A Phase 2 Dose Finding Study Evaluating the Safety and Efficacy of Linaclotide in Pediatric Subjects 6 Months to Less Than 2 Years of Age With Functional Constipation (FC).
Phase: PHASE2
Conditions: Functional Constipation
Sponsor: AbbVie



 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
TABLE OF CONTENTS 
1 
SYNOPSIS 
5 
2 
INTRODUCTION 
7 
2.1 
BACKGROUND AND RATIONALE 
7 
2.2 
BENEFITS AND RISKS TO SUBJECTS 
10 
3 
OBJECTIVES AND ENDPOINTS 
11 
3.1 
OBJECTIVE AND HYPOTHESIS 
11 
3.2 
KEY EFFICACY ENDPOINTS AND ESTIMAND 
12 
3.3 
ADDITIONAL EFFICACY ENDPOINTS 
12 
3.4 
SAFETY ENDPOINTS 
12 
4 
INVESTIGATIONAL PLAN 
12 
4.1 
OVERALL STUDY DESIGN AND PLAN 
12 
4.2 
DISCUSSION OF STUDY DESIGN 
15 
5 
STUDY ACTIVITIES 
16 
5.1 
ELIGIBILITY CRITERIA 
16 
5.2 
PROHIBITED MEDICATIONS AND THERAPY 
19 
5.3 
PRIOR AND CONCOMITANT THERAPY 
21 
5.4 
DOSE INTERRUPTION 
22 
5.5 
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY 
22 
5.6 
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY 
25 
5.7 
STUDY DRUG 
25 
5.8 
RANDOMIZATION/DRUG ASSIGNMENT 
27 
5.9 
PROTOCOL DEVIATIONS 
27 
5.10 RESCREENING 
28 
5.11 DATA SAFETY MONITORING 
28 
6 
SAFETY CONSIDERATIONS 
29 
6.1 
COMPLAINTS AND ADVERSE EVENTS 
29 
6.2 
TOXICITY MANAGEMENT 
32 
Page 2 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
7 
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE 
33 
7.1 
STATISTICAL AND ANALYTICAL PLANS 
33 
7.2 
DEFINITION FOR ANALYSIS POPULATIONS 
33 
7.3 
HANDLING POTENTIAL INTERCURRENT EVENTS FOR THE PRIMARY AND KEY SECONDARY ENDPOINTS 
33 
7.4 
STATISTICAL ANALYSES FOR EFFICACY 
34 
7.5 
STATISTICAL ANALYSES FOR SAFETY 
34 
7.6 
OVERALL TYPE I ERROR CONTROL 
35 
7.7 
SAMPLE SIZE DETERMINATION 
35 
8 
ETHICS 
35 
8.1 
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD 
35 
8.2 
ETHICAL CONDUCT OF THE STUDY 
35 
8.3 
SUBJECT CONFIDENTIALITY 
35 
9 
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION 
36 
10 DATA QUALITY ASSURANCE 
36 
11 START AND COMPLETION OF THE STUDY 
36 
12 REFERENCES 
37 
LIST OF TABLES 
TABLE 1. 
DOSE LEVELS (µG) BY WEIGHT IN PEDIATRIC SUBJECTS TREATED WITH LINACLOTIDE IN 
STUDY LIN-MD-62 
9 
TABLE 2. 
RESCUE CONCOMITANT MEDICATIONS/THERAPY 
22 
TABLE 3. 
POTENTIALLY CLINICALLY SIGNIFICANT ELECTROLYTE VALUES 
23 
TABLE 4. 
POTENTIALLY CLINICALLY SIGNIFICANT ECG VALUES 
23 
TABLE 5. 
IDENTITY OF STUDY DRUG 
26 
LIST OF FIGURES 
FIGURE 1. 
STUDY SCHEMATIC 
13 
Page 3 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
FIGURE 2. 
STUDY VISIT SCHEMATIC FOR PARTS 1 AND 2 
13 
LIST OF APPENDICES 
APPENDIX A. STUDY-SPECIFIC ABBREVIATIONS AND TERMS 
38 
APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR 
40 
APPENDIX C. LIST OF PROTOCOL SIGNATORIES 
41 
APPENDIX D. ACTIVITY SCHEDULE 
42 
APPENDIX E. LIVER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP ASSESSMENTS 
44 
APPENDIX F. 
PROTOCOL SUMMARY OF CHANGES 
46 
APPENDIX G. OPERATIONS MANUAL 
48 
 
 
 
Page 4 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
2 INTRODUCTION 
2.1 Background and Rationale 
Background 
Functional Constipation (FC) is a common healthcare problem in children of all ages, with a worldwide 
prevalence ranging between 0.7% and 29.6%.1 The pathophysiology of FC is multifactorial and include 
genetic predisposition, inadequate fiber and fluid intake, and immobility. The most common etiological 
factor, especially in younger children, is withholding behavior, which usually develops as a consequence 
of painful or frightening evacuation of stools.2 This can lead to a self-reinforcing cycle, where voluntary 
stool retention leads to increased water absorption from the feces and, thereby, harder stools and 
inherently more difficult and painful defecation. Colonic dysmotility, a common cause of FC in adults, 
can be a cause, but also a consequence of FC most likely due to longstanding fecal stasis. Symptoms 
suggestive of FC include infrequent (≤ 2 bowel movements [BMs]/week) hard or large diameter stools, 
painful defecation, retentive posturing, and fecal incontinence. If left untreated, FC may have other 
clinical consequences such as poor appetite, failure to thrive, encopresis, anal fissures, and cystitis. 
These symptoms can have a severe impact on a child's quality of life and may lead to school 
absenteeism and substantial costs related to healthcare utilization. 
Initial nonpharmacological interventions include education, dietary advice (sufficient fiber and fluid 
intake), and behavioral modifications. In older children, additional nonpharmacological interventions 
include toilet training, a reward system, and keeping a stool diary. However, many children ultimately 
require pharmacological treatment. If a fecal mass is suspected to be present, disimpaction should be 
attempted through either rectally administered enemas or high doses of oral polyethylene glycol (PEG), 
followed by maintenance treatment and eventually a weaning phase after a sustained period of 
symptom relief. Despite chronic pharmacological treatment, approximately 40% of children with FC who 
are referred to a pediatric gastroenterologist remain symptomatic after 5 years and 20% of children still 
have symptoms after 10 years of treatment. In some cases, symptoms may persist into adolescence or 
adulthood. Potential reasons for ineffectiveness of treatment include suboptimal dosage regimens, poor 
compliance with treatment, or the use of treatments that do not address the underlying 
pathophysiological mechanism. Children with a longstanding history of untreated constipation may 
require longer treatment durations to break the vicious pathophysiological cycle associated with chronic 
withholding long fecal stasis, and subsequent impairment of colonic function.1 
There are currently no approved therapies for FC in pediatric patients in the European Union (EU) or in 
pediatric patients less than 6 years of age in the US and Canada; PEG, the current treatment of choice, is 
used off-label. Reports of potential neurological adverse events have been associated with the use of 
PEG, which has triggered concerns in patients and caregivers and is currently being further investigated. 
Effective treatments are needed to provide symptomatic relief in children with FC that are supported by 
safety and efficacy data from well controlled studies. 
Linaclotide offers a potential therapeutic option to treat these symptoms in this pediatric population, as 
it is currently indicated for the treatment of irritable bowel syndrome with constipation (IBS-C) and 
chronic idiopathic constipation (CIC) in the adult population and for the treatment of FC in children 6 to 
Page 7 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
17 years of age in US and Canada. In the European Union (EU) linaclotide (CONSTELLA) is indicated for 
the symptomatic treatment of moderate to severe irritable bowel syndrome with constipation (IBS-C) in 
adults. Linaclotide is a 14-amino acid peptide that acts on the apical surface of epithelial cells 
surrounding the intestinal lumen to stimulate the receptor guanylate cyclase subtype C (GC-C). By 
activating GC-C, orally administered linaclotide has been found to increase both intestinal fluid secretion 
and intestinal transit and to also decrease visceral (abdominal) pain. Linaclotide has minimal oral 
bioavailability (≤ 0.2%) in several animal species and is minimally absorbed with low systemic availability 
in adults.3,4 
Pediatric Linaclotide Program 
Pediatric subjects (2 to 17 years of age) have been treated with linaclotide in multiple Phase 2 and Phase 
3 studies in FC (LIN-MD-62 [FC, NCT02559570], LIN-MD-67 [FC, NCT04110145], and LIN-MD-64 
[NCT04026113]) and IBS-C pediatric populations (LIN-MD-63 [IBS-C, NCT02559817] and LIN-MD-64 
[NCT04026113]). Overall, linaclotide was well tolerated in pediatric subjects with FC and IBS-C across all 
doses evaluated.5 Additional details regarding the completed pediatric FC studies in subjects 2 to 17 
years of age with linaclotide are described below.  
Phase 2 Study in FC: LIN‑MD‑62 
LIN-MD-62 was a Phase 2 -double-blind, placebo controlled, parallel group, safety and efficacy study of a 
range of linaclotide doses administered to 173 subjects, 6 to 17 years of age, who fulfilled modified 
Rome III criteria for FC (refer to Table 1 for dosing information). The objective of LIN-MD-62 was to 
evaluate the dose response, safety, and efficacy of 4 weeks of study intervention with 1 of 3 linaclotide 
doses (Dose A, B, and C, defined in Table 1) compared with placebo in pediatric subjects who fulfill 
modified Rome III criteria for child/adolescent FC with the goal of selecting an optimal dose of 
linaclotide to evaluate in a confirmatory study. 
Overall, linaclotide was well tolerated across all doses and both age groups. The safety profile was 
consistent with prior adult linaclotide studies for CIC. The most frequently reported treatment-emergent 
adverse event (TEAE) was diarrhea, which occurred in 7.6% of linaclotide-treated subjects versus 0% in 
the placebo group. The majority of the TEAEs of diarrhea reported were mild; none were severe. In the 
12 to 17 years of age group, 1 subject experienced moderate diarrhea (related) leading to 
discontinuation in the linaclotide Dose C group. 
There were no reported adverse events of special interest (AESIs) (i.e., significant volume depletion 
and/or significant electrolyte abnormalities and/or Electrocardiogram [ECG] abnormalities that were 
considered by the investigator or sponsor to be related to diarrhea) or deaths. There were 2 Serious 
adverse event (SAE) (suicidal ideation and vomiting), each reported in 1 subject 12 to 17 years of age, 
neither of which were considered related to study intervention. Moreover, in the younger pediatric 
subjects, 6 to 11 years of age, no SAEs or AEs leading to discontinuation were reported.5 
Page 8 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
Table 1. 
Dose Levels (µg) by Weight in Pediatric Subjects Treated with Linaclotide in 
Study LIN-MD-62 
Age Group 
Weight 
Linaclotide Dose A 
N = 36 
Linaclotide Dose B 
N = 41 
Linaclotide Dose C 
N = 39 
 
Dose (µg) 
 
Subjects 6-11 yearsa 
 
 
 
 
18 to < 35 kg 
9 
18 
36 
 
≥ 35 kg 
18 
36 
72 
Subjects 12-17 yearsb 
 
 
 
 
-- 
18 
36 
72 
a. 
Subjects 6 to 11 years of age received linaclotide or placebo in a liquid oral solution. 
b. 
Subjects 12 to 17 years of age received linaclotide or placebo in a solid oral capsule or a liquid oral solution. 
 
