN-MD-64
Linaclotide
12
LIN-MD-64 Statistical Analysis Plan for FC Participants (Amendment #1)
6.0
PARTICIPANT POPULATIONS
6.1
SCREENED POPULATION
Screened Population will consist of all participants who undergo the Screening Visit (Visit 1) 
and receive a participant identification (PID) number.
6.2
RANDOMIZED POPULATION
Randomized Population will consist of all participants in the Screened Population who are 
randomized to a study intervention group.
6.3
MODIFIED INTENT-TO-TREAT POPULATION
The Modified Intent-to-Treat (mITT) Population will consist of all participants in the 
Randomized Population who receive at least 1 dose of double-blind study intervention. 
Participants will be summarized according to the randomized study intervention for all efficacy 
analysis variables/endpoints.
6.4
SAFETY POPULATION
The Safety Population will consist of 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 received for all 
safety analysis variables/endpoints. If a participant received study intervention other than 
randomized study intervention, actual study intervention received will be determined based on 
the study intervention received for the majority of the double-blind Study Intervention Period. If 
there is a tie, the higher dose will be considered the actual study intervention for that participant.  
The actual study intervention will be listed for the participants in the listing related to study 
intervention dosing information.


CONFIDENTIAL
Protocol LIN-MD-64
Linaclotide
13
LIN-MD-64 Statistical Analysis Plan for FC Participants (Amendment #1)
7.0
PARTICIPANT DISPOSITION
The number and percentage of participants in 3 study populations (Randomized, mITT, and 
Safety) will be summarized overall, by study intervention group, country, and study center; the 
number of participants screened will be summarized overall, only by country, and study center.
Screen-failure participants (ie, participants who are screened but do not enter into the 
Preintervention Period), participants ineligible for randomization (ie, participants who enter into 
the Preintervention Period but are not randomized at Visit 3, also labeled as preintervention
failures), and the associated reasons for failure as recorded in the electronic case report forms 
(eCRF) will be tabulated overall for all screened participants.
The number and percentage of participants who complete the study, complete the double-blind 
Study Intervention Period, complete the Postintervention Period, prematurely discontinue the 
study, prematurely discontinue the double-blind Study Intervention Period, and prematurely 
discontinue the Postintervention Period will be presented for each study intervention group and 
pooled across study intervention groups for the Randomized Population. The reasons for 
premature discontinuation from the double-blind Study Intervention Period and the 
Postintervention Period as recorded in the eCRF will be summarized (number and percentage) by 
study intervention group for the Randomized Population. All participants who prematurely 
discontinue during the Study Intervention Period or Postintervention period will be listed by 
discontinuation reason for the Randomized Population.
Please note that a participant is considered to have completed the study if he/she has completed 
12 weeks of double-blind study intervention, End-of-Treatment visit, and the EOS visit. 
Participants who rollover to the long-term safety study, LIN-MD-66, before the EOS Visit will 
be considered to have completed the study if he/she has completed 12 weeks of study 
intervention and the End-of-Treatment Visit.


CONFIDENTIAL
Protocol LIN-MD-64
Linaclotide
14
LIN-MD-64 Statistical Analysis Plan for FC Participants (Amendment #1)
8.0
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS
Demographic parameters (age; age group [6-11 and 12-17 years (inclusive)]; race; ethnicity; sex) 
and baseline characteristics (weight; height; and body mass index, calculated as weight 
[kg]/(height [m])2) will be summarized descriptively by study intervention group for the mITT, 
and Safety Populations. The above demographics parameters will also be summarized by age 
group (6-11 and 12-17 years (inclusive)) within the Safety Population.
Other baseline characteristics (including efficacy parameters related to the bowel habits and 
symptoms as discussed in Section 10.0) will be summarized descriptively by study intervention
group for the mITT Population.
Continuous variables will be summarized by number of participants, mean, standard deviation 
(SD), median, minimum, and maximum values. Categorical variables will be summarized by 
number and percentage of participants.
Abnormalities in participants’ medical and surgical histories will be coded using the Medical 
Dictionary for Regulatory Activities, version 23.0 or newer. The number and percentage of 
participants with abnormalities in medical and surgical histories in each system organ class and 
preferred term will be summarized by study intervention group for the Safety Population.
Prior medication is defined as any medication 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 prior medications stopped more than 30 days before the 
date of the first dose of study intervention and any concomitant medications started after the date 
of the last dose of study intervention will not be presented in the summary tables but will be 
included in the participant data listings.
Both prior and concomitant medications will be coded by drug name and therapeutic class. The 
use of prior and concomitant medications will be summarized by the number and percentage of 
participants in each study intervention group for the Safety Population. If a participant took a 
specific medication multiple times or took multiple medications within a specific therapeutic 
class, that participant would be counted only once for the coded drug name or therapeutic class.
The World Health Organization (WHO) Drug Dictionary, version Global B3 March 2020 or 
newer, will be used to classify prior and concomitant medications by therapeutic class and drug 
name.
Unique participants reporting significant protocol deviations will be summarized in total and by 
study intervention group for the Randomized Population.


CONFIDENTIAL
Protocol LIN-MD-64
Linaclotide
15
LIN-MD-64 Statistical Analysis Plan for FC Participants (Amendment #1)
9.0
EXTENT OF EXPOSURE AND STUDY INTERVENTION COMPLIANCE
9.1
EXTENT OF EXPOSURE
Exposure to the study intervention for the Safety Population during the double-blind Study 
Intervention Period will be summarized for study intervention duration, calculated as the number 
of days from the date of the first dose of study intervention to the date of the last dose of study 
intervention, inclusive. Descriptive statistics (number of participants, mean, SD, median, 
minimum, and maximum) will be presented by study intervention group.
Patient-years, defined as exposure to the study intervention in years, will be summarized by 
study intervention for the Safety Population.
9.2
MEASUREMENT OF STUDY INTERVENTION COMPLIANCE
Dosing compliance for the double-blind Intervention Period is defined as number of capsules 
actually taken by a participant during that period divided by the number of capsules prescribed 
for that period multiplied by 100. This information will be obtained from the study intervention
record of the participant’s eCRF.
The number of capsules expected to be taken for the double-blind Intervention Period will be 
calculated by multiplying the number of days in that period by the number of capsules to be 
taken per day. Descriptive statistics for study intervention compliance will be presented by study 
intervention group between 2 consecutive visits, as well as for the whole double-blind 
Intervention Period for the Safety Population.
9.3
EDIARY COMPLIANCE
Participants will complete the electronic diary (eDiary) twice daily, once in the morning and 
once in the evening. Participant’s eDiary compliance will be assessed based on the number of 
days with fully completed morning and evening assessments in a specific period. Morning or 
evening assessments will be considered fully completed if the participant responded to each 
question in the corresponding morning or evening eDiary. eDiary compliance will be 
summarized for the Preintervention Period, double-blind Intervention Period, Postintervention
Period, and for each week within each period based on the mITT Population.
Compliance for each participant/interval will be calculated using the following formula:
%	
 = 100 ∗ #   
ℎ 		 	 
   !
  
 
 
ℎ
 ℎ 
!	
#  "  
ℎ
 ℎ 
!	
On randomization day, the morning diary and/or clinic diary will be included in Preintervention
Period and the evening diary will be included in the double-blind Intervention Period. On the day 
after last dose date, the morning diary will be included in the double-blind Intervention Period
and the evening diary will be included in the Postintervention Period.


CONFIDENTIAL
Protocol LIN-MD-64
Linaclotide
16
LIN-MD-64 Statistical Analysis Plan for FC Participants (Amendment #1)
10.0
EFFICACY ANALYSES
The efficacy analyses will be based on the mITT Population.
Baseline values for efficacy endpoints related to daily eDiary responses will be derived from the 
eDiary in the Preintervention Period, specifically the time period from 14 days before 
randomization up to the time of randomization.
A SBM is a BM that occurs in the absence of laxative, suppository, or enema use on the calendar 
day of the BM or the calendar day before the BM. A complete spontaneous bowel movement 
(CSBM) is an SBM that is associated with a sense of complete evacuation.
The baseline SBM and CSBM weekly rates, stool consistency, straining, and abdominal 
symptoms (abdominal pain and bloating) will be derived as discussed in Section 16.3 from
14 days prior to randomization and up to randomization (as appropriate). A participant’s baseline 
stool consistency and straining cannot be assessed if the participant does not have at least 1 SBM 
during the Preintervention Period. For participants who report no SBMs during a study period, 
the stool consistency and straining assessments will be considered missing for that study period 
in the analyses. Participants with missing baseline stool consistency and straining will be 
excluded from the respective stool consistency and straining analyses that involve change from 
baseline.
Baseline value for the participant-completed global change and severity items, and observer 
completed global change and severity items, will be based on the last non-missing assessment on 
or before the date of first dose of study intervention.
An observed-cases (OC) approach to missing postbaseline data will be applied. Sensitivity 
analyses to handle missing data are planned for only primary and secondary efficacy endpoints
and details are provided in Sections 10.1.2 and 10.2.2 for primary and secondary endpoints 
respectively.
All statistical tests will be 2-sided at 5% level of significance. All confidence intervals will be 
2-sided 95% confidence intervals, unless stated otherwise.
Multiplicity adjustment for the overall Type 1 error rate will be based on primary and secondary 
endpoints. The overall Type 1 family-wise error rate for testing the primary and secondary 
efficacy endpoints will be controlled at the 5% level of significance (2-sided) using a sequential 
testing procedure as stated in Table 10-1.


