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)
Phase: PHASE3
Conditions: Functional Constipation, Irritable Bowel Syndrome With Constipation
Sponsor: AbbVie



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
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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
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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
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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
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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)