Phase 3 Study in FC: LIN‑MD‑64 
Study LIN-MD-64 was 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 
subjects, 6 to 17 years of age, with a diagnosis of FC based on modified Rome III Child/Adolescent 
Criteria (i.e., who fulfilled modified Rome III criteria for child/adolescent FC). The objective of this study 
was to evaluate the safety and efficacy of 12-weeks of linaclotide therapy (72 μg daily) in comparison 
with placebo in pediatric subjects, 6 to 17 years of age, who fulfilled modified Rome III Criteria for 
Child/Adolescent FC. 
Treatment with linaclotide demonstrated a statistically significant increase in the SBM frequency rate 
(SBMs/week) from baseline and improvement in stool consistency (as measured by the p-BSFS) from 
baseline during the 12-week intervention period compared to placebo. 
AEs were reported for 28 subjects (17.1%) in the linaclotide group and for 35 subjects (21.3%) in the 
placebo group. The majority of AEs in each treatment group were nonserious. Treatment-emergent 
serious adverse events (TESAEs) were reported for 2 subjects (1.2%) in the linaclotide group and 
2 subjects (1.2%) in the placebo group. AEs leading to study treatment discontinuation were reported 
for 2 subjects (1.2%) in the linaclotide group and for 3 subjects (1.8%) in the placebo group. No AEs 
leading to death were reported. 
Linaclotide was well tolerated across 6 to 17-year-olds with no deaths. The majority of TEAEs 
experienced by subjects were mild or moderate in severity. Overall, no unexpected or clinically relevant 
changes to vital signs, volume depletion, or ECG abnormalities were reported. There was one AESI of 
severe diarrhea. Overall, the safety profile of linaclotide in pediatric subjects is consistent with prior 
linaclotide studies in adults with CIC and IBS-C. 
Phase 2 Study in FC: LIN‑MD‑67 
LIN-MD-67 was a Phase 2, randomized, double-blind, placebo-controlled, sequential, ascending, 
multidose study designed to evaluate the dose response, safety, and efficacy of 4 weeks of linaclotide 
Page 9 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
compared with matching placebo in 35 pediatric subjects (2 to 5 years of age) who met modified Rome 
III criteria for childhood FC.5 
Overall, linaclotide was well tolerated across all doses evaluated. Although there was no clear dose-
response relationship, numerically better efficacy results were consistently observed at the linaclotide 
72 μg dose group compared to placebo in three out of four key efficacy endpoints: change from baseline 
in 4-week overall Spontaneous Bowel Movement (SBM) frequency rate (SBMs/week), change from 
baseline in 4-week stool consistency, and change from baseline in 4-week straining. The safety profile 
was consistent with that of the prior linaclotide study in 6 to 17 year‑old FC subjects (Study LIN‑MD‑62) 
and prior linaclotide studies in adults with CIC. There were no deaths, SAE, AESI (i.e., significant volume 
depletion and/or significant electrolyte abnormalities and/or ECG abnormalities that were considered by 
the investigator or sponsor to be related to diarrhea), or AE leading to study drug discontinuation. Two 
subjects receiving 18 μg experienced TEAEs of otitis media, increased blood creatine, and cough 
(1 [14.3%] subject for each TEAE), no subject receiving 36 μg experienced TEAEs, and 2 subjects 
receiving 72 μg experienced TEAEs of upper abdominal pain, diarrhea, and an ear infection (1 [7.7%] 
subject for each TEAE). All TEAEs experienced by subjects were mild or moderate in severity.5 
These data provide the rationale for the 9 µg, 18 µg, and 36 µg doses being studied in this Phase 2 
Study M21-862. Refer to Dose Justification (Section 4.2) for additional details. 
Additional information from studies conducted with linaclotide can be found in the most current version 
of the linaclotide Investigator's Brochure (IB).5 Refer to Section 2.2 for benefit and risks discussion. 
Rationale 
AbbVie is conducting this Phase 2 study to investigate the potential therapeutic dose(s) of linaclotide in 
pediatric subjects age 6 months to less than 2 years with FC. The rationale for conducting the study in 
this population is that FC is highly prevalent in this age group, there is currently no approved treatment 
for this population, and safety and tolerability have been established in pediatric subjects 2 to less than 
18 years of age. 
This dose-ranging study will evaluate if once daily (qd) administration of 9, 18, or 36 µg of linaclotide for 
a 4-week study intervention period is safe and effective in pediatric subjects, 6 months to less than 
2 years of age, with FC. 
2.2 Benefits and Risks to Subjects 
Linaclotide has the potential to improve FC symptoms. Diarrhea was the most common adverse reaction 
in studies of adults with IBS-C or CIC and older children with IBS-C and FC. In studies of adults with IBS-C 
or CIC abdominal pain, flatulence, and abdominal distension were also reported. In completed pediatric 
studies linaclotide was well tolerated across all doses (LIN‑MD‑62, LIN‑MD‑67, LIN‑MD‑63, and 
LIN-MD-64), the safety profile was consistent with prior adult linaclotide studies for CIC and IBS‑C.5 
Refer to the IB for a more detailed description of the chemistry, pharmacology, efficacy, and safety of 
linaclotide, based on studies conducted in animals, healthy volunteers, and in subjects with IBS-C and 
CIC. 
Page 10 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
There are currently no pharmacologic therapies for the treatment of FC approved in the pediatric 
population in EU and in children less than 6 years of age in US and Canada. Thus, there is a need for new 
agents with favorable safety and tolerability profiles that are effective in providing relief for the variety 
of symptoms associated with FC in pediatrics. 
Linaclotide provides an important treatment option for adult subjects with CIC and pediatric subjects 
with FC (6 to 17 years of age in US and Canada). The sponsors consider the benefit-risk balance 
favorable and support further clinical development of linaclotide as a treatment for FC in younger 
children. 
See Section 4 for details of study procedures, dose, and study design justification. 
Considering the coronavirus disease  2019 (COVID-19) pandemic and based on the information to date, 
the mechanism of action, and preclinical and clinical information, there is no expected risk for study 
subjects treated with linaclotide for COVID-19 or for subjects to experience more serious illness if 
infected. 
This study has been designed to involve as little pain, discomfort, fear and any other foreseeable risk as 
possible for the subjects. The study will be monitored throughout its course with routine medical 
monitoring and pharmacovigilance activities to ensure that the risk threshold, degree of distress, and 
the risks and benefits are being carefully managed. Details regarding criteria for dose interruptions, 
criteria for discontinuation of study drug or study, independent Data Safety Monitoring Board (DSMB), 
Internal Dose Escalation Review Committee, and additional safety considerations can be found in 
Section 5.4, Section 5.5, Section 5.10, and Section 6.  
Taken together, the efficacy and safety data from linaclotide studies to date show a favorable benefit-
risk profile for linaclotide and support the continued investigation of linaclotide in pediatric patients less 
than 6 years of age with FC. 
3 OBJECTIVES AND ENDPOINTS 
3.1 Objective and Hypothesis 
Objective for Part 1: 
To identify a tolerable, safe, and efficacious dose of linaclotide administered for 4 weeks in pediatric 
subjects, 6 months to less than 2 years of age, with FC for Part 2. 
Objective for Part 2: 
To evaluate the safety and efficacy of 4 weeks of study intervention with linaclotide in pediatric 
participants, 6 months to less than 2 years of age, with FC. 
There is no formal hypothesis corresponding to the objectives. 
Page 11 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
3.2 Key Efficacy Endpoints and Estimand 
Key efficacy endpoints for Part 1 and Part 2: 
• 
Change from baseline in 4-week overall SBM frequency rate (SBMs/week) during the Study 
Intervention Period 
• 
Change from baseline in 4-week stool consistency (Bristol Stool Form Scale) reported by a legally 
authorized representative (LAR)/parent/guardian/caregiver during the Study Intervention Period 
• 
Change from baseline in 4-week straining reported by LAR/parent/guardian/caregiver during the 
Study Intervention Period 
 
The estimands corresponding to the efficacy endpoint are the mean change from baseline in overall 
SBM frequency rate, stool consistency, and straining, regardless of premature discontinuation or 
interruption of study drug and without use of rescue medications in the linaclotide and placebo groups 
in the intent-to-treat (ITT) population. 
3.3 Additional Efficacy Endpoints 
Additional Endpoints For Part 1 and Part 2: 
• 
Achievement of no longer meeting Rome IV criteria for FC at the end of the 4-week Study 
Intervention Period 
• 
Global change in symptoms and the global severity of symptoms at each week during the Study 
Intervention Period 
 
3.4 Safety Endpoints 
Safety evaluations include frequency of AEs including AESI, clinical laboratory assessments (complete 
blood count [CBC], clinical chemistry, and urinalysis), vital sign measurements (including postural vital 
signs whenever possible according to a subject's age), ECG, physical examinations, height, and weight, as 
measures of safety and tolerability for the entire study duration. 
4 INVESTIGATIONAL PLAN 
4.1 Overall Study Design and Plan 
M21-862 is a phase 2 study to assess the safety of linaclotide (Part 1) and to evaluate the safety and 
efficacy of linaclotide in pediatric subjects (Part 2) (6 months to less than 2 years of age). The schematic 
of the study is shown in Figure 1 and Figure 2. Further details regarding study procedures are located in 
the Operations Manual. 
See Section 5 for information regarding eligibility criteria. 
Page 12 of 76

 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
Figure 1. 
Study Schematic 
 
TBD = to be determined in Part 1 
 
Figure 2. 
Study Visit Schematic for Parts 1 and 2 
 
 
This study consists of 2 Parts that include 4 cohorts in total. Part 1 has three open label cohorts and 
Part 2 has a double-blind cohort. Part 1 cohorts will be open label and enrolled sequentially with 
linaclotide in ascending doses. A linaclotide dose will be chosen for Part 2 based on the overall benefit-
risk profile of the open label cohort(s) in Part 1. Part 2 will include a double-blind cohort to assess the 
efficacy of linaclotide vs placebo. All cohorts will have a study intervention period of 4 weeks. 
Page 13 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
Up to 30 and at least 18 subjects, 6 months to less than 2 years of age, will be sequentially enrolled into 
this study: six subjects in each cohort for Cohorts 1-3 and twelve subjects for Part 2. Cohorts 1 to 3 will 
be open label with linaclotide only. Part 2 will be double blinded, and subjects will be randomized at a 
1:1 ratio to linaclotide or placebo. 
All cohorts will be of 9 to 12 weeks in duration: 0 to 4-week Screening Period (the minimal of 0 to 
4-week period only applies to subjects that need wash out from prohibited medications), a 2 to 3-week 
Preintervention Period, followed by a 4-week Study Intervention Period, and a 1-week Postintervention 
Period.  
In Part 1, linaclotide will be administered orally QD at the dose of 9 µg, 18 µg, and 36 µg for Cohort 1, 
Cohort 2 and Cohort 3, respectively. Part 2 will include additional subjects at the dose of linaclotide 
(either the 9, 18, or 36 µg dose) that exhibited the best benefit-risk profile from Part 1; and subjects 
receiving matching placebo. 
In Cohorts 1-3, at least 5 subjects per cohort will need to complete treatment with an acceptable safety 
profile assessed by an internal Dose Escalation Review Committee which will give special attention to 
the presence of AESIs for the cohort to be declared safe to escalate to the next dose level. 
In each cohort of Part 1, at least 1 subject will need to be ≤ 12 months of age. The study investigator and 
the LAR/parent/guardian will be given the option for the subject to continue in the next higher cohort 
(dose escalation) if the safety profile favors a trial cohort at a higher dose. In Part 1, new subjects will be 
recruited for each cohort, but existing subjects from previous cohorts (Cohorts 1 and 2) will be given the 
opportunity to participate in the next cohort (up to Cohort 3) if their symptoms have not improved at 
that respective dose (≤ 2 SBM per week), the subject has an acceptable tolerability to the study drug, 
and the LAR/parent/guardian is willing to continue in the study. 
Subjects who are participating in intrasubject dose escalation will need to repeat all screening 
procedures and eDiaries if > 30 days have elapsed since the subject's last dose in the previous cohort. 
Note: the screening number assigned by the Interactive response technology (IRT) at the initial 
screening visit should still be used. If symptoms have improved at the current dose level, the subject will 
be invited to participate in a long-term safety extension study, once the study is active and accepting 
subjects. An internal Dose Escalation Review Committee will be monitoring the safety of Cohorts 1-3 and 
will provide a recommendation for the dose escalation to the next cohort or to stop the study based on 
the overall benefit-risk profile. The dose will be selected based on: 1) the absence of treatment-related 
AESI within the cohort and 2) an increase in SBM frequency per week compared to baseline with or 
without improvement of at least 1 point in the Bristol Stool Form Scale (BSFS) scale. The minimum 
effective dose will be selected. 
Once the best benefit-risk dosing profile from Cohorts 1-3 has been identified, Part 2 (the final cohort) 
will include 12 subjects at 4 weeks of double-blind study intervention with linaclotide vs. placebo using 
that selected dose. An independent DSMB will review unblinded interim safety data for that cohort. 
Based on this review, the DSMB will assess the overall safety of the subjects in Part 2. 
In Part 2, new subjects will be recruited. Data based on the final selected dose will be analyzed and 
compared with a placebo. Similarly, safety and efficacy will be analyzed across all cohorts (Parts 1 and 2) 
and to placebo. Those results will be used to support the feasibility of a confirmatory Phase 3 study. 
Page 14 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
The Phase 2 open-label ascending, multidose dose finding portion of the study (Part 1) will provide a 
safe and efficient method of identifying a suitable dose to assess in Part 2 of the study, where blinding 
to randomized controlled treatment can then be employed to provide more confidence on the safety 
and efficacy of linaclotide in this young pediatric population and to support further research in a Phase 3 
study. 
4.2 Discussion of Study Design 
Choice of Study Population 
The inclusion and exclusion criteria are meant to identify a population of pediatric subjects that is well 
characterized as having FC as defined by Rome IV criteria. 
Appropriateness of Measurements 
Standard statistical, clinical, and laboratory procedures will be utilized in this study. All efficacy and 
safety-related measurements in this study are standard for assessing disease activity in subjects with FC. 
All clinical and laboratory procedures in this study are standard and generally accepted. 
Suitability of Subject Population 
Despite the fact that children with FC are commonly prescribed various and miscellaneous 
pharmacologic agents, it is notable that there are no approved products indicated for FC in children less 
than 6 years of age or well controlled trials of these frequently prescribed agents. Thus, effective 
treatments are needed to provide symptomatic relief in children less than 6 years of age with FC, with 
the evidence for safety and efficacy of these based on the results of adequate and well-controlled 
studies. 
This study is being conducted in pediatric subjects aged 6 months to less than 2 years who meet Rome 
IV criteria for FC based on the linaclotide pediatric developmental program and discussions with 
regulatory agencies. Section 5.1 outlines the eligibility criteria and the eligible subject population. 
Dose Justification 
The dose selection in this study is based on extrapolation of efficacy and safety data from Phase 2 
studies in FC subjects 2 to 17 years of age, Phase 3 studies in adult subjects with CIC, and a clinical 
research GC-C ontogeny study in pediatric patients. 
In the Phase 2 FC study, Lin-MD-67, children (2- to 5-year-olds), were administered linaclotide doses of 
18, 36, and 72 µg for 4 weeks. Those doses correspond to 1.8, 3.6, and 7.2 µg/kg in a 10 kg (22 pound) 
subject (minimum weight of a 2-year-old), respectively. Overall linaclotide was well tolerated across all 
doses evaluated in LIN-MD-67, the safety profile being consistent with that of the prior FC study 
LIN-MD-62 in 6 to 17 year‑olds and prior studies in adults with CIC. There were no deaths, SAEs, AESIs 
(i.e., significant volume depletion and/or significant electrolyte abnormalities and/or ECG abnormalities 
that were considered by the investigator or sponsor to be related to diarrhea), or AEs leading to study 
drug discontinuation for LIN-MD-67 with all TEAEs experienced by subjects being mild or moderate in 
severity. 
Page 15 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
Additionally, in the GC-C ontogeny study MCP-103-311, GC-C mRNA expression in the small bowel was 
shown to be flat with no age-dependent trend in patients 6 months to < 18 years of age.6 The doses of 
9, 18, and 36 µg QD being employed in Study M21-862 correspond to 1.8, 3.6 and 7.2 µg/kg in a 5 kg 
(11 pound) subject (minimum weight of a 6 month old), respectively and are therefore equivalent to the 
doses tested and safe in 2- to 5- year-old subjects on µg/kg basis and are expected to have an 
acceptable safety profile. Dose escalation between cohorts will be assessed based on the review of all 
available safety/tolerability data by an internal Dose Escalation Committee. Regarding risks, patients are 
closely monitored for AEs including diarrhea and well-defined AESIs. Safety measures are in place 
including stopping criteria, a safety monitoring plan, and an independent DSMB. 
5 STUDY ACTIVITIES 
5.1 Eligibility Criteria 
Subjects must meet all of the following criteria in order to be included in the study. Anything other than 
a positive response to the questions below will result in exclusion from study participation. 
Consent 
 1. The Subjects' LAR/parent/guardian must voluntarily sign and date an informed consent, 
approved by an independent ethics committee (IEC)/institutional review board (IRB), prior to 
the initiation of any screening or study-specific procedures. 
 2. The LAR/parent/guardian who will be completing the electronic diary (eDiary) is able to read 
and understand the assessments in the eDiary device and must undergo training 
 3. Subject's LAR/parent/guardian are willing and able to comply with procedures required in this 
protocol and do not have any neurodevelopmental disabilities that could impact their ability to 
complete the eDiary and study questionnaires. 
 