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Protocol LIN-MD-64
Linaclotide
17
LIN-MD-64 Statistical Analysis Plan for FC Participants (Amendment #1)
Table 10-1
Sequential Testing Procedure
Step 1 Primary Endpoint: Change from baseline 
in 12-week SBM frequency rate (SBMs/week) 
during Study Intervention Period
Compare the linaclotide 72 µg dose versus placebo 
for the primary efficacy endpoint.

If superiority is demonstrated over placebo 
at alpha=0.05 (2-sided), proceed to Step 2.

Otherwise stop.
Step 2 Secondary Endpoint:  Change from 
baseline in 12-week stool consistency during Study 
Intervention Period 
Compare the linaclotide 72 µg dose versus placebo 
for the secondary efficacy endpoint.

Stop
Nominal p-values will be provided for the other efficacy endpoints as discussed in Section 10.3.
Depending on the enrollment status for FC participants in this study, an interim analysis (IA) for 
futility may be considered (details in Section 13.0). A futility check in this IA (when performed) 
will be performed based on the pre-selected non-binding futility boundary. Following a 
conservative approach, the final analysis will be performed at a slightly reduced alpha level of 
0.049 (2-sided) in case this futility IA is conducted. The optional futility IA at 50% information 
is not planned to stop the study for efficacy.
10.1
PRIMARY EFFICACY ENDPOINT
The primary efficacy endpoint is the change from baseline in 12-week SBM frequency rate 
(SBMs/week) during the Study Intervention Period. The SBM frequency rate per week during 
the Study Intervention Period will be derived based on the total number of SBMs a participant 
reported during this period in the morning and evening assessments on the eDiary. The details of 
the derivation of this efficacy endpoint are provided in Section 16.3.4.
10.1.1
Main Analysis Approach
The statistical null hypothesis for the primary endpoint is as follows: linaclotide 72 ug is the 
same as placebo with respect to the primary efficacy analysis endpoint. This hypothesis will be 
tested using an analysis of covariance (ANCOVA) model with study intervention, age group (6-
11 years of age and 12-17 years of age) as fixed factors and baseline value as a covariate. Least 
squares means (LSMs) for each study intervention group, difference in LSMs between 
linaclotide versus placebo, associated 2-sided 95% CI for these difference in LSMs, and the 
corresponding statistical test p-value will be reported. 
Missing BM response and rescue medication response will be imputed as discussed in 
Section 16.3.2 unless mentioned specifically for sensitivity analyses.


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Protocol LIN-MD-64
Linaclotide
18
LIN-MD-64 Statistical Analysis Plan for FC Participants (Amendment #1)
10.1.2
Sensitivity Analysis
Three sensitivity analyses will be performed to assess the robustness of ANCOVA based on an 
OC approach.
Sensitivity Analysis 1: Under the Assumption of Missing at Random (MAR)
In this sensitivity analysis, participants need to complete all daily questions in both morning and 
evening diaries to have a complete diary day. If participant had either missing morning and/or 
evening diary on the same day, the diary day will be considered missing. If participant has less 
than 4 completed diary days (with both morning and evening diaries) in a postbaseline week 
during the Study Intervention Period, the corresponding postbaseline week value will be 
considered missing for that participant.
In this first sensitivity analysis to handle missing data in the nature of MAR, change from 
baseline in SBM frequency rate/week will be analyzed using a mixed effect model for repeated 
measures (MMRM) with study intervention, week, age group (6-11 years of age and 12-17 years 
of age), and study intervention-by-week interaction as fixed effects and baseline value as a 
covariate. All 12 weeks’ data will be included in the MMRM model. The study intervention 
comparison between linaclotide group and placebo group for change from baseline in 12-week 
SBM frequency rate (SBM/week) during the Study Intervention Period will be estimated from 
the MMRM model. An unstructured covariance matrix will be used to model the covariance of 
within-participant results. The Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom (Kenward and Roger 1997).
Sensitivity Analysis 2: Under the Assumption of Not Missing at Random (NMAR)
In this sensitivity analysis, postbaseline week value will be left missing as discussed in first 
sensitivity analysis if participant has less than 4 completed diary days (with both morning and 
evening diaries) in a postbaseline week during the Study Intervention Period. In this second 
sensitivity analysis to handle missing data with NMAR, a missing postbaseline week during the 
Intervention Period will be imputed using the pattern-mixture model with control-based pattern 
imputation of Ratitch and O’Kelly (2011).

Intermittent (non-monotone) missing data in both study intervention groups are imputed 
using the MCMC method under the MAR assumption.

Remaining monotone missing data are imputed using a pattern-mixture model approach 
using a sequential regression imputation model estimated based on data from the placebo 
arm only.


CONFIDENTIAL
Protocol LIN-MD-64
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LIN-MD-64 Statistical Analysis Plan for FC Participants (Amendment #1)
Fifty imputed datasets will be generated. Based on each imputed dataset, change from baseline in 
SBM frequency rate/week will be analyzed using the MMRM model as discussed in the first 
sensitivity analysis. Model based estimates within each study intervention group and between 
study intervention comparison will be obtained for change from baseline in 12-week SBM 
frequency rate with each imputed dataset. The estimates will be combined using standard 
multiple imputation analysis techniques (via Proc MIANLYZE in SAS Version 9.4 or newer) to 
provide a single within group estimate, the single estimate of difference between linaclotide and 
placebo, associated 95% CI and p-value for linaclotide versus placebo comparison. Each imputed 
dataset will be provided in the listing.
Sensitivity Analysis 3: Imputing Missing Data With Worst Response
The third sensitivity analysis will be conducted imputing the postbaseline missing daily data
during Intervention Period in the specific diary with the worst response for SBM (i.e. assuming 
‘0’ frequency for missing BM response and assuming ‘Yes’ response for missing rescue
medication use). Based on this imputed data, the primary efficacy endpoint will be analyzed 
using the ANCOVA model in a similar way as discussed in the main analysis approach.
10.1.3
Exploratory Analysis 
Study intervention-by-age group interaction will be investigated as an exploratory analysis using 
ANCOVA with study intervention, age group, study intervention-by-age group as fixed factors 
and baseline value as a covariate to assess whether the effects of study intervention on primary 
endpoint are consistent across age groups.
Cumulative distribution function plots will also be provided for the primary endpoint by study 
intervention group. A by-week summary of the primary endpoint will be provided by study 
intervention group.
10.1.4
Estimand Framework
10.1.4.1
Main Analysis Approach
Population
The target population is participants with FC, ages 6-17 years old, satisfying the inclusion and 
exclusion criteria as specified in Sections 5.1 and 5.2 of the protocol, respectively. The analysis 
population is mITT as discussed in Section 6.3.
Variable
The variable is the change from baseline in the participant’s 12-week SBM frequency rate 
(SBMs/week) during the Study Intervention Period as derived from the twice daily eDiary 
(morning and evening).


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Accounting for Intercurrent Events
Intercurrent events and their handling rules are as follows:

The BMs for the participants who took a laxative, enema, or suppository on the calendar 
day of the BM or the calendar day before the BM will not be considered as SBMs for the 
analysis.

Participants who discontinue prematurely during but prior to the completion of the 
double-blind Study Intervention Period will have their eDiary data included up to the 
morning diary following the last dose date for primary endpoint. SBM frequency rate 
based on included eDiary data up to morning diary after last dose date will be considered 
equivalent to the 12-week SBM frequency rate.

Participants with any intermediate missing diary data during the 12-week study 
intervention period will have their data included as observed. The SBM frequency rate 
(SBMs/week) will be calculated based on the available data (as discussed in 
Section 16.3.4) and this SBM frequency rate will be considered to be equivalent to the 
rate over the 12-week study intervention period.
Population-level Summary
The population-level summary for the primary endpoint is the difference in primary variable 
means between the linaclotide dose arm and placebo based on difference in LSMs from the 
ANCOVA model in main analysis approach (Section 10.1.1).
10.1.4.2
Sensitivity Analysis 1: Under the Assumption of MAR
Population and variable will be same as discussed for main analysis approach.
Accounting for Intercurrent Events
Intercurrent events and their handling rules are as follows:

Presence of rescue medication will be handled in the same way as discussed for main 
analysis approach. 

For any postbaseline analysis week, if participant has less than 4 completed diary days 
(i.e. a completed diary day means completed both morning and evening diaries in a day) 
in an analysis week, participant’s corresponding week’s response will be considered 
missing. 
Population-level Summary
The population-level summary for the primary endpoint is the difference in primary variable 
means between the linaclotide dose arm and placebo based on estimated difference between 
intervention groups during the 12-week study intervention period from the MMRM model as 
discussed in Section 10.1.2 for the first sensitivity analysis.


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10.1.4.3
Sensitivity Analysis 2: Under the Assumption of NMAR
Population and variable will be same as discussed for main analysis approach.
Accounting for Intercurrent Events
Intercurrent events and their handling rules are as follows:

Presence of rescue medication will be handled in the same way as discussed for main 
analysis approach. 

For any postbaseline analysis week, if participant has less than 4 completed diary days 
(i.e. completed both morning and evening diaries) in an analysis week, participant’s 
corresponding week’s analysis value will be considered missing and the postbaseline
missing week during the intervention period will be imputed using the pattern mixture 
model with control-based pattern imputation.
Population-level Summary
The population-level summary for the primary endpoint is the difference in primary variable 
means between the linaclotide and placebo based on combined estimate using multiple 
imputation techniques, where each estimate for the difference between the linaclotide and 
placebo will be estimated from each imputed data using MMRM model as discussed in 
Section 10.1.2.
10.1.4.4
Sensitivity Analysis 3: Imputing Missing Data With Worst Response
Population and variable will be same as discussed for main analysis approach.
Accounting for Intercurrent Events
Intercurrent events and their handling rules are as follows:

Presence of rescue medication will be handled in the same way as discussed for main 
analysis approach. 