Demographic and Laboratory Assessments 
 4. Individuals must be 6 months to less than 1 year and 11 months old, at the time the 
LAR/parent/guardian signs the informed consent in alignment with local requirements. 
 5. Subject has no condition or clinically significant findings on a physical examination, vital sign 
assessment, ECG, or clinical laboratory tests at Screening (Visit 1), as determined by the 
investigator, based on consideration of whether the finding could represent a safety concern or 
a condition that would be exclusionary, could prevent the subject from performing any protocol 
assessments, or could confound study assessments 
 6. Subject has weight-for-height/length ratio of ≥ 3rd percentile for age 6 months to less than 
24 months at the time the LAR/parent/guardian has provided signed consent. (Investigators can 
choose to use CDC or WHO growth charts based on their current clinical practice). 
 7. Laboratory values meet the following criteria within the screening of assessments period and 
prior to the first dose of study drug:  
• 
Serum alanine transaminase (ALT) < 2 × upper limit of normal (ULN); 
Page 16 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
Per investigator's discretion all other laboratory values obtained in the screening period 
prior to the first dose of study drug must not be considered clinically significant 
abnormalities.  
 8. Subject's LAR/parent/guardian must have not been directly or indirectly involved in the 
conduct and administration of this study as an investigator, study coordinator, or other study 
staff member. In addition, any subject, LAR/parent/guardian must not have a first-degree family 
member, significant other, or relative residing with him/her who are directly or indirectly 
involved in this study. 
 
Disease/Condition Activity 
 9. Subject meets Rome IV criteria for FC as outlined below: 
For at least 1 month before Screening (Visit 1), the subject must meet 2 or more of the following 
(a-e): 
a) 2 or fewer defecations per week (with each defecation occurring in the absence of any 
laxative, suppository, or enema use during the preceding 24 hours) 
b) History of excessive stool retention 
c) History of painful or hard bowel movements (BMs) 
d) History of large-diameter stools 
e) Presence of a large fecal mass in the rectum 
Accompanying symptoms may include irritability, decreased appetite, and/or early satiety. The 
accompanying symptoms disappear immediately following passage of a large stool. 
 10. LAR/Parent/Guardian is willing to discontinue any laxatives used before the Preintervention 
Visit in favor of the protocol-permitted rescue medicine. 
• 
11. Based on the eDiary, the LAR/Parent/Guardian/Caregiver reports the subject did not have 
more than 1 loose, mushy stool (eDiary recorded stool consistency of 6 on the Bristol Stool Form 
Scale) or any watery stool (eDiary recorded stool consistency of 7 on the Bristol Stool Form 
Scale) with any SBM that occurred in the absence of laxative use on the calendar day of the BM 
or the calendar day before the BM during the 14 days before and up to 
enrollment/randomization (including the daily eDiary assessment reported before 
administration of the first dose of study intervention on the enrollment/randomization day). 
 12. Based on the eDiary, the Subject has an average of ≤ 2 spontaneous bowel movements 
(SBMs) per week during the 14 days before the enrollment/randomization day and up to the 
enrollment/randomization (including the morning eDiary assessments reported before 
administration of first dose of study intervention on the enrollment/randomization day). An 
SBM is defined as a bowel movement (BM) that occurs in the absence of laxative, enema, or 
suppository use on the calendar day of the BM or the calendar day before the BM. 
 13. LAR/Parent/Guardian/Caregivers are compliant with eDiary requirements by completing 
daily assessments for 10 out of the 14 days immediately preceding the 
enrollment/randomization visit. 
 
Page 17 of 76

 
 
 
 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
Subject History 
 14. No conditions that could interfere with drug absorption including but not limited to short 
bowel syndrome. 
 15. No history of clinically significant medical conditions or any other reason that the 
investigator determines would interfere with the subject's participation in this study or would 
make the subject an unsuitable candidate to receive study drug. 
 16. No participation in an interventional study within 30 days before Screening (Visit 1) or plans 
to receive study intervention (other than that administered during this study) 
 17. No fecal impaction at Visit 2 (Preintervention) after failing outpatient clean-out during the 
Screening Period OR no fecal impaction at Visit 3 (enrollment/randomization). 
 18. No required manual dis-impaction within 6 months prior to enrollment/randomization 
 19. No current condition of unexplained AND clinically significant alarm symptoms (lower 
gastrointestinal [GI] bleeding [rectal bleeding or heme-positive stool], iron-deficiency anemia, or 
any unexplained anemia, or weight loss) and systemic signs of infection or colitis, or any 
neoplastic process 
 20. No surgery that meets any of the following criteria: 
a) Surgery to remove a segment of the GI tract at any time before Screening (Visit 1) 
b) Surgery of the abdomen, pelvis, or retroperitoneal structures during the 6 months before 
the Screening Visit 
c) An appendectomy or cholecystectomy during the 60 days before Screening (Visit 1) 
d) Other major surgery during the 30 days before Screening (Visit 1) 
 21. No known or suspected mechanical bowel obstruction or pseudo-obstruction 
 22. No known allergy, allergic reaction, or significant sensitivity to the study intervention or its 
components and/or other medications in the same drug class 
 23. No history of: 
a) Celiac disease, or positive serological test for celiac disease or the condition is suspected but 
has not been ruled out by endoscopic biopsy 
b) Cystic fibrosis 
c) Hypothyroidism that is untreated or treated with thyroid hormone at a dose that has not 
been stable for at least 3 months prior to Screening (Visit 1) 
d) Down's syndrome or any other chromosomal disorder 
e) Active anal fissure (investigator has confirmed an active anal fissure and subject reports 
known anal fissure symptoms [i.e., streaks of blood on the stool or on diaper or toilet paper 
and pain/crying with bowel movement within 2 weeks prior to Screening]). (Note: Anal 
fissures that have resolved at least 2 weeks prior to screening would not be exclusionary). 
However, if in the investigator's opinion, an anal fissure(s) may be the primary cause of 
subject's Rome IV FC criteria, the subject would not be eligible to participate in the study. 
f) Anatomic malformations (e.g., imperforate anus, anal stenosis, anterior displaced anus) 
Page 18 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
g) Intestinal nerve or muscle disorders (e.g., Hirschsprung disease, visceral myopathies, visceral 
neuropathies) 
h) Neuropathic conditions (e.g., spinal cord abnormalities, neurofibromatosis, tethered cord, 
spinal cord trauma) 
i) 
Lead toxicity, hypercalcemia 
j) 
Inflammatory bowel disease 
k) Lactose intolerance that is associated with symptoms which could confound the 
assessments in this study 
l) 
History of cancer. (Note: Subjects with a history of cancer are allowed provided that the 
malignancy has been in a complete remission before enrollment/randomization (Visit 3). 
A complete remission is defined as the disappearance of all signs of cancer in response to 
treatment) 
 24. No known active SARS-CoV-2 infection. Per local requirements/recommendations 
SARS-CoV-2 infection should be ruled out before entering the study. Subjects who do not meet 
SARS-CoV-2 infection eligibility criteria must be screen failed and may re-screen upon recovery 
from COVID-19. 
 
Concomitant Medications 
 25. Subject did not use a protocol-specified prohibited medicine before the start of the 
Preintervention Period (Visit 2) or failed to meet the stable-dose requirements of certain 
medications 
 26. Subject did not use rescue medication on the calendar day before the 
enrollment/randomization visit and on the day of the enrollment/randomization visit prior to 
enrollment/randomization. 
 27. Subject did not participate in an interventional study within 30 days before Screening 
(Visit 1) or is planning to receive study intervention (other than that administered during this 
study). 
 28. Subject must not have been treated with any investigational drug within 30 days or 
5 half-lives of the drug (whichever is longer) prior to Screening (Visit 1) or is currently or 
planning to enroll in another clinical study or was previously enrolled in this study. 
 
5.2 Prohibited Medications and Therapy 
All medications listed below (1-day washout and 14-day washout) will be excluded during the 
Preintervention, Study Intervention, and Postintervention Periods. A 1-day washout means that 
particular medicine is not allowed during the calendar day before the Preintervention Visit (not 
permitted 24-hours prior to the Preintervention Visit); a 14-day washout means that the particular 
medicine is not allowed during the 14 calendar days before the Preintervention Visit. Per investigator's 
discretion, subjects who are screen failed for failing to meet washout requirements may be re-screened. 
Page 19 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
1 Day Washout 
1. Any over the counter or prescription laxative, suppository, or enema (e.g., polyethylene glycol, 
lactulose, Fleet enema) and any herbal or natural agent that might be taken for constipation. 
(Note: The use of fiber, bulk laxatives, stool softeners, and probiotics is acceptable, provided 
that the subject has been on a stable dose for 30 days before the Screening Visit (Visit 1) and 
plans to continue stable dosing for the duration of the study) 
2. Any medicine used to treat diarrhea (e.g., bismuth subsalicylate, kaolin) 
 
14 Day Washout 
1. Drugs with known pharmacologic activity at 5-HT4, 5-HT2b or 5-HT3 receptors (e.g., cisapride, 
tegaserod, prucalopride, ondansetron, tropisetron, granisetron, dolasetron, mirtazapine) 
2. Any of the following treatments either alone or in combination: plecanatide, lubiprostone, 
colchicine, linaclotide, and misoprostol. 
3. Prokinetic agents (e.g., metoclopramide, itopride, domperidone) 
4. Anticholinergic agents (e.g., dicyclomine, flavoxate, scopolamine, hyoscyamine, propantheline, 
oxybutynin, tolterodine, solifenacin, darifenacin, trospium). (Note: inhaled ipratropium and 
tiotropium are permitted at the discretion of the investigator) 
5. Bile acid sequestrants (e.g., cholestyramine, colestipol) 
6. Cholinomimetic agents (e.g., bethanechol, pyridostigmine, tacrine, physostigmine). 
(Note: intraocular cholinomimetic agents such as pilocarpine are permitted at the discretion of 
the investigator) 
7. Antipsychotic agents (e.g., risperidone, haloperidol, droperidol, chlorpromazine, perphenazine 
and any other phenothiazines, quetiapine, olanzapine, clozapine), unless the subject has been 
on a stable dose for 30 days before the Screening Visit (Visit 1) and plans to continue stable 
dosing for the duration of the study. (Note: paliperidone is permitted at the discretion of the 
investigator) 
8. Antidepressants, unless the subject has been on a stable dose for 30 days before the Screening 
Visit (Visit 1) and plans to continue stable dosing for the duration of the trial. Specifically 
included are the following prohibited antidepressants: 
a) Tricyclic antidepressants (e.g., amitriptyline, imipramine, nortriptyline) 
b) Monoamine oxidase inhibitors (e.g., furazolidone, isocarboxazid, pargyline, phenelzine, 
selegiline, tranylcypromine) 
c) Selective serotonin reuptake inhibitors (e.g., fluoxetine, sertraline, paroxetine, escitalopram, 
citalopram, vilazodone) 
d) Serotonin-norepinephrine-reuptake inhibitors (e.g., levomilnacipran, duloxetine, 
venlafaxine, desvenlafaxine succinate) 
e) Other antidepressants (e.g., trazodone, bupropion) 
Page 20 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
9. Calcium-channel blocker verapamil, unless the subject has been on a stable dose for 30 days 
before the Screening Visit (Visit 1) and plans to continue stable dosing for the duration of the 
study. (Note: all other calcium-channel blockers [e.g., nifedipine, diltiazem, amlodipine, 
felodipine, nicardipine, nimodipine, nisoldipine] are permitted and may be used without 
restriction) 
10. Oral and parenteral antibiotics; however, 1 standard regimen (up to 10 days) of oral antibiotics 
is permitted during the Study Intervention and Postintervention Periods 
11. Any study intervention or imported drugs that have not been approved for human use. 
12. All narcotics (e.g., tramadol, codeine, morphine, propoxyphene, loperamide, diphenoxylate, 
paregoric), either alone or in combination. Note: narcotics used as anesthesia for a colonoscopy 
require a 5-calendar day wash-out prior to the subject entering into the Preintervention Period. 
Dextromethorphan, the cough suppressant in many over-the counter cold and cough medicines, 
is allowed 
13. Any medicine that is known to cause diarrhea or constipation (e.g., acarbose) 
14. Proton pump inhibitors (e.g., omeprazole, lansoprazole, esomeprazole, pantoprazole, 
rabeprazole), unless the subject has been on a stable dose for 30 days before the Screening Visit 
(Visit 1) and plans to continue stable dosing for the duration of the study 
15. Other drugs such as barbiturates (e.g., butalbital, phenobarbital) and chronic oral or parenteral 
glucocorticoids, which must be discontinued at least 3 months before screening. However, one 
10-day course of oral or 1 injection of parenteral glucocorticoids is permitted during the Study 
Intervention and Postintervention Periods. Pregabalin is acceptable, provided the subject has 
been on a stable dose during the 30 days before the Screening Visit and plans to continue stable 
dosing throughout the study. 
 
5.3 Prior and Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements) that the subject is receiving at the time of enrollment or receives during the study 
must be recorded from 28 days prior to study drug administration through the 1-week postintervention 
visit ([Visit 6]). 
Any questions regarding concomitant or prior therapy should be raised to the AbbVie emergency 
contact. Information regarding potential drug interactions with linaclotide can be located in the 
linaclotide IB. 
Subjects must be able to safely discontinue any prohibited medications 5 half-lives or 4 weeks prior to 
initial study drug administration. Legally authorized representative/parent/guardian must provide 
consent for the study prior to the subject discontinuing any prohibited medications for the purpose of 
meeting study eligibility. Protocol-permitted rescue medications are shown in Table 2. 
Page 21 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
Table 2. 
Rescue Concomitant Medications/Therapy 
Rescue Concomitant 
Medications/Therapy  
Comments/Notes 
Lactulose (oral) 
Rescue medication may be taken when at least 72 hours have passed since the 
subject's previous BM or when their symptoms become intolerable. 
Glycerin suppositories 
(rectal) 
If fecal impaction is identified at Screening (Visit 1), subjects will receive a 
disimpaction regimen with either oral or rectal medication managed at the 
discretion of the investigator. Options will include any over-the-counter or 
prescription laxative, suppository, or enema (e.g., polyethylene glycol, lactulose, 
Fleet enema). 
BM = bowel movement 
 
5.4 Dose Interruption 
Subjects with poor tolerability (as determined by the investigator), can temporarily interrupt the study 
drug for 3 consecutive days and resume the same dose if tolerability improves. If not, subjects will 
discontinue the investigational drug per the Discontinuation Criteria Section of this document 
(Section 5.5 and Section 6.2). 
5.5 Withdrawal of Subjects and Discontinuation of Study 
A subject whose LAR/parent/guardian gave consent may voluntarily withdraw the subject or the subject 
can be withdrawn from the study at any time for reasons including, but not limited to, the following: 
• 
Clinically significant abnormal laboratory results or AEs, which rule out continuation of the study 
drug, as determined by the investigator or the Sponsor. 
• 
The investigator believes it is in the best interest of the subject. 
• 
The LAR/parent/guardian requests withdrawal from the study. 
• 
Eligibility criteria violation was noted after the subject started study drug and continuation of 
the study drug would place the subject at risk. 
• 
Introduction of prohibited medications or dosages and continuation of the study drug would 
place the subject at risk. 
• 
The investigator determines the subject is significantly noncompliant with study procedures. 
 
Discontinuation Criteria 
A premature discontinuation will occur when a subject (whose LAR/parent/guardian who gave consent) 
ceases participation in the study, regardless of circumstances, before the completion of the protocol-
defined study procedures. 
Page 22 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
Subjects must be prematurely discontinued from the study for reasons of safety including those who 
experience: 
• 
An SAE considered by the investigator or the sponsor to be possibly related or related to study 
intervention,  
• 
An AESI (Clinically significant [per investigator's discretion] dehydration due to diarrhea causing 
hospitalization, significant electrolyte abnormalities related to diarrhea and/or ECG 
abnormalities related to diarrhea that are considered by the investigator or sponsor to be 
related to the study drug. Refer to Table 3 and Table 4), 
• 
The presence of intentional overdose or intentional misuse per investigator discretion, 
• 
The occurrence of any other AE that in the opinion of the investigator or the sponsor is possibly 
related or related to the study intervention that represents a clinically significant safety risk to 
the subject. 
 
Table 3. 
Potentially Clinically Significant Electrolyte Values 
Parameter 
Lower Limit 
Upper Limit 
Bicarbonate 
< 0.9 × LLN 
> 1.1 × ULN 
Chloride 
< 0.9 × LLN 
> 1.1 × ULN 
Magnesium 
< 0.9 × LLN 
> 1.1 × ULN 
Potassium 
< 0.9 ×LLN 
> 1.1 × ULN 
Sodium 
< 0.9 × LLN 
> 1.1 × ULN 
LLN = lower limit of normal value provided by the laboratory; ULN = upper limit of normal value provided by the laboratory 
 
Table 4. 
Potentially Clinically Significant ECG Values 
Parameter 
Higher Limit 
QRS interval 
QRS ≥ 115 msec  
PR interval 
PR > 225 msec  
QTc 
> 480 msec 
ECG = electrocardiogram; QTc = QT interval corrected for heart rate 
 
Subjects may also be prematurely discontinued from the study for reasons of safety including those who 
experience: 
• 
A vital sign, ECG, and/or laboratory abnormality judged to be clinically significant by the 
investigator and that in the opinion of the investigator or the sponsor is possibly related or 
related to the study intervention  
• 
An intolerable AE (defined as an AE that subjectively would cause a subject to consider study 
withdrawal), as determined by the investigator or the Sponsor. 
 
Page 23 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
Additionally, discontinuation of study intervention for abnormal liver function should be considered by 
the investigator when a subject meets the criteria for Hy's law or the appearance of abnormal 
laboratory test results suggesting severe drug-induced liver injury (DILI), or if the investigator believes 
that it is in best interest of the subject. If Hy's law criteria are met and it is considered, in the opinion of 
the investigator or the Sponsor, to be possibly related to the study drug, the subject must be 
discontinued from the study. Refer to Appendix E for additional information. 
All enrolled subjects who prematurely discontinue from the study, regardless of cause, should be seen 
for the assessments to be completed at the End of Treatment (EOT) Visit. The EOT assessments are 
defined as completion of evaluations scheduled for all subjects. 
Subjects who discontinue from the study and do not return to the study site for EOT Visit (Visit 5) must 
be requested in writing to return to the study site for procedures required at the EOT Visit as defined in 
the Activity Schedule (Appendix D) and return any unused study intervention. A copy of the letter, 
together with the source documentation, will be kept in the investigator's files. The reason for 
premature discontinuation from the study will be recorded on the Study Termination Page of the 
electronic case report form (eCRF). Study site staff will be contacted by the sponsor after each 
premature discontinuation to ensure proper characterization of the reason for discontinuation is 
captured. 
See the Activity Schedule (Appendix D) for data to be collected at the time of study intervention 
discontinuation and follow-up and for any further evaluations that need to be completed. 
Subjects in this study who prematurely discontinue study intervention will not be replaced (e.g., no 
more subjects will be allowed to enter the study once randomization is completed). 
Criteria for Consideration of Study Discontinuation 
Dosing and enrollment will be immediately paused for all subjects at all sites and a thorough review will 
be initiated after any one of the following conditions has been met in subjects who have received study 
intervention at any time in the study: 
• 
Any life-threatening SAE that is considered by the investigator or the sponsor to be possibly 
related or related to the study intervention. 
• 
Any SAE resulting in death that is considered by the investigator or the sponsor to be possibly 
related or related to the study intervention. 
 
In the event of a pause in enrollment and dosing, the DSMB will be notified and their recommendation 
on an appropriate course of action will be sought. This may include resuming enrollment, continuing a 
hold on enrollment, resuming the study intervention, amending the protocol or stopping the study 
(refer to Section 5.10 for additional data safety monitoring information). The decision to restart or to 
stop the study will be made by the sponsor, following a thorough review of all clinical, laboratory, DSMB 
recommendations, and other available safety data. 
Lost to Follow up  
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled visits 
and is unable to be contacted by the study site. 
Page 24 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
The following actions must be taken if a subject fails to return to the clinic for a required study visit: 
• 
The site must attempt to contact the subject's LAR/parent/guardian and reschedule the missed 
visit as soon as possible and counsel them on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in the 
study. 
• 
Before a subject is deemed lost to follow-up, the investigator or designee must make every 
effort to regain contact with the subject's LAR/parent/guardian (where possible, 3 telephone 
calls and, if necessary, a certified letter to the subject's last known mailing address or local 
equivalent methods). These contact attempts will be documented in the subject's study record. 
• 
Should the subject's LAR/parent/guardian continue to be unreachable, the subject will be 
considered to have withdrawn from the study. 
 
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the subject's final status. At a minimum, 2 telephone calls must be made and 1 certified 
letter must be sent and documented in the subject's source documentation. 
AbbVie may terminate this study prematurely, either in its entirety or at any site. The investigator may 
also stop the study at their site if they have safety concerns. If AbbVie terminates the study for safety 
reasons, AbbVie will promptly notify the investigator. 
5.6 Follow-Up After Subject Discontinuation of Study Drug or from 
Study 
To minimize missing data for efficacy and safety assessments, subjects who prematurely discontinue 
study drug treatment due to an AE should continue to be followed for all regularly scheduled visits, 
unless subject's LAR/parent/guardian has decided to discontinue the study participation entirely 
(withdrawal of informed consent). Subjects should be advised on the continued scientific importance of 
their data even if they discontinue treatment with study drug early. 
If a subject prematurely discontinues study participation (withdrawal of informed consent), the 
procedures outlined for the Premature Discontinuation visit (PD visit) should be completed as soon as 
possible, preferably within 2 weeks of the last visit. In addition, if the LAR/parent/guardian is willing, the 
1-week postintervention visit (after the last dose of study drug) may be completed to ensure all 
treatment-emergent AEs/SAEs have been resolved. 
5.7 Study Drug 
Study drug will be administered at the study site after confirming eligibility. 
Study drug dose preparation and administration instructions will be provided separately. 
Linaclotide (or matching placebo for Part 2 only) will be taken orally once daily beginning on Day 1 
(Baseline) and should be taken at approximately the same time each day, 15 - 30 minutes before a meal. 
If subjects should forget to take their study drug dose at their regularly scheduled dosing time, they 
Page 25 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
should take the forgotten dose as soon as they remember as long as it is at least 15 - 30 minutes before 
their next meal. Otherwise, they should take the next dose at the next scheduled dosing time; subjects 
may eat 15 - 30 minutes after dosing. No redosing will be allowed on the same day. 
The subject must complete at least 4 weeks (28 days) intervention period before returning for the 
Week 4/Day 29 End of Treatment (EOT) (Visit 5). 
Subject dosing will be recorded on a subject dosing eDiary. The LAR/parent/guardian will be instructed 
to return all drug containers (even if empty) to the study site personnel at each study visit. If required, 
the LAR/parent/guardian should also return the receptacle containing unused solution to the study site 
personnel for destruction. The study site personnel will document compliance.  
AbbVie will provide study drug for linaclotide (or matching placebo for Part 2 only). AbbVie provided 
study drug should not be substituted or alternately sourced unless otherwise directed by AbbVie. Study 
drug will only be used for the conduct of this study. 
If a subject's LAR/parent/guardian is unable to come to the study site to pick up the subject's study drug 
due to COVID-19, a direct-to-patient (DTP) study drug shipment can be made from the study site to the 
subject's LAR/parent/guardian if allowed by local regulations. AbbVie will submit any required 
notifications to the regulatory authority as applicable. Refer to the Operations Manual in Appendix G for 
details on DTP shipment of study drug. 
Linaclotide and matching placebo will be packaged in bottles with quantities sufficient to accommodate 
study design. Each kit will be labeled per local requirements and this label must remain affixed to the kit. 
Upon receipt, study drug should be stored as specified on the label. Each kit will contain a unique kit 
number. This kit number is assigned to a subject via IRT and encodes the appropriate study drug to be 
dispensed at the subject's corresponding study visit. Site staff will complete all blank spaces on the label 
before dispensing to subjects. 
Upon completion of or discontinuation from study treatment, all original study drug units (containing 
unused study drugs) will be returned to the sponsor (or designee) or destroyed on site. All return or 
destruction procedures will be according to instructions from the sponsor and according to local 
regulations following completion of drug accountability procedures. 
AbbVie will provide instructions to the LAR/parent/guardian for drug preparation. 
Table 5. 
Identity of Study Drug 
Study Drug 
Linaclotide 
Linaclotide 
Linaclotide 
Placebo for 
Linaclotide 
Dosage Forma 
Capsulea 
Capsulea 
Capsulea 
Capsulea 
Strength 
72 µg 
145 µg 
290 µg 
N/A 
Route of Administration 
Oral 
Oral 
Oral 
Oral 
N/A = not applicable 
a. 
The entire capsule contents will be used in dose preparation of an oral solution to achieve the assigned dosage strength 
per cohort. The LAR/parent/guardian will prepare the dose prior to subject's administration of the study drug. Complete 
dosing instructions will be provided to the LAR/parent/guardian. 
 