If the response to the question of rescue medication usage is missing during postbaseline, 
any missing response during Study Intervention Period will be imputed with ‘yes’ 
response (i.e. participant took medicine to help poop, other than the study medicine 
during the specific diary period). 

Data for early discontinued participants will be handled in the same way as discussed for 
main analysis approach. 
Population-level Summary
The population level summary will be handled in the same way using ANCOVA model as 
discussed for main analysis approach.


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10.2
SECONDARY EFFICACY ENDPOINTS
There is only one secondary efficacy endpoint in this study, which is change from baseline in 
12-week stool consistency during the Study Intervention Period. The details of the derivation of 
this efficacy endpoint are provided in Section 16.3.5.
10.2.1
Main Analysis Approach
The statistical null hypothesis for the secondary endpoint is as follows: linaclotide 72 ug is the 
same as placebo with respect to the secondary efficacy analysis endpoint. This hypothesis will be 
tested using the same ANCOVA model as for the primary endpoint in main analysis approach. 
LSMs for each study intervention group, difference in LSMs between linaclotide group versus 
placebo, associated 2-sided 95% CI for this difference in LSMs, and the corresponding statistical 
test p-value will be reported. 
10.2.2
Sensitivity Analysis
The sensitivity analyses with MMRM (MAR) and worst response imputation with ANCOVA 
model as discussed for primary efficacy endpoint will also be performed for secondary efficacy 
endpoint. The worst response imputation of missing postbaseline stool consistency response 
during Study Intervention Period is discussed in Section 10.2.4 (at accounting for intercurrent 
events). 
10.2.3
Exploratory Analysis
Study intervention-by-age group interaction will be investigated as an exploratory analysis using 
the ANCOVA with study intervention, age group, study intervention-by-age group as fixed 
factors and baseline value as a covariate to assess whether the effects of study intervention on 
secondary endpoint are consistent across age groups.
Cumulative distribution function plots will also be provided for the secondary efficacy endpoint 
by study intervention group.
By-week summary of the secondary endpoint will be provided by study intervention group.
10.2.4
Estimand Framework
Population
The population is similar to that for the primary endpoint. However, only participants with both 
baseline and at least one postbaseline stool consistency value from SBM during the Study 
Intervention Period will be included. 
Variable
The variable is the change from baseline in the participant’s 12-week stool consistency during 
the Study Intervention Period as derived from the twice daily eDiary (morning and evening).


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Accounting for Intercurrent Events
Handling of intercurrent events will be similar to primary endpoint as discussed for the main 
analysis approach and first (MAR) sensitivity analysis.
In the second sensitivity analysis of imputing the missing data with worst response, missing 
postbaseline stool consistency value for SBM during Study Intervention Period will be imputed 
as Type 1 (looks like small hard lumps or balls, like pebbles).
Population Level Summary
Difference in means for secondary endpoint between linaclotide and placebo will be based on the 
following:

Main Analysis Approach: Based on difference in LSMs from ANCOVA model

Sensitivity Analysis 1 (MAR): Based on estimated difference from MMRM model in 
sensitivity analysis with MAR

Sensitivity Analysis 2 (worst response imputation): Based on difference in LSMs from 
ANCOVA model 
10.3
OTHER EFFICACY ENDPOINTS
The other efficacy endpoints are as follows:

Overall SBM responders during the Study Intervention Period

Weekly SBM + 2 responder during the Study Intervention Period

Change from baseline in 12-week CSBM frequency rate (CSBMs/week) during the Study 
Intervention Period

Change from baseline in 12-week abdominal pain (daytime, nighttime, and combined 
daytime and nighttime symptoms) during the Study Intervention Period

Proportion of days with daytime fecal incontinence during the Study Intervention Period

Change from baseline in 12-week straining during the Study Intervention Period

Change from baseline in 12-week abdominal bloating (daytime, nighttime, and combined 
daytime and nighttime symptoms) during the Study Intervention Period

Proportion of participants with an SBM within 24 hours after the first dose of study 
intervention

Proportion of participants with an SBM within 48 hours after the first dose of study 
intervention


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
Time to the first report of SBM after the first dose of study intervention

Proportion of participants with an increase in rescue medicine or any other laxative, 
suppository, or enema use during 12-week Study Intervention Period

Proportion of participants who report using rescue medicines or any other laxatives, 
suppositories, or enemas during 12-week Study Intervention Period

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 participant-completed 
global change items (pooping problems and tummy problems) at each week during Study 
Intervention Period

Proportion of participants with each individual item score for the participant-completed 
global severity items (pooping problems and tummy problems) at each week during 
Study Intervention Period

Change from baseline in participant-completed global severity items (pooping problems 
and tummy problems) at each week during Study Intervention Period

Proportion of participants with each individual item score for the observer completed 
global change item and global severity item at each week during Study Intervention 
Period (collected for age group of 6-11 years only)
Overall SBM Responders During the Study Intervention Period
Overall SBM responders are defined as participants who have a change from baseline of 
≥2 SBMs/week in the 12-week SBM frequency rate over the Intervention Period.
The above response threshold of at least 2-point change from baseline in 12-week SBM 
frequency rate (SBMs/week) to define the overall SBM responder may be revisited before 
unblinding based on the findings of blinded psychometric analysis to determine within 
participant clinically meaningful change. If this is the case, the revised response threshold will be 
documented in a SAP amendment.
To be qualified for an overall SBM responder, a participant must also meet the following
conditions simultaneously:

At least 4 weeks of study intervention duration,

At least 48 completed diary days during the 12-week Study Intervention Period, and

At least 4 completed diary days per analysis week in the last 4 intervention weeks


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LIN-MD-64 Statistical Analysis Plan for FC Participants (Amendment #1)
The participant needs to fill out both morning and evening diary on the same day to have a 
completed diary day.
The proportion of responders in the linaclotide group will be compared with the proportion in the 
placebo group using a CMH test controlling for age group (6 - 11 years of age versus
12 - 17 years of age). Participants who are not assessable for the responder parameters due to 
missing information are considered non-responders. The number and percentage of responders 
for each study intervention group, the difference in responder rates between the linaclotide group 
and the placebo group, the corresponding 95% confidence interval, Mantel-Haenszel based odds 
ratio and corresponding 95% confidence interval, and the 2-sided p-value associated with the 
CMH tests will be presented.
Weekly SBM + 2 Responder During the Study Intervention Period
For any week in the study intervention period, a weekly SBM + 2 responder is a participant who 
has an SBM increase ≥ 2 in the SBM weekly rate from baseline for that week. For the analysis 
week, if a participant did not have at least 4 full days (with both completed morning and evening 
diaries) of diary entries, the participant will not be considered a weekly SBM + 2 responder for 
that corresponding week.
The threshold of at least 2 to define the weekly SBM responder may be revisited before 
unblinding based on the findings of blinded psychometric analysis to determine within 
participant clinical meaningful change. If this is the case, the revised response threshold will be 
documented in a SAP amendment.
This responder endpoint will be analyzed in a similar way as discussed for the Overall SBM 
Responders endpoint.
Change From Baseline in Other Efficacy Endpoints Related to Bowel Habits and 
Abdominal Symptoms
The derivations of 12-week CSBM frequency rate (CSBMs/week), abdominal pain (daytime, 
nighttime, and combined daytime and nighttime symptoms), straining, and abdominal bloating 
(daytime, nighttime, and combined daytime and nighttime symptoms) during the Study 
Intervention Period are discussed in details from Sections 16.3.4 to 16.3.8.
For change from baseline in 12-week CSBM frequency rate (CSBMs/week), 12-week abdominal 
pain (daytime, nighttime, and combined daytime and nighttime symptoms), 12-week straining, 
and 12-week abdominal bloating (daytime, nighttime, and combined daytime and nighttime 
symptoms), the linaclotide group will be compared to the placebo group using the same 
ANCOVA model as discussed for primary endpoint in main analysis approach (Section 10.1.1).
Cumulative distribution function plots will also be provided for the change from baseline other 
efficacy endpoints by study intervention group.
By-week summary of the other efficacy endpoints will be provided by study intervention group.


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Proportion of Days with Daytime Fecal Incontinence During the Study Intervention Period 
Fecal incontinence will be collected daily in the evening eDiary. Participants are asked a 
question (as discussed in Section 16.3.9) regarding episodes of fecal incontinence in the evening 
diary. A "yes" response to that question will be counted as presence of daytime fecal 
incontinence in the corresponding day. The proportion of days with daytime fecal incontinence 
during the Study Intervention Period will be derived based on number of non-missing reported 
days with fecal incontinence responses during the Study Intervention Period in the denominator.
Descriptive statistics (mean, median, SD, standard error of mean, minimum, and maximum) by 
study intervention group will be provided.
Proportion of Participants with an SBM within 24 Hours of First Dose of Study 
Intervention
A participant is a 24-hour responder if the participant has at least 1 SBM within 24 hours of first 
dosing of study intervention. Any SBM reported in the evening diary on randomization day and 
in the morning diary at the day after first dose date (i.e., Day 2) will be considered a SBM within 
24 hours. The proportion of responders will be analyzed in a similar way as discussed earlier for 
SBM responder endpoints.
Proportion of Participants with an SBM within 48 hours of First Dose of Study 
Intervention
A participant is a 48-hour responder if the participant has at least 1 SBM within 48 hours of first 
dosing of study intervention. Any SBM reported from the evening diary on randomization day to 
the morning diary on the second day after first dose date (i.e., Day 3) will be considered a SBM 
within 48 hours. The proportion of responders will be analyzed in a similar way as discussed 
earlier for SBM responder endpoints.
Time to First Report of SBM After the First Dose of Study Intervention
Time to first report of SBM after the first dose of study intervention (i.e. time to diary reporting 
with first SBM) is defined as the number of hours elapsed from the first dose of study 
intervention taken to the diary reporting time with the first SBM. Reporting may not occur in real 
time; first eDiary reporting will be approximately within 12 hours after the first dose with all 
subsequent reports occurring in 12-hour spans twice daily (morning and evening) Participants 
who do not achieve an SBM during the Intervention Period will be considered censored, with the 
censoring time defined as number of hours elapsing from the first dose of study intervention 
taken to 11:59 AM (morning diary end period) on the day after last dose date. 


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Proportion of Participants With an Increase in Rescue Medicine or Any Other Laxatives, 
Suppositories, or Enema Use During 12-week Study Intervention Period
The proportion of participants who have an increase from baseline in the percentage of days 
using rescue medicine or any other laxatives, suppositories, or enemas in the linaclotide dose 
group during the 12-week Intervention Period will be compared to the proportion in the placebo 
group using a CMH test controlling for age group. The number and percentage of responders for 
each study intervention group, the difference in responder rates between the linaclotide group 
and the placebo group, the corresponding 95% confidence interval, Mantel-Haenszel -based odds 
ratio and corresponding 95% confidence interval, and the 2-sided p-value associated with the 
CMH tests will be presented. 
Proportion of Participants Who Report Using Rescue Medicines or Any Other Laxative, 
Suppositories, or Enema During 12-week Study Intervention Period 
The proportion of participants who report using rescue medicines or any other laxative, 
suppositories, or enemas during the Study Intervention Period in the linaclotide group will be 
compared with the proportion in the placebo group using a CMH test controlling for age group. 
The similar analyses as discussed for the proportion of participants with an increase in rescue 
medicine or any other laxatives, suppositories, or enema use will be provided by study 
intervention group.
Participant-Completed Global Change Items and Global Severity Items at Each Week 
During Study Intervention Period
The details of participant-completed global change item scores and global severity item scores 
are discussed in Section 16.3.10. For each of the participant-completed global change items 
(pooping problems and tummy problems) and global severity items (pooping problems and 
tummy problems), study intervention comparison (linaclotide versus placebo) will be performed 
using a CMH test, controlling for age group at each week after randomization during the Study
Intervention Period. Counts and percentages for each category within each individual item will 
be provided by study intervention group.
Change from baseline in the participant-completed global severity items (pooping problems and 
tummy problems) at each post baseline week during the Study Intervention Period will also be 
analyzed using the same ANCOVA model as discussed for primary endpoint in main analysis
approach (Section 10.1.1).
Observer-Completed Global Change Item and Global Severity Item at Each Week During 
Study Intervention Period
The observer-completed global change item and global severity item will be assessed on a 
weekly basis in the eDiary, for the 6 - 11 years of age group only as discussed in Section 16.3.11. 
Summary statistics of observer-completed global items will be provided by study intervention 
group in the 6 - 11 years of age group at each week during the Study Intervention Period. Counts
and percentages for each category of global change item and global severity item will be 
provided by study intervention group.


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Proportion of Participants Who No Longer Fulfill Modified Rome III Criteria for FC at 
the End of the Study Intervention Period
The details of the derivation of this endpoint are discussed in Section 16.3.12. The proportion of 
participants who no longer fulfill modified Rome III criteria for FC at the end of the study 
intervention period will be presented by study intervention group.
10.4
SUBGROUP ANALYSIS FOR EFFICACY ENDPOINTS
Primary and secondary efficacy endpoints will be analyzed in a similar way as discussed for 
main analysis approach (except age not included as factor in the model for age subgroup 
analyses) for the following subgroups (within each subgroup category) based on the mITT 
Population if sample size allows.

Age group (6-11 years group, 12-17 years group) 

Region (North American, EU, and Other), 

Race (white, non-white), 

Gender (male, female)
Due to the reduction in the number of participants included in analyses of subgroups, p-values
will not be reported in the presentations of results obtained in subgroup analyses. Subgroups will 
be interpreted with caution due to limited sample size within each subgroup category.


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11.0
SAFETY ANALYSES
The safety analysis will be performed using the Safety Population. The safety parameters will 
include adverse events (AEs) and clinical laboratory parameters, vital sign (including postural), 
electrocardiographic (ECG) parameters, height, and weight. For each safety parameter of the 
clinical laboratory, vital signs, height, weight, and ECG parameters, the last non-missing safety 
assessment before the first dose of study intervention will be used as the baseline for all analyses 
of that safety parameter. Continuous variables will be summarized by number of participants and 
mean, SD, median, minimum, and maximum values. Categorical variables will be summarized 
by number and percentage of participants. The safety summaries will be provided by study 
intervention group. 
11.1
ADVERSE EVENTS
Adverse events will be coded by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities, version 23.0 or newer.
An AE will be considered a treatment-emergent adverse event (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 30 days after the last dose of study intervention will not be counted 
as a TEAE. 
An AE will be considered a treatment-emergent serious adverse event (TESAE) if it is a TEAE 
that additionally meets any SAE criterion. 
The number and percentage of participants reporting TEAEs in each study intervention group 
will be tabulated by descending percentage in any group, by system organ class and preferred 
term, and further categorized by severity and causal relationship to the study intervention. 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 greatest severity and strictest causality for 
the summarization by severity and causal relationship. The above summaries of TEAEs, further 
categorized by severity and causal relationship will also be provided within each age group. If 
there are 5 or less participants with severe or related TEAEs in any study intervention group, the 
corresponding age group summaries for TEAEs by severity or causal relationship will not be 
provided. 
The incidence of common (≥5% of participants in any study intervention group) TEAEs will be 
summarized by system organ class, preferred term, and study intervention group. 
Summary tables will be provided for participants with TESAEs, AEs of special interest, and 
participants with TEAEs leading to premature discontinuation of study intervention. 


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For the Safety Population, separate listings will be presented for participants who died, 
participants with SAEs, participants with AEs leading to premature discontinuation, and 
participants with AEs of special interest. AEs during the Postintervention Period will also be 
included in the listings. Listing of all AEs will also be presented.
11.2
CLINICAL LABORATORY PARAMETERS
Descriptive statistics for clinical laboratory values (in International System of Units [SI] units) 
and changes from the baseline values at each assessment time point will be presented by study 
intervention group for the following laboratory parameters: 
Hematology:
Absolute and differential white blood cell count, erythrocyte count, 
hemoglobin, hematocrit, platelet count, red blood cell count, and red blood 
cell indices (mean corpuscular volume, mean corpuscular hemoglobin, and 
mean corpuscular hemoglobin concentration)
Chemistry:
Sodium, potassium, calcium, chloride, bicarbonate, magnesium, phosphate, 
glucose, blood urea nitrogen, creatinine, total protein, alkaline phosphatase
(ALP), albumin, total bilirubin (TBL), alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), total cholesterol
Urinalysis:
Specific gravity and pH
Clinical laboratory test values will be considered potentially clinically significant (PCS) if they 
meet either the lower-limit or higher-limit PCS criteria listed in Table 11-1. The number and 
percentage of participants who have PCS postbaseline clinical laboratory values will be tabulated 
by study intervention for the double-blind Intervention Period. The percentages will be
calculated relative to the number of participants with available non-PCS baseline values and at 
least 1 postbaseline assessment for the double-blind Intervention Period. The numerator will be
the total number of participants with available non-PCS baseline values and at least 1 PCS 
postbaseline value for the double-blind Intervention Period. A supportive tabular display of 
participants with PCS postbaseline values will be provided, including the PID number, baseline 
and all postbaseline (including non-PCS) values. In this listing, any participant with PCS value 
(if any) during the Post-intervention period will also be included.
In addition, a tabular display showing all AEs that occurred in participants who had PCS 
postbaseline clinical laboratory values will be provided.
Shift tables from baseline to the end of double-blind Intervention Period for clinical laboratory 
parameters listed above will be presented by study intervention group for the following 
categories: low, normal, and high, which are provided by lab vendor.