Page 26 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
5.8 Randomization/Drug Assignment 
All subjects will be assigned a unique identification number by the IRT at the screening visit. For subjects 
who rescreen, the screening number assigned by the IRT at the initial screening visit should be used. The 
IRT will assign a randomization number that will encode the subject's treatment group assignment 
according to the randomization schedule. 
Cohorts 1-3 will be open label linaclotide. Only Part 2 (the final cohort) will be randomized to either 
linaclotide or placebo at a 1:1 ratio. 
All AbbVie personnel with direct oversight of the conduct and management of the trial (with the 
exception of AbbVie Drug Supply Management Team), the investigator, study site personnel, and the 
subject's LAR/parent/guardian will remain blinded to each subject's treatment throughout Part 2 of the 
study. To maintain the blind, the linaclotide capsules and placebo capsules provided for the study will be 
identical in appearance.  
For Part 2, the IRT will provide access to unblinded subject treatment information in the case of a 
medical emergency. In the event of a medical emergency that requires unblinding of the study drug 
assignment, the investigator is requested to contact the Emergency Medical Contact (AbbVie 
Therapeutic Area Medical Director) prior to breaking the blind. However, if an urgent therapeutic 
intervention is necessary which warrants breaking the blind prior to contacting the AbbVie TA MD, the 
investigator can directly access the IRT system to break the blind without AbbVie notification or 
agreement. Unblinding is available in the IRT system via the Unblind Subject transaction, which is 
available only to the investigator. If the IRT system is unavailable, unblinding may occur by contacting 
the technical support of the IRT vendor via either phone (preferred) or email 
(support@endpointclinical.com). For country-specific phone numbers, please see the following website: 
https://www.endpointclinical.com/support/. 
In the event that the blind is broken before notification to the AbbVie TA MD, we request that the 
AbbVie TA MD be notified within 24 hours of the blind being broken. The date and reason that the blind 
was broken must be conveyed to AbbVie and recorded on the appropriate eCRF. 
5.9 Protocol Deviations 
AbbVie does not allow intentional/prospective deviations from the protocol except when necessary to 
eliminate an immediate hazard to study subjects. The investigator is responsible for complying with all 
protocol requirements, written instructions, and applicable laws regarding protocol deviations. If a 
protocol deviation occurs (or is identified, including those that may be due to COVID-19), the 
investigator is responsible for notifying independent ethics committee IEC/independent review board 
(IRB), regulatory authorities (as applicable), and AbbVie. Any deviations that occur as a result of 
COVID-19 should also be documented in the source records. 
Page 27 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
5.10 Rescreening 
Subjects who initially screen-failed for the study are permitted to rescreen once following reconsent. For 
additional rescreening, Sponsor approval is required for any subsequent rescreens (i.e., after the first 
rescreen). As appropriate, sites are encouraged to contact Sponsor to confirm if subjects should or 
should not be rescreened. All screening procedures will be repeated during rescreening. The subject 
must meet all the eligibility criteria at the time of rescreening in order to qualify for the study. There 
should be a 30 day gap period between screen-fail and rescreening.  
5.11 Data Safety Monitoring  
Part 1 Open Label Cohorts 
In Part 1 all AE data and the occurrence of intolerable diarrhea will be reported to the sponsor. The 
Internal Dose Escalation Review committee will monitor Part 1 and based on the frequency and severity 
of the events, could recommend halting the administration of the investigational product (more details 
are described in a separate charter). The Internal Dose Escalation Review committee will also give 
special attention to the presence of AESIs. A cohort will be stopped if 1 treatment-related AESI occurs. If 
no treatment-related AESI occurred, the Dose Escalation Review Committee will decide on whether to 
proceed with the next cohort. 
Part 2 Randomized Double Blind Placebo Controlled Cohort 
In Part 2 an external DSMB composed of clinicians and statisticians independent of AbbVie and with 
relevant expertise in their field will review unblinded safety data from the ongoing study. The DSMB is 
responsible for safeguarding the interests of trial subjects, assessing the safety of the interventions 
during the trial, as well as for monitoring the integrity and interpretability of the trial. The DSMB will 
provide recommendations to the sponsor regarding ongoing trial conduct or modifications to the trial as 
described in a separate DSMB charter. 
In order to maintain sponsor blinding, an external Statistical Data Analysis Center is responsible for 
performing the analyses described in the DSMB charter as well as additional analyses requested by the 
DSMB and facilitating interpretation and answering questions that arise before, during or after DSMB 
review. An independent DSMB will review unblinded interim safety data for Part 2. 
The DSMB will regularly review unblinded safety data from the ongoing study according to the schedule 
provided in the DSMB charter, including AEs, laboratory values, vitals sign values and ECG results. The 
occurrence of intolerable diarrhea will be reported to the sponsor and will be monitored; In addition to 
all AE data, by an external DSMB, who, based on the frequency and severity of the events, could 
recommend halting the administration of the investigational product. 
A separate DSMB charter will be prepared outside of the protocol and will further describe the roles and 
responsibilities of the DSMB members, frequency and scope of the data reviews, and expectations for 
blinded communications. 
Page 28 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
6 SAFETY CONSIDERATIONS 
6.1 Complaints and Adverse Events 
Complaints 
A complaint is any written, electronic, or oral communication that alleges deficiencies related to the 
physical characteristics, identity, quality, purity, potency, durability, reliability, safety, effectiveness, or 
performance of a product/device. Complaints associated with any component of this investigational 
product must be reported to AbbVie. 
Product Complaint 
A product complaint is any complaint related to the biologic or drug component of the product or to the 
medical device component(s). 
For a product this may include, but is not limited to, damaged/broken product or packaging, product 
appearance whose color/markings do not match the labeling, labeling discrepancies/inadequacies in the 
labeling/instructions (e.g., printing illegible), missing components/product, device damage or not 
working properly, or packaging issues. 
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 24 hours of the study site's knowledge of the event. 
Reporting will be done via electronic data capture (EDC). The date the product complaint details are 
entered into EDC and the form is saved represents the date reported to AbbVie. A back-up paper form 
will be provided for reporting complaints related to unassigned product or in the event of an EDC system 
issue. If a back-up paper form is used, the date the form is emailed to RD_PQC_QA@abbvie.com 
represents the date reported to AbbVie. 
All follow-up information is to be reported to the sponsor (or an authorized representative) and 
documented in source as required by the sponsor. Product complaints associated with AEs will be 
reported in the study summary. All other complaints will be monitored on an ongoing basis. Product 
complaints occurring during the study will be followed up to a satisfactory conclusion. 
Medical Complaints/Adverse Events and Serious Adverse Events: Linaclotide 
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not the event is considered causally related to the use of the 
product. 
Such an event can result from use of the drug as stipulated in the protocol or labeling, as well as from 
"special situations" such as accidental or intentional overdose, medication error, occupational or 
accidental exposure, off-label use, drug abuse, drug misuse, or drug withdrawal, all which must be 
reported whether associated with an AE or not. Any worsening of a pre-existing condition or illness is 
Page 29 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
considered an AE. Worsening in severity of a reported AE should be reported as a new AE. Laboratory 
abnormalities and changes in vital signs are considered to be AEs only if they result in discontinuation 
from the study, necessitate therapeutic medical intervention, meets protocol-specific criteria 
(see Section 6.2 regarding toxicity management), and/or if the investigator considers them to be AEs. 
The investigators will monitor each subject for clinical and laboratory evidence of AEs on a routine basis 
throughout the study. All AEs will be followed to a satisfactory conclusion. 
An elective surgery/procedure scheduled to occur during a study will not be considered an AE if the 
surgery/procedure is being performed for a pre-existing condition and/or the surgery/procedure has 
been pre-planned prior to study entry. However, if the pre-existing condition deteriorates unexpectedly 
during the study (e.g., surgery performed earlier than planned), then the deterioration of the condition 
for which the elective surgery/procedure is being done will be considered an AE. 
If an AE, whether associated with study drug or not, meets any of the following criteria, it is to be 
reported to AbbVie clinical pharmacovigilance as a SAE within 24 hours of the site being made aware of 
the SAE (refer to Section 4.2 of the Operations Manual for reporting details and contact information): 
Death of Subject 
An event that results in the death of a subject. 
Life-Threatening 
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not been 
taken. This does not include an event that would have been fatal if it 
had occurred in a more severe form. 
Hospitalization or 
Prolongation of 
Hospitalization 
An event that results in an admission to the hospital for any length 
of time or prolongs the subject's hospital stay. This does not include 
an emergency room visit or admission to an outpatient facility. 
Congenital Anomaly 
An anomaly detected at or after birth, or any anomaly that results in 
fetal loss. 
Persistent or Significant 
Disability/Incapacity 
An event that results in a condition that substantially interferes with 
the activities of daily living of a study subject. Disability is not 
intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle). 
Page 30 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
Important Medical Event 
Requiring Medical or Surgical 
Intervention to Prevent 
Serious Outcome 
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity). Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important 
medical event along with any suspected transmission of an 
infectious agent via a medicinal product if no other serious criterion 
is applicable. Examples of such events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug 
abuse. 
 
All adverse events reported from the time of study drug administration up to 30 days, after 
discontinuation of study drug administration will be collected, whether solicited or spontaneously 
reported by the subject. After 30 days, following the last dose of study drug or completion of study 
treatment only spontaneously reported SAEs will be collected (nonserious AEs will not be collected). In 
addition, study procedure-related serious and nonserious adverse events will be collected from the time 
the subject signs the study-specific informed consent. 
The following definitions will be used for Serious Adverse Reactions (SAR) and Suspected Unexpected 
Serious Adverse Reaction (SUSAR): 
SAR 
Defined as all noxious and unintended responses to an IMP related to any dose 
administered that result in an SAE as defined above. 
SUSAR 
Refers to individual SAE case reports from clinical trials where a causal 
relationship between the SAE and the IMP was suspected by either the sponsor 
or the investigator, is unexpected (not listed in the applicable Reference Safety 
Information), and meets one of the above serious criteria. 
 
AbbVie will be responsible for SUSAR reporting for the Investigational Medicinal Product (IMP) in 
accordance with global and local requirements. 
Adverse events will be monitored throughout the study to identify any of special interest that may 
indicate a trend or risk to subjects. 
Adverse Events of Special Interest 
The following AESI will be monitored during the study: 
• 
Clinically significant (per investigator's discretion) dehydration due to diarrhea causing 
hospitalization, which is considered by the investigator or sponsor to be related to the study 
drug. 
Page 31 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
• 
Clinically significant (per investigator's discretion) electrolyte abnormalities due to diarrhea, 
which is considered by the investigator or sponsor to be related to the study drug. 
• 
Clinically significant (per investigator's discretion) ECG abnormalities due to diarrhea, which is 
considered by the investigator or sponsor to be related to the study drug. 
 
The investigator should contact the sponsor if there is any question whether the criteria for an AESI have 
been met. 
To ensure the safety of the subjects, children will be carefully monitored for safety and tolerability. 
Legally authorized representative/parents/guardians will be instructed to stop the drug and contact the 
investigator in case of the onset of any AESI. Additionally, the occurrence of intolerable diarrhea (as 
assessed by the investigator), will be reported to the sponsor. Intolerable diarrhea and all AE data will be 
monitored by the DSMB, who, based on the frequency and severity of the events, could recommend 
halting the administration of investigational product (refer to Section 5.10 for additional details). 
Adverse Event Severity and Relationship to Study Drug 
The investigator will rate the severity of each AE according to the NCI CTCAE (Version 4.03)  
The investigator will use the following definitions to assess the relationship of the AE to the use of study 
drug: 
Reasonable 
Possibility 
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
sufficient evidence (information) to suggest a causal relationship. 
No Reasonable 
Possibility 
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
insufficient evidence (information) to suggest a causal relationship. 
 
6.2  Toxicity Management 
The management of specific AEs and laboratory parameters is described in the Operations Manual. This 
includes AEs of: 
• 
Clinically significant (per investigator's discretion) dehydration due to diarrhea causing 
hospitalization, which is considered by the investigator or sponsor to be related to the study 
drug. 
• 
Clinically significant (per investigator's discretion) electrolyte abnormalities due to diarrhea, 
which is considered by the investigator or sponsor to be related to the study drug. 
• 
Clinically significant (per investigator's discretion) ECG abnormalities due to diarrhea, which is 
considered by the investigator or sponsor to be related to the study drug. 
 
Page 32 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
This also includes the following laboratory abnormalities: Significant electrolyte abnormalities related to 
diarrhea. For allowed study drug interruption, the following rules apply: 
1. Allow study drug interruption up to 3 consecutive days for tolerability, AEs, and emergency 
surgery.  
2. If the subject must undergo emergency surgery, the study drug should be interrupted at the 
time of the surgery. After emergency surgery, allow reintroduction of study drug once the 
physician has examined the surgical site and determined that it has healed and there is no sign 
of infection. 
3. Additionally, the occurrence of intolerable diarrhea will be reported to the sponsor and will be 
monitored, in addition to all AE data, by an internal Dose Escalation Review Committee (open 
label cohorts Part 1) or an external DSMB (double-blind Part 2 [final cohort]), who, based on the 
frequency and severity of the events, could recommend halting the administration of 
investigational product. 
 
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE 
7.1 Statistical and Analytical Plans 
The statistical methods provided in this protocol will be focused on key analyses. Complete and specific 
details of the statistical analysis, including handling of missing data, will be described in the Statistical 
Analysis Plan (SAP). 
7.2 Definition for Analysis Populations 
The ITT Population includes all subjects who received at least 1 dose of study drug. The ITT Population 
will be used for all efficacy analyses. 
The Safety Analysis Set consists of all subjects who received at least 1 dose of study drug. 
7.3 Handling Potential Intercurrent Events for the Primary and Key 
Secondary Endpoints 
The key efficacy endpoints (defined in Section 3.2) will be analyzed on the ITT population and subjects 
with the following potential intercurrent events will be handled as follows: 
• 
The BMs for subjects 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 an SBM during the efficacy analysis. 
• 
Subjects who discontinue prematurely during but prior to the completion of the study 
intervention period will have their eDiary data included up to the last dose date for the 
endpoint. The SBM frequency rate based on included eDiary data up to the last dose date will be 
considered equivalent to the 4-week SBM frequency rate. 
Page 33 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
• 
Subjects who have study drug interruption will have their eDiary data included as observed 
(i.e., regardless of interruption of study drug). 
 