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Table 11-1
Criteria for Potentially Clinically Significant Laboratory Results
Parameter
SI Unit
Lower Limit
Higher Limit
CHEMISTRY
Albumin
g/L
< 0.9 × LLN
> 1.1 × ULN
Alanine aminotransferase (ALT)
U/L
—
≥ 3 × ULN
Alkaline phosphatase
U/L
—
≥1.2 x ULN: 6-12 (inclusive),
male & female;
13-15 (inclusive), male
≥ 3 × ULN:13-15 (inclusive),
female; 16- 17
(inclusive), male & female
Aspartate aminotransferase (AST)
U/L
—
≥3 × ULN
Bicarbonate
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Bilirubin, total
μmol/L
—
> 1.5 × ULN
Calcium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Chloride
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Cholesterol, Total
mmol/L
—
> 1.6× ULN
Creatinine
μmol/L
—
> 1.3 × ULN
Glucose, random, serum
mmol/L
< 0.8 × LLN
> 1.4 × ULN
Potassium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Protein, total 
g/L
< 0.9 × LLN
> 1.1 × ULN
Sodium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Urea Nitrogen (BUN)
mmol/L
—
> 1.2 × ULN
HEMATOLOGY
Basophils, absolute cell count
109/L
—
> 3 × ULN
Eosinophils absolute cell count
109/L
—
> 3 × ULN
Lymphocytes absolute cell count
109/L
< 0.7 × LLN
> 1.3 × ULN
Monocytes, absolute cell count
109/L
< 0.5 × LLN
> 2.0 × ULN
Neutrophils, absolute cell count
109/L
< 0.8 × LLN
> 1.5 × ULN
Hematocrit
Ratio
< 0.9 × LLN
> 1.1 × ULN
Hemoglobin
g/L
< 0.9 × LLN
> 1.1 × ULN
Platelet count
109/L
< 0.5 × LLN
> 1.5 × ULN
Red blood cell count
1012/L
< 0.9 × LLN
> 1.1 × ULN
White blood cell count
109/L
< 0.7 × LLN
> 1.5 × ULN
URINALYSIS
pH
—
< 0.9 × LLN
> 1.1 × ULN
Specific gravity
—
—
> 1.1 × ULN
LLN = lower limit of normal value provided by the laboratory; SI = Le Système International d’Unités (International 
System of Units); ULN = upper limit of normal value provided by the laboratory.
11.3
VITAL SIGNS
Descriptive statistics for height, vital signs (ie, temperature, body weight, respiratory rate, and 
supine pulse rate, supine systolic and diastolic BP) and changes from baseline values at each 
assessment time point will be presented by study intervention group.
Vital sign values will be considered PCS if they meet both the observed-value criteria and the 
change-from-baseline criteria listed in Table 11-2. The number and percentage of participants 
with PCS postbaseline values will be tabulated by study intervention group for the double-blind 
Intervention Period and Postintervention Period separately. The percentages will be calculated 
relative to the number of participants with available non-PCS baseline values and at least 1
postbaseline assessment in the specific period. The numerator will be the total number of 


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participants with available non-PCS baseline values and at least 1 PCS postbaseline value during 
the specific period. A supportive tabular display of participants with PCS postbaseline values 
will be provided, including the PID number, baseline and all postbaseline (including non-PCS) 
values.
In addition, a tabular display showing all AEs that occurred in participants who had PCS 
postbaseline vital sign values will be provided.
Table 11-2
Criteria for Potentially Clinically Significant Vital Signs
Parameter
Flag
Criteriaa
Observed Value
Change From Baseline
Systolic Blood 
Pressure, mmHg -
Postural Vital Signs
(Supine and 
Standing)
Decrease in systolic blood 
pressure of 20 mmHg or more 
from supine to standing
[*Change from supine 
SBP <= -20]
Decrease in systolic blood pressure from 
supine to standing at observed time point is at 
least 10 mmHg greater than the decrease in 
systolic blood pressure from supine to standing 
at baseline
[Postbaseline change from supine SBP –
baseline change from supine SBP <= -10]
Diastolic Blood 
Pressure, mmHg 
Postural Vital Signs
(Supine and 
Standing)
Decrease in diastolic blood 
pressure of 10 mmHg or more 
from supine to standing
[Change from supine 
DBP <= -10]
Decrease in diastolic blood pressure from 
supine to standing at observed time point is at 
least 10 mmHg greater than the decrease in 
diastolic blood pressure from supine to 
standing at baseline
[Postbaseline change from supine DBP –
baseline change from supine DBP <= -10] 
Pulse Rate, bpm -
Postural Vital Signs
(Supine and 
Standing)
Increase in heart rate of 20 
beats per minute or more from 
supine to standing
[Change from supine pulse rate 
>= 20]
Increase in heart rate from supine to standing at 
observed time point is at least 10 beats per 
minute greater than the increase in heart rate 
from supine to standing at baseline 
[Postbaseline change from supine pulse rate –
baseline change from supine pulse rate >= 10]
Systolic Blood 
Pressure, mm Hg 
(Supine)
High
Age 6-11 (inclusive): ≥ 140
Age 12-17 (inclusive): ≥ 155
Increase of ≥ 20
Low
Age 6-11 (inclusive): ≤ 80
Age 12-17 (inclusive): ≤ 90
Decrease of ≥ 20
Diastolic Blood 
Pressure, mm Hg 
(Supine)
High
Age 6-11 (inclusive): ≥ 95
Age 12-17(inclusive): ≥ 105
Increase of ≥ 15
Low
Age 6-11 (inclusive): ≤40
Age 12-17 (inclusive): ≤ 45
Decrease of ≥ 15
Pulse Rate, bpm 
(Supine)
High
Age 6-11 (inclusive): ≥ 140
Age 12-17 (inclusive): ≥ 120
Increase of ≥ 15
Low
Age 6-11 (inclusive): ≤ 50
Age 12-17 (inclusive): ≤ 40
Decrease of ≥ 15
Weight, kg
High
—
Increase of ≥ 5%
Low
—
Decrease of ≥5%
a
A postbaseline value is considered potentially clinically significant if it meets both the observed-value and the change-
from-baseline criteria.
bpm = beats per minute; DBP = diastolic blood pressure; SBP = systolic blood pressure.
*
Change from supine value = standing value – supine value


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11.4
ELECTROCARDIOGRAM
Descriptive statistics for ECG parameters (ventricular heart rate, RR interval, PR interval, QRS 
interval, QT interval, and QTc) and changes from baseline values at each assessment time point 
will be presented by study intervention group. The QTc will be calculated using both the Bazett 
and Fridericia corrections. 
Electrocardiographic parameter values are considered PCS if they meet or exceed the higher-
limit PCS criteria listed in Table 11-3. The number and percentage of participants with PCS 
postbaseline ECG values will be tabulated by study intervention group for the double-blind 
invention period. The percentages will be calculated relative to the number of participants with 
available non-PCS baseline values and at least 1 postbaseline assessment for the double-blind 
Intervention Period. The numerator is the total number of participants with available non-PCS 
baseline values and at least 1 PCS postbaseline value for the double-blind Intervention Period. A 
supportive tabular display of participants with PCS postbaseline values will be provided,
including the PID number, baseline, all postbaseline (including non-PCS) values, and change 
from baseline. In this listing, any participant with PCS value (if any) during Postintervention
Period will also be included.
In addition, a tabular display showing all AEs that occurred in participants who had postbaseline 
PCS ECG values will be provided. 
A shift table from baseline to the end of double-blind Intervention Period in the Investigator’s 
overall interpretation of the ECG will be presented by study intervention group for the following 
categories: normal; abnormal, not clinically significant; abnormal, clinically significant. A 
tabular display showing participants with postbaseline clinically significant ECG abnormalities 
according to the Investigator’s overall interpretation will be provided.
Table 11-3
Criteria for Potentially Clinically Significant Electrocardiograms
Parameter
Unit
Higher Limit
QRS interval
msec
QRS >= 115 msec (6-7 (inclusive) years)
QRS >= 125 msec (8-15 (inclusive) years) 
QRS >= 150 msec (16-17 (inclusive) years)
PR interval
msec
PR > 225 msec (6-7 (inclusive) years)
PR > 250 msec (8-17 (inclusive) years)
QTc(F)
msec
>480
QTc(F) = QT Corrected by Fridericia’s formula
11.5
OTHER SAFETY PARAMETERS
11.5.1
Potential Hy’s Law
Potential Hy’s Law criteria within a 24-hour window is defined by a post baseline elevation of 
ALT or AST ≥ 3x ULN, along with TBL ≥ 2x ULN and a non-elevated ALP < 2x ULN, all 
based on blood draws collected within a 24-hour period.


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Participants who meet the potential Hy’s Law criteria from the first dose of study drug to within 
30 days after the last dose of study intervention will be summarized. Supportive tabular displays 
will also be provided. 


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12.0
HEALTH OUTCOMES ANALYSES
Not applicable.


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13.0
INTERIM ANALYSIS
An IA to assess futility of linaclotide using the primary endpoint at 50% information may be 
considered based on the enrollment of FC participants in this study (ie, if the rate of enrollment is 
below expectations). The IA for FC participants will provide unblinded analysis of the primary
efficacy endpoint for FC to assess futility of linaclotide for FC with approximately 50% of FC 
participants who completed the 12-week double-blind intervention period or have discontinued 
prematurely from the 12-week double-blind intervention period (Table 13-1). In the event this 
interim futility analysis occurs, the Data Safety Monitoring Board (DSMB) (responsible for 
safety monitoring) will review the unblinded IA results and make recommendations regarding 
the continuation of the study. To maintain the scientific reliability of the final results and prevent 
potential bias into the conduct of the study and analysis, individuals involved in the IA will not 
be involved in any operational aspects of the study. The unblinded IA using the primary endpoint 
to assess futility will be performed by an independent statistician (not involved with study team).
Since there will be no plan to stop the trial for efficacy in this futility IA with nonbinding futility 
boundary, no alpha will be spent for the interim look. However, following a conservative 
approach, the final analysis for FC will still be conducted at an alpha level of 0.049 (2-sided) in 
case this futility IA is conducted.
Table 13-1
Summary of Interim Analysis Strategy for FC Participants
Key Endpoint for Interim Analysis
Timing of Interim Analysis
Purpose of Interim 
Analysis
Primary: Change from baseline in 
12-week SBM frequency rate 
(SBMs/week) during the study 
intervention period
The IA will be performed when the first 189 
FC participants randomized in this study 
complete the 12 weeks of study intervention 
or discontinue prior to the completion of the 
double-blind study intervention period. This 
represents approximately 50% of the total 
information available in the study in the 
corresponding treatment arm.
Stop for futility for FC
Note: Assumed standard deviation and treatment difference as in Table 14-1.
Conditional power (CP) will be utilized for futility assessment in FC according to the following 
guidelines:
For the comparison of linaclotide vs. placebo in FC, if the CP of rejecting the null hypothesis of 
no difference between linaclotide and placebo in the primary endpoint for FC participants at the 
final analysis (ie, final look) given the observed difference at the interim look is < 20%, the study 
in FC participants may be reconsidered to have met the futility boundary. In this case, the DSMB 
may recommend to stop further investigation in FC participants in this study.


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Conditional power will be calculated based on the formula of Chen et al (Chen 2004) which is 
given by:
  Φ









t
z
t
t
z
1
)
1(
2
/

, where Φ is the cumulative distribution function of standard normal 
distribution; t is the information fraction at the IA; z is the assumed standardized normal test 
statistic at the interim look and α=0.05.
A gamma spending function (Hwang 1990) will be used for the futility check with a gamma 
parameter of 1.02.
Figure 13-1 plots the cumulative amounts of Type II error spent for different proportions of 
planned sample size.
Figure 13-1
Plot of Type II Error Spending Functiona
a
Plot was generated using East Version 6.4.
The stopping boundary for this study in FC participants is non-binding. β spent at the interim 
look for futility as described above is approximately 9.4%. 
Scenarios of the IA at different information fractions with the corresponding conditional powers 
at current trend, treatment differences, amount of β spent, and the overall powers of the final 
analysis (if the study continues after IA) at total planned sample size of 378 are provided in 
Table 13-2 below.
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 


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Table 13-2
Different Interim Analysis Scenarios 
Percent of Randomized 
Participants at the IA
Conditional Power 
Under Current 
Trend (%)
Treatment Difference 
at Current Trend
β Spent
Overall Power 
(%)
30
2.5
0.1
0.055
86.7
40
9.6
0.295
0.074
85.8
50
20
0.424
0.094
85
60
31.5
0.513
0.111
84.5
70
43.4
0.579
0.127
84.1
Note: Assumed standard deviation and treatment difference as in Table 14-1.
East Version 6.4 was used.
a
Based on a total sample size of 378.
An IA plan will document further details (if required) regarding the IA and be prepared 
separately when a decision to perform the above specified futility IA is made.


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14.0
DETERMINATION OF SAMPLE SIZE
The sample size of this study was determined based on the primary efficacy endpoint. A total of 
326 participants are targeted to be randomized to this study in a 1:1 allocation ratio to receive 
either linaclotide 72 µg (163 participants) or placebo (163 participants) for 12-weeks of double-
blind Study Intervention Period. The assumptions and power estimate for this planned sample 
size are summarized in Table 14-1.
Table 14-1
Sample Size Assumptions for the Primary Efficacy Endpoint
Parameter
Assumption/Estimate
Primary efficacy analysis endpoint
Change from baseline in 12-week SBM frequency rate 
(SBMs/week) during the Study Intervention Period
Expected study intervention difference
1 point
(based on change from baseline in SBM frequency rate with a 
72 µg dose: Phase 2 LIN-MD-62 data, including the 6-11 year 
age group weighing ≥35 kg and the 12-17 year age group, and 
recent 72 µg adult study MCP-103-309 in CIC)
Assumed standard deviation
3 
(based on approximation from the Phase 2 LIN-MD-62 study 
with linaclotide 72 µg and placebo for change from baseline in 
SBM frequency rate)
Alpha
5%
Sides
2
Statistical test
2-sample t test
Sample size allocation ratio (Linaclotide: Placebo)
1:1
Power
85%
The secondary efficacy endpoint in this study is change from baseline in 12-week stool 
consistency during the Study Intervention Period. Assuming a detectable difference of 1.0 point 
between linaclotide 72 µg and placebo and common SD of 1.53 (based on LIN-MD-62), an 85% 
power test for this endpoint will require 88 participants in total (44 in each study intervention 
group). With 163 participants per group, there would be 99% power for the endpoint.
Depending on the enrollment status (i.e if enrollment is very slow) for FC participants in this 
study, an IA for futility may be considered. Assuming that this optional futility IA is performed 
at 50% of information based on using the primary efficacy endpoint for FC participants, a total 
sample size of 378 FC participants (189 participants in each study intervention group) will need 
to be randomized to ensure 85% power for the final analysis at a slightly reduced significance 
level of 4.9% (following a conservative approach, Section 10.0) to demonstrate that linaclotide is 
superior to placebo (based on the same assumptions as presented in Table 14-1). The optional IA 
for futility in FC participants is discussed in Section 13.0.


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15.0
STATISTICAL SOFTWARE
Statistical analyses will be performed using version 9.4 (or newer) of SAS on a Linux operating 
system.


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16.0
DATA HANDLING CONVENTIONS
16.1
VISIT TIME WINDOWS FOR SAFETY ANALYSES
Table 16-1 presents the visits assigned for safety analyses and the corresponding range of study 
intervention days (window) during which an actual visit may occur.
Table 16-1
Visit Time Windows
Derived Visit
Scheduled Visit Daya
Window
Baseline
Day 1
Days ≤ 1
Week 2 Visit
Day 15
Days [2, 21]
Week 4 Visit
Day 29
Days [22, 42]
Week 8 Visit
Day 57
Days [43, 70]
Week 12 Visit
Day 85
Days [Day 71, max (last dose day+1, Visit 7 date)]
Post-intervention Visit
Day 92
Days >= max (last dose day+1, Visit 7 date)+1
End of Double-Blind 
Intervention Periodb
Final or Termination Visit during the double-blind Intervention Period
a
Relative to the date of the first dose of double-blind study intervention. Day 1 = the date of the first dose of double-blind 
study intervention. There is no Day 0 or Week 0.
b
Presented in analysis tables for safety parameters, including but not limited to electrocardiograms, clinical laboratory values, 
and vital signs.
Participants who rollover to the long-term safety study, LIN-MD-66, before the EOS visit (i.e. 
Visit 8, post-intervention visit) are not required to have this EOS visit or post-intervention visit. 
If the assessment date (if the assessment date is unavailable, use visit date instead) is on or after 
the date of the first dose of study intervention, the study day is calculated by assessment date –
date of the first dose of study intervention + 1. If the assessment date is before the date of the 
first dose of study intervention, the study day is calculated by assessment date – date of the first 
dose of study intervention. Therefore, a negative day indicates a day before the start of the study 
intervention.
If a participant has 2 or more visits within the same window, the last visit with a non-missing 
value will be used for analysis.
16.2
VISIT TIME WINDOWS FOR EFFICACY ANALYSES
Table 16-2 below presents the analysis weeks assigned for the efficacy analysis of the participant
daily diary data related to BM and/or abdominal symptom characteristics. These analysis weeks 
will be used in the calculations for all week-based endpoints (eg, SBM weekly frequency rate, 
stool consistency weekly scores, etc.).


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Table 16-2
Analysis Time Windows for Efficacy Analysis - Daily Questions
Period
Analysis Week
Beginsa
Endsa
Preintervention 
(Baselineb) 
Week -2
Day -14
Day -8
Week -1
Day -7
Day 1, time of randomization
Intervention
Week 1
Day 1, time after 
randomization
Day 7
Week 2
Day 8
Day 14
Week 3
Day 15
Day 21
Week 4
Day 22
Day 28
Week 5
Day 29
Day 35
Week 6
Day 36
Day 42
Week 7
Day 43
Day 49
Week 8
Day 50
Day 56
Week 9
Day 57
Day 63
Week 10
Day 64
Day 70
Week 11
Day 71
Day 77
Week 12
Day 78
Day of last dose +1
Post-intervention
Post-intervention
Day of last dose + 1
Day of end of study visit
Note: On randomization day, if participant already completed morning diary, at the clinic visit, participants fill out a clinic diary 
and the assessments in the clinic diary will be part of the Preintervention Period. Morning diary assessments on randomization 
day will also be part of Preintervention Period. eDiary assessments in evening diary on the day of randomization will be part of 
the Intervention Period. eDiary assessments in morning diary at the day after the last dose day will be considered as assessments 
in the Intervention Period.
a
Relative to the date of randomization; Day 1 = the day of randomization. 
b
Baseline values for efficacy parameters will be derived from the daily morning and evening eDiaries and eCRF data 
collected in the Preintervention Period, specifically the period of time from 14 days before randomization up to the time of 
randomization.
For the Intervention Period, daily diary day is calculated as (diary date - date of 
randomization + 1). For the Preintervention Period, daily diary day is calculated as (diary 
date - date of randomization). However, the day of randomization is study Day 1 regardless. 
Participants will complete their diary entries twice per day for daily diary. 
If a participant withdraws during the Intervention Period, the participant’s morning diary 
assessments of daily eDiary on the day after last dose day will be captured as assessments in the 
Intervention Period. The impacted Intervention Period week shall be shortened to the end of the 
withdrawn participant’s Intervention Period and all subsequent Intervention Period weeks will be 
missing for that participant.
Table 16-3 below presents the weekly periods assigned for the efficacy analysis of the participant
weekly diary data related to global severity items and global change items. 