7.4 Statistical Analyses for Efficacy 
The efficacy analysis will be summarized in the ITT Population descriptively and no statistical testing will 
be performed in this study. 
Summary and Analysis of the Key Efficacy Endpoints 
Analysis of the key efficacy endpoints will be conducted on the ITT population. The key efficacy 
endpoints will be analyzed via descriptive summary statistics in terms of mean, median, standard 
deviation, standard error of mean, minimum, and maximum. 
The numerator of the SBM rate (SBMs/week) during the Study Intervention Period will be derived based 
on the total number of SBMs reported by a LAR/parent/guardian/caregiver as being directly observed 
during this period in the eDiary. Additional analysis will also be performed based on the total number of 
SBMs reported during the Study Intervention Period (including SBMs not directly observed by the 
LAR/parent/guardian/caregiver) and the corresponding baseline SBM frequency rate will be determined 
based on the total number of SBMs reported during the Preintervention period. 
Stool consistency for each LAR/parent/guardian/caregiver-observed BM will be measured daily in the 
eDiary using the 7-point ordinal BSFS. A participant's BSFS score for the Study Intervention Period will be 
the average of the non-missing BSFS scores from the caregiver-observed SBMs during the 4-week Study 
Intervention Period. If no caregiver-observed SBMs are present at baseline, the baseline BSFS score 
reported by the caregiver will be missing and, therefore, that subject will not be included in the change 
from baseline stool consistency analysis. 
Straining for each LAR/parent/guardian/caregiver caregiver-observed BM will be collected daily in the 
eDiary device, using a 4-point scale based on two questions. The subject's average straining score for 
each caregiver-observed BM will be derived based on the average of nonmissing responses of the two 
straining questions. The participant's straining score in the 4-week Study Intervention Period will be the 
average of the non-missing average straining scores from all caregiver-observed SBMs during the 
4-week Study Intervention Period. If a subject has no caregiver-observed SBMs at baseline, then the 
baseline straining score reported by the caregiver will be missing and, therefore, that subject will not be 
included in the change from baseline straining analysis. 
Subgroup Analysis for Efficacy 
The key efficacy endpoints will be summarized descriptively for age groups from 6-months to less than 
1 year and 1 year to 2 years of age. 
7.5 Statistical Analyses for Safety 
All safety analyses will be conducted on the safety population. No statistical analysis will be performed 
on any of the safety assessments. 
Page 34 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
Adverse events, growth parameters of height and weight, vital signs, and clinical laboratory 
measurements will be summarized using descriptive statistics for continuous variables and frequency 
distributions for categorical variables. For all safety variables, subject data listings will be provided. 
Adverse events will be tabulated using the MedDRA system organ class and Preferred Term. Adverse 
events will be summarized by the number of subjects with AEs. For clinical laboratory parameters, 
values outside the normal ranges and clinically significantly abnormal laboratory values will be listed. 
All safety endpoints and analyses will be fully defined in the SAP. 
7.6 Overall Type I Error Control 
No multiplicity adjustment will be applied because there are no statistical hypotheses for the key 
efficacy endpoints. 
7.7 Sample Size Determination 
The planned total sample size is up to 30 and at least 18 subjects. Sample size in this study is not driven 
by statistical consideration. Instead, this study is designed to enroll a sufficient number of pediatric 
subjects to observe the clinical response trends and monitor safety. 
8 ETHICS 
8.1 Independent Ethics Committee/Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the Independent Ethics Committee/Institutional Review Board (IEC/IRB) for review and 
approval. Approval of both the protocol and the informed consent form(s) must be obtained before any 
subject is enrolled. Any amendment to the protocol will require review and approval by the IEC/IRB 
before the changes are implemented to the study. In addition, all changes to the consent form(s) will be 
IEC/IRB approved. 
8.2 Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, Operations Manual, International Council 
for Harmonisation (ICH) guidelines, applicable regulations, and guidelines governing clinical study 
conduct and the ethical principles that have their origin in the Declaration of Helsinki. Responsibilities of 
the investigator are specified in Appendix B. Investigators should notify AbbVie if any urgent safety 
measures are taken to protect the subjects against any immediate hazard. 
8.3 Subject Confidentiality 
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes." No identifiable information will be provided to AbbVie. 
Page 35 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
For the personal data that AbbVie, and for sites in the EU AbbVie Deutschland GmbH & Co, controls and 
maintains, AbbVie has developed a robust security program focused on due diligence in design, 
managed change, and information security governance. Information security policies govern the 
information security functions including identity and access management, operations, infrastructure, 
application, and third-party security requirements. The risk-based AbbVie Data Classification Tool 
dictates the level of scrutiny and control required for the relevant activities per AbbVie's information 
security policies taking into account the sensitivity of the data. 
Before subject data are shared with AbbVie, the study doctor and staff will replace any information that 
could directly identify a subject (such as name, address, and contact information) with a generic code 
which AbbVie cannot link to that subject's identity to protect the confidentiality of the data. 
AbbVie has a data protection impact assessment (DPIA) program to ensure and document the 
appropriate controls and safeguards stated above are in place for clinical trial data that it controls and 
maintains, and these processing activities respect the privacy of clinical trial subjects. AbbVie also 
maintains robust security incident response policies and procedures, including requirements for the 
containment of any data related incidents, the mitigation measures where needed, and notification to 
authorities or affected individuals where required. 
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported. All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data. Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s). During the COVID-19 pandemic remote data review/verification may be employed if 
allowed by the local regulatory authority, IRB/IEC, and the study site. 
10  DATA QUALITY ASSURANCE 
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits in order to ensure human subject protection and reliability of study results. Data 
will be generated, documented, and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements. 
11  START AND COMPLETION OF THE STUDY 
The start-of-study is defined as the date of the first site activated. 
The end-of-study is defined as the date of end of study participation by the last subject in the last 
country where the study was conducted. 
Page 36 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
12  REFERENCES 
1. Koppen IJN, Saps M, Lavigne JV, et al. Recommendations for pharmacological clinical trials in 
children with functional constipation: The Rome foundation pediatric subcommittee on clinical 
trials. Neurogastroenterol Motil. 2018;30(4):e13294. 
2. Loening-Baucke V. Constipation in early childhood: patient characteristics, treatment, and longterm 
follow up. Gut. 1993;34(10):1400-4. 
3. Bryant AP, Busby RW, Bartolini WP, et al. Linaclotide is a potent and selective guanylate cyclase C 
agonist that elicits pharmacological effects locally in the gastrointestinal tract. Life Sci. 
2010;86(19-20):760-5. 
4. Eutamene H, Bradesi S, Larauche M, et al. Guanylate cyclase C-mediated antinociceptive effects of 
linaclotide in rodent models of visceral pain. Neurogastroenterol Motil. 2010;22(3):312-e84. 
5. Ironwood Pharmaceuticals, Inc. Investigator's Brochure, Edition 15. 2021. 
6. Cohen MB, Gold BD, Xanthakos SA, et al. Intestinal Guanylate Cyclase-C mRNA Expression in 
Duodenum and Colon of Children. J Pediatr Gastroenterol Nutr. 2021;73(6):703-9. 
7. Food and Drug Administration. Guidance for Industry: Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. Silver Spring, MD: FDA; 2007. 
 
Page 37 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
APPENDIX A. STUDY-SPECIFIC ABBREVIATIONS AND TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
AESI 
adverse event of special interest 
ALT 
alanine transaminase 
AST 
aspartate aminotransferase 
BMs 
bowel movements 
BSFS 
Bristol Stool Form Scale 
CBC 
complete blood count 
CIC 
chronic idiopathic constipation 
COVID-19 
coronavirus disease - 2019 
DILI 
drug-induced liver injury 
DPIA 
data protection impact assessment 
DSMB 
data Safety Monitoring Board 
DTP 
direct-to-patient 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EDC 
Electronic data capture 
eDiary 
electronic diary 
EOT 
End of Treatment 
EU 
European Union 
EudraCT 
European Clinical Trials Database 
FC 
functional constipation 
GC-C 
guanylate cyclase subtype C 
GCP 
Good clinical practice 
GFR 
glomerular filtration rate 
GI 
gastrointestinal 
IB 
investigator's Brochure 
IBS-C 
irritable bowel syndrome with constipation 
ICH 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use 
IEC 
Independent ethics committee 
IEC/IRB 
Independent Ethics Committee/Institutional Review Board 
Page 38 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
Abbreviation 
Definition 
IMP 
Investigational Medicinal Product 
INR 
international normalized ratio 
IRB 
Institutional review board 
IRT 
Interactive response technology 
ITT 
intent-to-treat 
IWRS 
Interactive web response system 
LAR 
legally authorized representative 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRNA 
messenger RNA 
PD visit 
premature discontinuation visit 
PEG 
polyethylene glycol 
PK 
Pharmacokinetic(s) 
qd 
once daily 
QTc 
QT interval corrected for heart rate 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAR 
serious adverse reaction 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SBM 
Spontaneous Bowel Movement 
SUSAR 
Suspected unexpected serious adverse reactions 
TA MD 
Therapeutic Area Medical Director 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US 
United States 
 
Page 39 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR 
Protocol M21-862: A Phase 2 Dose Finding Study Evaluating the Safety and Efficacy of Linaclotide in Pediatric 
Subjects 6 Months to Less Than 2 Years of Age with Functional Constipation (FC). 
Protocol Date:  25 November 2024 
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practices (GCP) and local laws and 
regulations and guidelines governing the study at the site location. In signing the Investigator Agreement, the 
investigator is agreeing to the following: 
1. Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, current 
protocol and operations manual, and making changes to a protocol only after notifying AbbVie and the 
appropriate Institutional Review Board (IRB)/IEC, except when necessary to protect the subject from 
immediate harm. 
2. Personally conducting or supervising the described investigation(s). 
3. Informing all subjects, or persons used as controls, that the drugs are being used for investigational 
purposes and complying with the requirements relating to informed consent and ethics committees 
(e.g., IEC or IRB) review and approval of the protocol and its amendments. 
4. Reporting complaints that occur in the course of the investigation(s) to AbbVie. 
5. Reading the information in the IB/safety material provided, including the instructions for use and the 
potential risks and side effects of the investigational product(s). 
6. Informing all associates, colleagues, and employees assisting in the conduct of the study about their 
obligations in meeting the above commitments. 
7. Maintaining adequate and accurate records of the conduct of the study, making those records available 
for inspection by representatives of AbbVie and/or the appropriate regulatory agency, and retaining all 
study-related documents until notification from AbbVie. 
8. Maintaining records demonstrating that an ethics committee reviewed and approved the initial clinical 
protocol and all of its amendments. 
9. Reporting promptly (within one (1) calendar day to AbbVie), the ethics committees/institutional review 
boards (as required) and other appropriate individuals (e.g., coordinating investigator, institution 
director): 
• 
All changes in the research activity and all unanticipated problems involving risks to human subjects 
or others 
• 
Any departure from relevant clinical trial law or regulation, GCP, or the trial protocol that has the 
potential to affect the following: 
• 
Rights, safety, physical or mental integrity of the subjects in the clinical trial 
• 
Scientific value of the clinical trial, reliability or robustness of data generated 
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB review, 
and regulatory inspection(s). 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Name of Principal Investigator (printed or typed) 
 
 
Page 40 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
APPENDIX C. LIST OF PROTOCOL SIGNATORIES 
Name 
Title 
Functional Area 
Clinical Development 
Statistics  
 
Page 41 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
APPENDIX E. LIVER SAFETY: SUGGESTED ACTIONS AND 
FOLLOW-UP ASSESSMENTS 
Close monitoring should be initiated for the following subjects: 
• 
Subjects with normal baseline serum AT who develop an increase of serum AT ≥ 2 × ULN 
• 
Subjects with elevated baseline AT who develop an increase of serum AT > 2 × the baseline 
value 
 
The subject should return to the study site and be evaluated for potential drug-induced liver injury (DILI) 
as soon as possible, preferably within 48 to 72 hours from the time the investigator becomes aware of 
the abnormal results. Evaluation should typically include repeat testing of all 4 of the usual serum 
biochemical measures (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline 
phosphatase, and total bilirubin) to confirm the abnormalities and to determine if they are increasing or 
decreasing. 
If it is difficult for the subject to return to the study site promptly, the subject should be retested locally, 
but normal laboratory ranges should be recorded, results should be made available to sponsor's study 
physician and the investigator immediately, and the data should be included in the eCRF. If repeat 
testing within this time frame is not possible, the study intervention should be discontinued. 
It is critical to initiate close monitoring immediately upon detection and confirmation of signals of 
potential DILI as early as possible and not to wait until the next scheduled visit or monitoring interval. 
Close monitoring of the subject should be initiated in conjunction with the sponsor and consideration 
given to the following: 
• 
Obtain a more detailed history of symptoms and prior or concurrent diseases. 
• 
Obtain a history of concomitant drug use, including nonprescription medications, herbal 
products and dietary supplements, alcohol and recreational drug use, and special diets. 
• 
Obtain a history of exposure to environmental chemical agents. 
• 
Initiation of appropriate evaluations including applicable laboratory tests (e.g., direct bilirubin, 
international normalized ratio [INR]), physical assessments, and other assessments 
(e.g., imaging) 
• 
Rule out other potential causes of biochemical abnormalities, e.g., acute viral hepatitis types 
A, B, C, D, and E; autoimmune or alcoholic hepatitis; non-alcoholic steatohepatitis; 
hypoxic/ischemic hepatopathy; and biliary tract disease. 
• 
Consider gastroenterology or hepatology consultations. 
 