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Table 16-3
Analysis Time Windows for Efficacy Analysis - Weekly Questions
Analysis Week
Beginsa
Endsa
Week -2
Visit 2 day
Visit 2 day + 7
Week -1 (Baseline)
Visit 2 day + 8
Day 1
Week 1
Day 2
Day 8
Week 2
Day 9
Day 15
Week 3
Day 16
Day 22
Week 4
Day 23
Day 29
Week 5
Day 30
Day 36
Week 6
Day 37
Day 43
Week 7
Day 44
Day 50
Week 8
Day 51
Day 57
Week 9
Day 58
Day 64
Week 10
Day 65
Day 71
Week 11
Day 72
Day 78
Week 12
Day 79
last dose date +1
Post-intervention
Day of last dose date + 8
Day of end of study visit
a
Begin and end of each week from Week 1 onwards are relative to the date of the first dose of double-blind study 
intervention. Day 1 = the date of the first dose of double-blind study intervention. There is no Day 0 or Week 0. End of 
Week 1 to Week 12 will be day of last dose + 1 or corresponding end day in table whichever comes earlier.
Participants who rollover to the long-term safety study, LIN-MD-66, before the EOS visit (i.e. 
Visit 8, post-intervention visit) are not required to have the EOS visit or post-intervention visit.
16.3
DERIVED VARIABLES
16.3.1
Missed Morning/Evening eDiary Assessments
No imputation or derivation will be performed for missed morning/evening assessments unless 
otherwise specified.
16.3.2
Incomplete Morning/Evening eDiary Assessments
Missing responses in incomplete morning and/or evening assessments will not be imputed for 
most of the parameters, with the exception of rescue medication (RM) use and BM frequency.
If the answer to the RM use question is missing for any assessment (morning or evening), no RM 
usage will be considered during that diary period (morning or evening diary) in eDiary, with the 
exception that the missing RM will be considered “used” if the other available assessment during 
that diary period is “yes”.
If the answer to the question related to BM frequency is missing in any assessment (morning or 
evening), BM frequency will be considered as zero for that diary period (morning or evening 
diary) in the eDiary. 


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16.3.3
Incomplete Clinic Diary on Randomization Visit (If Present)
Missing responses in an incomplete clinic diary on randomization day will be handled in a 
similar way as mentioned for incomplete daily morning/evening assessments. Clinic diary on 
randomization day will be considered as part of morning diary on randomization day.
16.3.4
Stool frequency
Spontaneous Bowel Movement (SBM)
A SBM is a BM that occurs in the absence of laxative, suppository, or enema use on the calendar 
day of the BM or the calendar day before the BM.
Complete Spontaneous Bowel Movement (CSBM)/Incomplete Evacuation
A CSBM is an SBM that is associated with a sense of complete evacuation.
Stool Frequency Rates 
The components for calculating a participant’s stool frequency rates (SBM/CSBM weekly rates) 
for a given period are as follows:

The number of BMs that occurred during that specific period

The number of those BMs that were SBMs

The number of those SBMs that were CSBMs

The number of days during that specific period:
o
Randomization day with evening diary will be considered a half day for the 
double-blind Intervention Period.
o
Randomization day with morning and/or clinic diary will be considered -a half 
day for the Preintervention Period.
o
The day after last dose will be considered a half day for the double-blind 
Intervention Period with morning diary and for the Postintervention Period with 
evening diary.
Duration of an Analysis Week
With respect to a participant’s scheduled analysis weeks, the term duration is used. In regard to 
the duration of a week, it is expected that 1 or more of a participant’s “weeks” may not be 
exactly 7 days in duration (eg, a participant may withdraw or discontinue early from the trial, 
may have half day data with diary entries, or may have missing diary day). Deviations from the 
7 days norm are structural in nature; and, as such, the calculations of the weekly rates of SBMs 
or CSBMs will incorporate the actual days contributed within the time period (week or specific 
phase).


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LIN-MD-64 Statistical Analysis Plan for FC Participants (Amendment #1)
Weekly Stool Frequency Rate Calculations
The weekly frequency rate for SBMs (CSBMs) will be based on the total number of SBMs 
(CSBMs) occurring based on the diary entries during that time period, adjusting for differences 
in the length of the time period. Weekly stool frequency rates for each specific period will be 
calculated as follows:

Weekly Frequency Rate (Specific Period) =
#$%&' ()*+,- $. ,/,(%0 (2340 $- 52340) 7)-8(9 %:, 0;,<8.8< ;,-8$7 
=)*+,- $. 7&>0 7)-8(9 %:, 0;,<8.8< &(&'>080 ;,-8$7
X 7
16.3.5
Stool Consistency
Participants will use the pediatric Bristol Stool Form Scale (p-BSFS), to rate their stool 
consistency for each BM:
"Choose the poop that is most like the poop you had."
Type 1 = looks like small hard lumps or balls, like pebbles
Type 2 = looks like fat sausage shape but lumpy and hard
Type 3 = looks like a sausage but with cracks on it
Type 4 = looks like a sausage or snake, smooth and soft
Type 5 = looks like chicken nuggets, soft smooth blobs
Type 6 = looks like oatmeal, fluffy mushy pieces
Type 7 = looks like a milkshake, watery
99 - I don’t know
Stool consistency will be collected twice daily (morning and evening) in the eDiary and 
measured using the 7-point p-BSFS. Stool consistency (p-BSFS) score during a specific analysis 
period will be derived as mean of participant’s non-missing, SBM-associated p-BSFS scores 
during that specific period.
16.3.6
Straining 
For every BM, participants will assess the degree of straining by responding to the following in 
the morning and evening eDiaries:

When you pooped, how hard did you push?
0 = not hard at all
1 = I pushed a tiny bit hard
2 = I pushed a little hard
3 = I pushed hard
4 = I pushed very hard
Straining will be collected twice daily (morning and evening) in the eDiary and measured using a 
5-point scale. The participant’s straining score in a specific analysis period will be the mean of 
participant’s non-missing, SBM-associated straining scores during that specific period.


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16.3.7
Abdominal Bloating
Abdominal bloating scores will be collected twice daily in the eDiary (morning and evening). 
Abdominal Bloating - Daytime
For this parameter, participants will record their assessment of abdominal bloating during the day 
by responding to the following in the evening eDiary:

From when you got up this morning until now, did your tummy FEEL big and full?  
o
Yes
o
No 
If “yes” then participant answers the following question:

How big and full did your tummy FEEL?
1 = a tiny bit
2 = a little 
3 = medium 
4 = very
Abdominal Bloating - Nighttime
For this parameter, participants will record their assessment of nighttime abdominal bloating by 
responding to the following in the morning eDiary:

From bedtime last night until now, did your tummy FEEL big and full?
o
Yes
o
No
If “yes”, then the participant answers the following question:

How big and full did your tummy FEEL? 
1 = a tiny bit
2 = a little 
3 = medium 
4 = very
Abdominal Bloating - Combination (Total 24-hour Period)
This parameter will be determined based on combined daytime symptoms of abdominal bloating 
in evening assessments and nighttime symptoms of abdominal bloating in morning assessments. 


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The participant’s abdominal bloating score for a specific period based on evening assessments 
(daytime symptoms), morning assessments (nighttime symptoms), and combined morning and 
evening assessments will be derived as the mean of the non-missing abdominal bloating scores 
within the corresponding diaries during the specific period. The abdominal bloating scores of 0, 
1, 2, 3, and 4 will be used to calculate the average, where ‘0’ indicates no bloating.
16.3.8
Abdominal Pain
Abdominal pain scores will be collected twice daily in the eDiary (morning and evening). 
Abdominal Pain - Daytime
For this parameter, participants will rate their abdominal pain during the daytime by responding 
to the following in the evening eDiary:

From when you got up this morning until now, did your tummy hurt at all?
o
Yes
o
No
If “yes”, then participant answers the following question:

How much did your tummy hurt? 
1 = a tiny bit
2 = a little 
3 = some 
4 = a lot
Abdominal Pain - Nighttime
For this parameter, participants will rate their abdominal pain during the nighttime by responding 
to the following in the morning eDiary:

From bedtime last night until now, did your tummy hurt at all?
o
Yes
o
No
If “yes”, then the participant answers the following question:

How much did your tummy hurt? 
1 = a tiny bit
2 = a little 
3 = some 
4 = a lot
Abdominal Pain - Combination (Total 24-hour Period)
This parameter will be determined based on combined daytime symptoms of abdominal pain in 
evening eDiary assessments and nighttime symptoms of abdominal pain in morning eDiary 
assessments. 


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The participant’s abdominal pain score for a specific period based on evening assessments 
(daytime symptoms), morning assessments (nighttime symptoms), and combined morning and 
evening assessments will be derived as the mean of the non-missing abdominal pain scores 
within the corresponding diaries during the specific period. The abdominal pain scores of 0, 1, 2, 
3, and 4 will be used to calculate the average, where ‘0’ indicates no abdominal pain.
16.3.9
Fecal Incontinence - Daytime
Participants will record their episodes of fecal incontinence by responding to the following 
assessment in their evening eDiary.