Page 44 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
If any of the following criteria are met, discontinuation of study intervention should be considered (if 
indicated, prior to receipt of confirming retest biochemistry laboratory test results) and the Sponsor 
notified of the discontinuation: 
• 
ALT or AST ≥ 2 × ULN and the subject is symptomatic with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia (> 5%) 
• 
ALT or AST ≥ 2 × ULN and total bilirubin > 2 × ULN or INR > 1.5 
• 
ALT or AST ≥ 2 × ULN for more than 2 weeks 
• 
ALT or AST ≥ 2 × ULN 
 
If Hy's law criteria are met and it is considered, in the opinion of the investigator or the Sponsor, to be 
possibly related to the study drug, the subject must be discontinued from the study. 
Page 45 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
APPENDIX F. PROTOCOL SUMMARY OF CHANGES 
Previous Protocol Versions  
Protocol 
Date 
Version 1.0 
19 December 2022 
Version 1.1 (EU Only) 
08 September 2023 
 
The purpose of this version is to address the following concerns: 
• 
Throughout: update minor clerical errors.  
• 
Title Page and throughout as applicable: adjust number of sites to approximately 36. 
• 
Title Page and throughout as applicable in protocol and operations manual: update Sponsor 
emergency medical contact to Shelly Gupta.  
• 
Section 2.1 Background and Rationale: Clarify approved therapies for FC and indications for 
Linaclotide in various regions for various age ranges.  
• 
Section 2.1 Background and Rationale: add a results for Study LIN-MD-64 to pediatric 
linaclotide program summary. 
• 
Section 2.2 Benefits and Risks to Subjects: Added language to benefit-risk clarifying safety 
monitoring during the study and referencing additional sections in the protocol. 
• 
Section 4.1 Overall Study Design and Plan and throughout as applicable in protocol and 
operations manual: Clarified up to 30 subjects and a minimum of 18 will be enrolled. Added text 
regarding criteria for selecting dose level (Part 2 [the final cohort]). Additionally, Figure 2 was 
updated to incorporate changes for protocol version 2.0. 
• 
Section 4.2 Dose Justification: Added text to Dose Justification to discuss potential risks to 
subjects and safety monitoring. 
• 
Section 5.1 Eligibility Criteria: Clarification of weight-for-height/length ratio added. 
• 
Section 5.5 Discontinuation Criteria and Appendix E: Revised text for Hy's Law discontinuation 
criteria. 
• 
Section 5.8 Randomization/Drug Assignment: Added text regarding emergency unblinding 
procedure. 
• 
Section 5.10 Rescreening: section added to define criteria for rescreening after screen-fail. This 
includes a 30 day gap period between screen-fail and rescreening. 
• 
Section 5.11 Data Safety Monitoring: Clarified criteria for the termination of the dose 
escalation. 
• 
Section 6.1 Adverse Events of Special Interest: update instructions for investigator rating of 
AEs. Additionally, change of AE grading scale from Vaccine grading scale to CTCAE to align with 
the scale built in EDC. 
• 
Section 8.3 Subject Confidentiality: Revised subject confidentiality and mitigation language. 
Page 46 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
• 
Appendix C. List of Protocol Signatories: Revised protocol signatories, added Shelly Gupta, MD 
• 
Appendix D. Activity table: Adjust eDiary data review process to remove review of eCOA 
eligibility report and include eDiary data manual review for subject eligibility. 
• 
Operations Manual - Section 1 Contacts: contacts updated to reflect current roles. 
• 
Operations Manual – throughout as applicable: adjust eDiary review to include manual review 
for eligibility. 
• 
Operations Manual – Section 3 Rescue Medication: add rescue medication records clarification 
to be recorded in the EDC and eDiary.  
• 
Operations Manual – Section 3.8 Optional Pharmacokinetic Sampling:  clarify blood should be 
collected from a vein. Blood collected from heel, finger or ear stick may contain 
interstitial/tissue fluid and therefore is not acceptable. 
• 
Operations Manual – Section 4.2 Reporting Adverse Events and Intercurrent Illnesses: Update 
emergency medical contact to Shelly Gupta, MD.  
• 
Operations Manual – Appendix B Acceptable Protocol Modifications: update to specify 
unforeseen circumstances and clarify what protocol activities can be modified.   
 
Page 47 of 76

 
 
 
 
  
STUDY M21 862 | Version 2.0 | EU CT 2022 501947 34 00 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
APPENDIX G. OPERATIONS MANUAL 
 
Page 48 of 76

 
 
 
 
p. 2 of 26 
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21 862 Version 2.0 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
1 CONTACTS 
Sponsor/ 
Emergency 
Medical Contact 
 
, MD 
AbbVie Inc. 
1 N Waukegan Road  
North Chicago, IL 60064-1802 
 
EMERGENCY 24-hour Number:  
+1 (973) 784-6402 
Mobile:
Email:  
Safety Questions 
Internal Medicine Safety Team 
Email:  
SafetyManagement_Internal 
Medicine @abbvie.com 
SAE Reporting 
outside of EDC 
Email: 
 
PPDINDPharmacovigilance@abbvie.com 
Fax: 
+1 (847)-806-2062 
Back-up: +1 (847) 935-2844 
Protocol 
Deviations and 
Product 
complaints 
 
AbbVie Inc. 
100 Park Avenue 
Florham Park, NJ 07932  
Office: 
Cell: 
Email: 
Certified Clinical 
Lab 
LabCorp 
1447 York Ct 
Burlington, NC 27215-3361 
Phone: 
+1 (336) 584-5171 
PK Sample Lab 
Charles River Laboratories  
Massachusetts 
Attn: Sample Management  
334 South Street 
Shrewsbury, MA 01545 
Phone: 
+1 (508) 925-6808 
Observer-
Reported 
Outcome 
Signant Health 
785 Arbor Way 
Blue Bell, PA 19422 
Phone: 
+1 (267) 422-1700 
ECG eResearch 
Technology 
Clario Analytics 
1818 Market St Suite 2600 
Philadelphia, PA 19103 
Phone: 
+1 (215) 972-0414 
Email:  
customercare@ert.com 
IRT 
Endpoint Clinical 
701 Edgewater Dr Suite 320 
Wakefield, Massachusetts 01880 
Phone:  +1 (877) 810-4786 
Email:  
support@endpointclinical.com 
EDC system 
Medidata RAVE 
350 Hudson Street 
New York, NY 10014 
Phone:  +1 (866) 633-4328 
Email:  
helpdesk@mdsol.com 
 
Page 50 of 76

 
 
 
 
p. 3 of 26 
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21 862 Version 2.0 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
TABLE OF CONTENTS 
1 
CONTACTS 
2 
2 
PROTOCOL ACTIVITIES BY VISIT 
5 
2.1 
INDIVIDUAL TREATMENT PERIOD VISIT ACTIVITIES 
5 
2.2 
INDIVIDUAL POST-TREATMENT PERIOD VISIT ACTIVITIES 
11 
3 
STUDY PROCEDURES 
12 
3.1 
STUDY SUBJECT INFORMATION AND INFORMED CONSENT 
12 
3.2 
MEDICAL HISTORY 
13 
3.3 
RESCUE MEDICATIONS 
13 
3.4 
LIFESTYLE MODIFICATIONS 
13 
3.5 
ROME IV ASSESSMENT 
14 
3.6 
ADVERSE EVENT ASSESSMENT 
14 
3.7 
OBSERVER-REPORTED OUTCOMES 
14 
3.8 
OPTIONAL PHARMACOKINETIC SAMPLING 
15 
3.9 
ELECTROCARDIOGRAM 
16 
3.10 HEIGHT AND WEIGHT 
17 
3.11 VITAL SIGNS (INCLUDING WEIGHT) AND POSTURAL VITAL SIGNS 
17 
3.12 PHYSICAL EXAMINATION 
17 
3.13 FECAL IMPACTION ASSESSMENT 
17 
3.14 DISPENSE STUDY DRUG 
18 
3.15 CLINICAL LABORATORY TESTS 
18 
3.16 SUBJECT WITHDRAWAL 
19 
4 
SAFETY MANUAL 
20 
4.1 
METHODS AND TIMING OF SAFETY ASSESSMENT 
20 
4.2 
REPORTING ADVERSE EVENTS AND INTERCURRENT ILLNESSES 
20 
5 
COUNTRY-SPECIFIC REQUIREMENTS 
21 
5.1 
SUSAR REPORTING 
21 
5.2 
TREATMENT AFTER END OF STUDY 
21 
6 
STUDY DRUG 
22 
Page 51 of 76

 
 
 
 
p. 4 of 26 
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21 862 Version 2.0 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
6.1 
TREATMENTS ADMINISTERED 
22 
6.2 
PACKAGING AND LABELING 
22 
6.3 
STORAGE AND DISPOSITION OF STUDY DRUG 
22 
6.4 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS 
23 
6.5 
SELECTION AND TIMING OF DOSE FOR EACH SUBJECT 
23 
7 
REFERENCES 
23 
LIST OF APPENDICES 
APPENDIX A. EDIARY COMPLETION 
24 
APPENDIX B. ACCEPTABLE PROTOCOL MODIFICATIONS 
25 
 
 
 
Page 52 of 76

 
 
 
 
p. 8 of 26 
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21 862 Version 2.0 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
b. 
The clinic eDiary will be completed on the day of enrollment/randomization. Study site staff 
will verify compliance with the eDiary and remind LAR/parent/guardian/caregivers to 
complete their assessments daily. Assessment of global change in symptoms and global 
severity of symptoms will be completed in the weekly Diary. The global severity items will be 
completed beginning at the Preintervention Period through the 1-week postintervention 
visit (Visit 6), and the global change items will be completed from one week after 
enrollment/randomization through the 1-week postintervention visit (Visit 6). 
c. 
Manual review of eDiary subject eligibility must be completed prior to 
enrollment/randomization.  
d. 
Vital signs include weight, temperature, and respiratory rate. Postural vital signs (supine and 
standing whenever possible according to subject's age) include pulse rate and systolic and 
diastolic blood pressure. Blood pressure and pulse measurements should be preceded by at 
least 5 minutes of rest for the subject in a quiet setting. At all visits, postural vital signs must 
be obtained after subjects have been in a supine position for at least 2 to 3 minutes, 
followed by a standing position for at least 1 minute. If possible, temperature should be 
obtained using the same method at each visit. 
e. 
A fecal impaction assessment is performed at the enrollment/randomization Visit (Visit 3) 
prior to enrollment/randomization and dosing for all subjects. If there is no fecal impaction 
at the enrollment/randomization Visit (Visit 3) (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), the subject may enter the enrollment/randomization period. 
If fecal impaction is present upon examination, the subject will not be eligible for 
enrollment/randomization. 
f. 
Protocol-permitted rescue medication (outlined in Section 5.3 of the protocol) will be site-
supplied or site-dispensed from preintervention to Week 4 (Visits 2-5). The 
LAR/parent/guardian may choose a different protocol-permitted rescue medication at any 
subsequent visit, where available. Additional protocol permitted rescue medications may be 
site-supplied or site-dispensed as needed at any subsequent visits, where available. Subject 
must not have used rescue medication until randomized; this includes the calendar day 
before the enrollment/randomization visit and on the day of the enrollment/randomization 
visit prior to enrollment/randomization. 
g. 
Rescue medication will be recorded, refer to Section 3.3 for details. 
h. 
IWRS will be contacted to obtain the study drug (bottle number) to be dispensed. Study 
drug will be prepared by parent/caregiver at the site after instructions how to prepare IP 
solution have been explained and video reviewed. LAR/parent/guardian will administer first 
study drug at the study site. Site will document training and first dose preparation by 
parent/caregiver, as also administration. Subjects may eat 15 - 30 minutes after dosing. 
 
Page 56 of 76

 
 
 
 
p. 11 of 26 
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21 862 Version 2.0 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
g. 
Protocol-permitted rescue medication (outlined in Section 5.3 of the protocol) will be site-
supplied or site-dispensed from preintervention to Week 4 (Visits 2-5). The 
LAR/parent/guardian may choose a different protocol-permitted rescue medication at any 
subsequent visit, where available. Additional protocol permitted rescue medications may be 
site-supplied or site-dispensed as needed at any subsequent visits, where available. Subject 
must not have used rescue medication until randomized; this includes the calendar day 
before the enrollment/randomization visit and on the day of the enrollment/randomization 
visit prior to enrollment/randomization. 
h. 
All enrolled/randomized subjects who prematurely discontinue from the study, regardless of 
cause, should be seen for the assessments completed at EOT (Visit 5, Week 4). 
i. 
Rescue medication will be recorded, refer to Section 3.3 for details. 
 
2.2 Individual Post-Treatment Period Visit Activities 
This section presents a list of activities performed during each visit, organized by visit. The dot pattern 
on the upper right indicates the place of the visit in the overall Post-Treatment Period Activity Schedule. 
Activities are grouped by category (Interview, Exam, etc.). Further information about the activities is 
presented in Section 3. 
Page 59 of 76

 
 
 
 
p. 13 of 26 
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21 862 Version 2.0 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
Information regarding benefits for subjects and information regarding provisions for treating and/or 
compensating subjects who are harmed because of participation in the study can be found in the 
informed consent form. 
Samples for optional pharmacogenetic analyses or other exploratory analyses will only be collected if 
the LAR/parent/guardian of the subject has voluntarily signed and dated a separate written consent 
form for this testing that has been approved by an IRB/IEC, after the nature of the testing has been 
explained and the subject has had an opportunity to ask questions. The separate written consent may 
be part of the main consent form. If the subject does not consent to the testing, it will not impact the 
subject's participation in the study. 
3.2 Medical History 
A complete medical history including demographics will be taken at screening. The subject's medical 
history will be updated at the Study Day 1 visit. This updated medical history will serve as the baseline 
for clinical assessment. 
3.3 Rescue Medications 
Refer to Table 2 of Protocol Section 5.3 for the protocol-permitted rescue medications. Of note, 
• 
Any laxatives are to be discontinued prior to the Preintervention Visit in favor of the site-
supplied, protocol-permitted rescue medications. 
• 
Rescue medication is not to be used on the calendar day before enrollment/randomization 
(Visit 3) and on the day of the enrollment/randomization Visit (Visit 3) until 
randomization/enrollment. 
• 
Rescue medication (name of medication, dose, and route of administration) records will include 
medication given by the caregiver/parent/guardian/LAR as well as information from secondary 
caregivers if the participant was in the care of others. Rescue medication is recorded in the EDC 
and the eDiary. 
• 
Rescue medication may be taken when at least 72 hours have passed since the subject's 
previous BM or when their symptoms become intolerable. 
 
3.4 Lifestyle Modifications 
During the Preintervention Period, LAR/parent/guardians will be advised to have subjects adopt the 
following nonpharmacologic habits and instructed to maintain them throughout the study. 
• 
Adequate fluids: The investigator will discuss the fluid intake necessary to maintain a hydrated 
state (intake requirements may vary amongst children  e.g., child athletes, children in hot 
climates). 
• 
A high-fiber diet: High-fiber foods include beans, whole grains, fruits, and vegetables. Start 
slowly, adding just several grams of fiber a day over the Screening Period to reduce the amount 
Page 61 of 76

 
 
 
 
p. 14 of 26 
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21 862 Version 2.0 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
of gas and bloating that can occur in someone who is not used to consuming high-fiber foods. 
The optimum intake of dietary fiber for infants and children younger than two years of age is 
not known. Studies of weaning diets with the gradual introduction of solid foods, including 
increased fiber, suggest that an intake of 5 g per day is beneficial provided the children ingest 
adequate calories, vitamins, and minerals. 1,2 
• 
Increased physical activity: Subjects should be physically active throughout the day. Caregivers 
of subjects should encourage active play that includes a variety of activity types. 
• 
Adequate time for bowel movements: 
• 
LAR/parents/guardians will be requested not to start the toilet training process with their 
child during the child's participation in the study. Changes in toileting skills may impact 
bowel habits and accurate reporting of bowel movements and fecal incontinence. 
 