From when you got up this morning until now, did you have a pooping accident (even a 
little)? 
o
Yes
o
No
16.3.10
Participant-completed Global Items
Participant-completed global change and global severity items were developed by the sponsors. 
The participant-completed global items consist of 4 items, 2 assessing global change in the 
participant’s symptoms and 2 assessing the global severity of the participant’s symptoms. All 
4 participant-completed global items have a 7-day recall period and will be completed weekly on 
the eDiary device. The global severity items will be completed beginning at the Preintervention 
Period through End-of-Study (EOS) and the global change items will be completed beginning at 
Randomization through EOS.
Participant-completed Global Change Items
The 2 participant-completed global change items assess self-reported change in the participant’s 
bowel symptoms (“pooping problems”) and abdominal symptoms (“tummy problems”) and are 
as follows:

Compared to 7 days ago, my pooping problems today are:
0 = a lot better
1 = a little better
2 = the same
3 = a little worse
4 = a lot worse

Compared to 7 days ago, my tummy problems today are:
0 = a lot better
1 = a little better
2 = the same
3 = a little worse
4 = a lot worse


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Global Severity Items
The 2 participant-completed global severity items assess self-reported severity of the 
participant’s constipation using the same child-friendly terminology as detailed for the global 
change items above and are as follows:

How bad have your pooping problems been over the past 7 days:
0 = I have not had pooping problems
1 = a little bad
2 = bad
3 = very bad

How bad have your tummy problems been over the past 7 days:
0 = I have not had tummy problems
1 = a little bad
2 = bad
3 = very bad
16.3.11
Observer-completed Global Items
The observer-completed (parents/caregivers) global items consist of 2 items, one assessing 
global change in the child’s symptoms and the other assessing the global severity of the child’s 
symptoms. Both observer-completed global items will be completed weekly on the eDiary 
device. The global severity item will be completed beginning at the Preintervention Period 
through the EOS and the global change item will be completed beginning at Randomization 
through the EOS.  
Only parents/caregivers of participants 6 to 11 years of age will complete these items.
Observer-completed Global Change Item
The observer-completed global change item assesses the change in the child’s constipation 
symptoms (1 item) as follows:

Compared to 7 days ago, how would you rate your child’s constipation symptoms today?
o
completely relieved  
o
considerably relieved 
o
somewhat relieved
o
unchanged
o
somewhat worse
o
considerably worse
o
as bad as I can imagine


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Observer-completed Global Severity Item
The observer-completed global severity item assesses the severity of the child’s constipation 
symptoms (1 item) as follows:

How would you rate the severity of your child’s constipation over the past 7 days?
o
none
o
mild
o
moderate
o
severe
o
very severe
16.3.12
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 7). 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, the criteria will be assessed over the last 4 weeks of the double-blind 
study intervention period. In the event a participant discontinues the study prematurely, these 
criteria will be assessed over the last 4 weeks of double-blind study intervention, or over the 
duration of double-blind study intervention if less than 4 weeks.
16.4
REPEATED OR UNSCHEDULED ASSESSMENTS OF SAFETY 
PARAMETERS
If a participant has repeated assessments before the start of the first study intervention, the results 
from the final non-missing assessment made prior to the start of the study intervention will be 
used as baseline. If end-of-study assessments are repeated or if unscheduled visits occur, the last 
non-missing postbaseline assessment will be used as the end-of-study assessment for generating 
summary statistics. However, all postbaseline assessments will be used for PCS value 
determinations, and all assessments will be presented in the data listings.
16.5
MISSING DATE OF THE LAST DOSE OF STUDY INTERVENTION
When the date of the last dose of study intervention is missing for a participant in the Safety 
Population, all efforts should be made to obtain the date from the Investigator. If after all efforts 
are made it is still missing, the Visit 7 date (if available) -1 will be set as last dose date. In 
absence of the Visit 7 date, the double-blind disposition status date -1 will be set as last dose 
date.




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
If either the year of the incomplete start date is after the year of the date of the first dose 
of study intervention or if both years are the same but the month of the incomplete start 
date is after the month of the date of the first dose of study intervention, the first day of 
the month will be assigned to the missing day
If the stop date is complete and the imputed start date as above is after the stop date, the start 
date will be imputed by the stop date.
If the start date is completely missing and the stop date is complete, the following algorithm will 
be used to impute the start date:

If the stop date is after the date of the first dose of study intervention, the date of the first 
dose of study intervention will be assigned to the missing start date

If the stop date is before the date of the first dose of study intervention, the stop date will 
be assigned to the missing start date
16.9
MISSING DATE INFORMATION FOR PRIOR OR CONCOMITANT 
MEDICATIONS
For prior or concomitant medications, including rescue medications, incomplete (ie, partly 
missing) start dates and/or stop dates will be imputed. When the start date and the stop date are 
both incomplete for a participant, the start date will be imputed first.
16.9.1
Incomplete Start Date
The following rules will be applied to impute the missing numeric fields for an incomplete prior 
or concomitant medication start date. If the stop date is complete (or imputed) and the imputed 
start date is after the stop date, the start date will be imputed using the stop date.
Missing month and day

If the year of the incomplete start date is the same as the year of the first dose of study 
intervention, the month and day of the first dose of study intervention will be assigned to 
the missing fields

If the year of the incomplete start date is before the year of the first dose of study 
intervention, December 31 will be assigned to the missing fields

If the year of the incomplete start date is after the year of the first dose of study 
intervention, January 1 will be assigned to the missing fields
Missing month only

If only the month is missing, the day will be treated as missing and both the month and 
the day will be replaced according to the above procedure
Missing day only

If the month and year of the incomplete start date are the same as the month and year of 
the first dose of study intervention, the day of the first dose of study intervention will be 
assigned to the missing day


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
If either the year of the incomplete start date is before the year of the date of the first dose
of study intervention or if both years are the same but the month of the incomplete start 
date is before the month of the date of the first dose of study intervention, the last day of 
the month will be assigned to the missing day.

If either the year of the incomplete start date is after the year of the date of the first dose
of study intervention or if both years are the same but the month of the incomplete start 
date is after the month of the date of the first dose of study intervention, the first day of 
the month will be assigned to the missing day
16.9.2
Incomplete Stop Date
The following rules will be applied to impute the missing numeric fields for an incomplete prior 
or concomitant medication stop date. If the date of the last dose of study intervention is missing, 
impute it as descripted in Section 16.5. If the imputed stop date is before the start date (imputed 
or nonimputed start date), the imputed stop date will be equal to the start date.
Missing month and day

If the year of the incomplete stop date is the same as the year of the last dose of study 
intervention, the month and day of the last dose of study intervention will be assigned to 
the missing fields

If the year of the incomplete stop date is before the year of the last dose of study 
intervention, December 31 will be assigned to the missing fields

If the year of the incomplete stop date is after the year of the last dose of study 
intervention, January 1 will be assigned to the missing fields
Missing month only

If only the month is missing, the day will be treated as missing and both the month and 
the day will be replaced according to the above procedure
Missing day only

If the month and year of the incomplete stop date are the same as the month and year of 
the last dose of study intervention, the day of the last dose of study intervention will be 
assigned to the missing day

If either the year of the incomplete stop date is before the year of the date of the last dose
of study intervention or if both years are the same but the month of the incomplete stop 
date is before the month of the date of the last dose of study intervention, the last day of 
the month will be assigned to the missing day

If either the year of the incomplete stop date is after the year of the date of the last dose of 
study intervention or if both years are the same but the month of the incomplete stop date 
is after the month of the date of the last dose of study intervention, the first day of the 
month will be assigned to the missing day


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16.10
CHARACTER VALUES OF CLINICAL LABORATORY PARAMETERS
If the reported value of a clinical laboratory parameter cannot be used in a statistical summary 
table because, for example, a character string is reported for a parameter of the numeric type, a 
coded value must be appropriately determined for use in the statistical analyses. The actual 
values, however, as reported in the database will be presented in the data listings.
Table 16-4 shows examples of how some possible laboratory results should be coded for the 
analysis.
Table 16-4
Examples of Coding Special Character Values for Clinical Laboratory Parameters
Laboratory Test, SI Unit
Possible Laboratory Results
Coded Value for Analysis
CHEMISTRY
ALT, U/L
< 5
5
AST, U/L
< 5
5
Bilirubin, total, μmol/L
< 2
2
URINALYSIS
Glucose, mmol/L
= OR > 55, ≥55, > 0
Positive
≤0, negative
Negative
pH
> 8.0, ≥8.0
8.0
≥8.5
8.5
Protein
= OR > 3.0, ≥ 3.0, > 0
Positive
≤0
Negative
ALT = alanine aminotransferase; AST = aspartate aminotransferase; SI = Le Système International d’Unités (International 
System of Units).


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17.0
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL
There are no major changes to analyses specified in the amended protocol #1 (version dated 
June-2020).
The following other efficacy endpoint is added in Section 10.3 of the SAP.

Change from baseline in participant-completed global severity items (pooping problems 
and tummy problems) at each week during Study Intervention Period


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18.0
HISTORY OF CHANGES
Following changes have been made in this SAP Amendment:

Section 6.3: Updated mITT population to include all participants in the Randomized 
Population who receive at least 1 dose of double-blind study intervention. 

Section 7.0: Removed the reasons for premature discontinuation from the study in 
participant disposition as there is no corresponding eCRF.

Section 11.1: Modified TEAE definition to include any AE that occurs within 30 days 
(instead of 1 day) after the last dose of study intervention. 

Section 16.3.2: Modified the imputation rule for missing rescue medication (RM) use 
question. Missing RM usage will be considered as “used” for morning or evening diary if 
the other available assessment during that period indicated RM was taken.


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19.0
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Hwang IK, Shih WJ, and De Cani JS. Group sequential designs using a family of type 1 error 
probability spending functions. Stat Med. 1990;9(12):1439-1445.
Kenward, M.G., Roger, J.H. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics 1997; 53:983-97.
Ratitch B, and O’Kelly M. Implementation of Pattern-Mixture Models Using Standard
SAS/STAT Procedures. In Proceedings of PharmaSUG 2011 (Pharmaceutical Industry SAS 
Users Group). Paper SP04. Nashville.