3.5 Rome IV Assessment 
As outlined in Section 5.1 of the protocol, the subject meets the Rome IV criteria for FC. 
For at least 1 month before Screening (Visit 1), the subject must meet 2 or more of the following 
symptoms: 
• 
history of excessive stool retention; 
• 
history of painful or hard bowel movements (BMs); 
• 
presence of a large fecal mass in the rectum; 
• 
history of large-diameter stools; 
• 
2 or fewer defecations per week [with each defecation occurring in the absence of any laxative, 
suppository, or enema use during the preceding 24 hours]. 
 
Accompanying symptoms may include irritability, decreased appetite, and/or early satiety. The 
accompanying symptoms disappear immediately following passage of a large stool. 
3.6 Adverse Event Assessment 
Please refer to Section 4.1. 
3.7 Observer-Reported Outcomes 
An observer-reported outcome (ObsRO) eDiary instrument assessing key signs and symptoms of FC for 
use in children (6 months to 5 years of age) with FC was developed by AbbVie and Ironwood 
Pharmaceuticals based on extensive qualitative research with LAR/parent/guardian/caregivers of 
children with FC, as well as feedback from pediatric gastroenterologists, measurement experts, and 
health authorities. The ObsRO instrument was developed for completion by 
LAR/parent/guardian/caregivers on an electronic diary (eDiary) and is being employed in this study for 
Page 62 of 76

 
 
 
 
p. 15 of 26 
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21 862 Version 2.0 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
use in subjects 6 months to less than 2 years of age. Data collected in the eDiary will be used to derive 
the efficacy endpoints. 
All efficacy assessments will be determined by responses entered in the eDiary by the 
LAR/parent/guardian/caregiver. The LAR/parent/guardian/caregiver is identified as the individual who 
completes the eDiary and should be the same individual throughout the course of the study and must be 
able to read and understand the eDiary as a condition for study participation (inclusion criterion). At the 
start of the Preintervention Period, LAR/parent/guardian/caregivers will receive full training on the use 
and completion of the eDiary at the study visit in which they are given the eDiary device. If the 
LAR/parent/guardian/caregiver completing the diary changes, the study team should be notified and 
should document the date when it changed and who the new LAR/parent/guardian/caregiver is. The 
new LAR/parent/guardian/caregiver must also provide written informed consent before the initiation of 
any study-specific procedures. 
The key efficacy assessments, which will be used to determine the efficacy parameter of SBM frequency, 
are the items assessing BM frequency and rescue medication use in the daily eDiary, once a day in the 
evening. 
Assessments of global change in symptoms and global severity of symptoms will be completed weekly in 
the eDiary. The global assessments consist of 2 items; 1 assessing global change in the child's symptoms 
and 1 assessing the global severity of the child's symptoms. Both global items will be completed weekly 
on the eDiary by the LAR/parent/guardian/caregiver. The global severity item will be completed 
beginning at the Preintervention Period through the 1-week post intervention visit. 
At the enrollment/randomization visit, the LAR/parent/guardian/caregiver should complete the clinic 
eDiary before any clinical assessments and before any interaction with site personnel has occurred to 
avoid biasing the LAR/parent/guardian/caregiver's response. All other eDiary entries are to be 
completed at home. 
See Appendix A for further information on eDiary completion. 
3.8 Optional Pharmacokinetic Sampling 
An important consideration is whether oral bioavailability of linaclotide is similar in this study population 
(6 months to less than 2 years of age) as in adults and pediatric subjects of 2 to 17 years of age, or 
whether systemic exposure may be higher in this study population (6 months to less than 2 years of 
age). 
Optional PK sampling will therefore be included in this study to assess the PK of linaclotide in pediatric 
subjects of 6 months to less than 2 years of age. Blood samples for analysis of linaclotide and its 
metabolite MM-419447 in plasma will be collected at time points specified in Section 2.1. With the 
consent of the LAR/parent/guardian, the maximum volume of blood collected for each subject over the 
duration of the study for optional PK will not exceed 4 mL. Repeat or unscheduled samples may be taken 
for safety reasons or for technical issues with the sample. 
Additional information on the collection, handling/processing, disposition, and measurement methods 
can be found in the lab manual. Please note: Blood should be collected from a vein; blood collected 
Page 63 of 76

 
 
 
 
p. 16 of 26 
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21 862 Version 2.0 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
from heel, finger or ear stick may contain interstitial/tissue fluid and therefore is not acceptable.  
Samples will be shipped to the lab per the Lab Manual. 
3.9 Electrocardiogram 
Electrocardiogram (Single Only) 
Resting ECGs will be obtained singly as specified in specified in Section 2.1. 3-Lead or 12-Lead ECGs may 
be utilized per investigator's discretion. 
The ECG acquired prior to dosing will serve as the baseline measurements for clinical assessment. 
When an ECG is scheduled at the same time as a blood collection, the ECG will be obtained prior to the 
blood collection. ECGs occurring near meals will take place prior to meals. 
ECGs will be acquired after the subject has been in the supine position for at least 5 minutes. Subjects 
will be instructed to remain completely stationary (no talking, laughing, deep breathing, sleeping, or 
swallowing) for approximately 10 seconds during the ECG recording. While ECGs are being acquired, 
subjects and staff are prohibited from having devices (e.g., cellular telephones, fans, heaters, etc.) that 
emit electrical interference in the room. 
ECG Safety Review 
Each ECG will be evaluated by an appropriately trained physician, preferably a cardiologist (the "local 
reader"). This reading of the ECG will be used by the investigator for subject safety assessments, 
including adverse event determination and management and decision on whether a subject will be 
discontinued from the study. 
The local reader will sign and date the safety ECG and provide a global interpretation using the following 
categories: 
• 
Normal ECG 
• 
Abnormal ECG  Not clinically significant (NCS) 
• 
Abnormal ECG  Clinically significant (CS) 
• 
Unable to evaluate 
 
All local reader evaluations of safety ECGs will be entered into the source documents. If the global 
interpretation is Abnormal (NCS or CS), the local reader will provide further information (e.g., sinus 
bradycardia, arrhythmia). The QT interval corrected for heart rate will be calculated and documented for 
all ECGs. 
All ECG source documentation will be retained at the study site. The automatic cardiograph reading 
(i.e., cardiograph-generated measurements and interpretations) will not be collected for analysis. 
Page 64 of 76

 
 
 
 
p. 17 of 26 
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21 862 Version 2.0 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
3.10 Height and Weight 
Height will be measured at screening only and body weight will be measured at scheduled visits as 
specified in Section 2.1. The subject will wear lightweight clothing and no shoes during weighing. Where 
locally permitted, height will be measured at the Screening Visit (with shoes off). 
3.11 Vital Signs (including weight) and Postural Vital Signs 
Vital signs and postural vital signs will be obtained and documented as noted in Section 2.1. Vital signs 
will be assessed as follows: 
Vital signs include weight, temperature, and respiratory rate; postural vital signs (supine and standing 
whenever possible according to subject's age) include pulse rate and systolic and diastolic blood 
pressure. If possible, temperature should be obtained using the same method throughout the course of 
the study. Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for 
the subject in a quiet setting. 
At all visits, postural vital signs must be obtained after subjects have been in a supine position for at 
least 2 to 3 minutes, followed by a stationary position for at least 1 minute. Measurements should be 
assessed consistently throughout the study. Vital signs measurements determined prior to dosing on 
Day 1 will serve as baseline. 
Measurements should be assessed consistently throughout the study. Vital signs measurements 
determined prior to dosing on Day 1will serve as baseline. 
3.12 Physical Examination 
A complete physical examination, including height (at Screening only), will be performed at the 
designated study visits as specified in Section 2.1. The physical examination performed on Study Day 1 
will serve as the baseline physical examination for the entire study. Physical examination abnormalities 
noted at the Baseline Visit prior to the first dose of study drug should be recorded in the subject's 
medical history. Any significant physical examination findings after the first dose will be recorded as AEs. 
All findings, whether related to an AE or part of each subject's medical history, will be captured on the 
appropriate eCRF page. 
At any time, a symptom-directed physical examination can be performed as deemed necessary by the 
investigator. 
3.13 Fecal Impaction Assessment 
A fecal impaction assessment will be performed for all subjects at the designated study visits as 
specified in Section 2.1. 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. 
Page 65 of 76

 
 
 
 
p. 18 of 26 
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21 862 Version 2.0 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
If fecal impaction is identified at Screening (Visit 1), subjects will receive a disimpaction regimen with 
either oral or rectal medication. The choice of treatment will be determined by the investigator after 
discussing the options with the subject and the LAR/parent/guardian. Options will include any over-the-
counter or prescription laxative, suppository, or enema (e.g., polyethylene glycol, lactulose, Fleet 
enema). After the subject has received treatment for the impaction, the investigator must re-evaluate 
the subject for the presence of fecal impaction at the Preintervention Visit (Visit 2). If there is no fecal 
impaction at the Preintervention Visit, the subject may enter the Preintervention Period after adhering 
to any washout requirements (Protocol Section 5.3). If fecal impaction is present upon reexamination, 
the subject will not be eligible for the study (i.e., they have failed their outpatient clean-out regimen). 
 If fecal impaction is present upon examination at enrollment/randomization (Visit 3), the subject will 
not be eligible to be randomized into the study. 
3.14 Dispense Study Drug 
Study drug will be dispensed to subject's LAR/parent/guardian as specified in Section 2.1. The first dose 
of study drug will be administered after all other baseline (Day 1) procedures are completed. At the 
visits specified in Section 2.1, the site personnel will review returned study drug kits, and empty study 
drug packaging to verify compliance. 
Study drug (i.e., linaclotide) capsules should be prepared by the LAR/parent/guardian and the dose 
should be administered to the subject at approximately the same time each day, 15 - 30 minutes before 
a meal; subjects may eat 15 - 30 minutes after dosing. 
3.15 Clinical Laboratory Tests 
A certified laboratory will be utilized to process and provide results for the clinical laboratory tests. 
Laboratory reference ranges, including reference ranges from the local laboratory (to be used in the 
event of a safety event or if lab kits from the central laboratory are not available), will be obtained prior 
to the initiation of the study. 
Instructions regarding the collection, processing, and shipping of these samples will be provided by the 
central laboratory. Please note: Blood collection from heel-, finger-, or ear-stick may contain 
interstitial/tissue fluid, and therefore are not acceptable. Blood should only be collected from a vein, 
blood should not be collected from a heel-, finger-, or ear-stick. 
If a laboratory test value is outside the reference range and the investigator considers the laboratory 
result to be clinically significant, the investigator will: 
• 
repeat the test to verify the out-of-range value; 
• 
follow the out-of-range value to a satisfactory clinical resolution; or 
• 
discontinue the subject from the study or require the subject to receive treatment; in this case, 
the laboratory result will be recorded as an adverse event. 
 
Page 66 of 76

 
 
 
 
p. 19 of 26 
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21 862 Version 2.0 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
Clinical Chemistry 
A fast is not necessary for blood samples to be drawn for chemistry. 
The baseline laboratory test results for clinical assessment for a particular test will be defined as the last 
measurement prior to the initial dose of study drug. 
The maximum volume of blood collected from each subject over the duration of the study for clinical 
laboratory testing (which includes chemistry and hematology panels) will not exceed 13.5 mL. Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the sample. 
Clinical Laboratory Testsa 
Hematology 
Clinical Chemistryb 
Other Screening Tests 
Platelet count (estimate not 
 
acceptable) 
Red blood cell (RBC) count 
Hematocrit 
Hemoglobin 
 
RBC indices:  
MCV  
MCH  
MCHC 
 
White blood cell (WBC) count with 
differential absolute:  
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils  
Basophils 
Blood urea nitrogen (BUN/Urea) 
Creatinine 
Glucose non-fasting  
Potassium  
Sodium  
Chloride 
Bicarbonate/CO2  
Magnesium  
Phosphate 
Total protein 
Total bilirubin  
Calcium  
Alanine transaminase (SGPT/ALT)  
Aspartate transaminase (SGOT/AST) 
Alkaline phosphatase 
Total, direct and indirect bilirubin 
Total cholesterol  
Albumin 
 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean cell volume of RBC; 
RBC = red blood cell; WBC = white blood cell 
a. 
All study-required laboratory assessments will be performed by a central laboratory. 
b. 
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are provided in the protocol. 
 
3.16 Subject Withdrawal 
All attempts must be made to determine the date of the last study drug dose and the primary reason for 
discontinuation of study drug or study participation. The information will be recorded on the 
appropriate eCRF page. However, these procedures should not interfere with the initiation of any new 
treatments or therapeutic modalities that the investigator feels are necessary to treat the subject's 
condition. Following discontinuation of study drug, the subject will be treated in accordance with the 
investigator's best clinical judgment, irrespective of whether the subject decides to continue 
participation in the study. 
Page 67 of 76

 
 
 
 
p. 22 of 26 
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21 862 Version 2.0 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
discontinuation of study drug. At the subject's last study visit, the investigator will discuss the 
appropriate subsequent treatment with the subject. If symptoms improve at the current dose level, the 
subject will be given the option to participate in a long-term safety extension study, once the study is 
active and accepting subjects. 
6 STUDY DRUG 
6.1 Treatments Administered 
The study drug linaclotide (or matching placebo for Part 2 only) will be dispensed in the form of a 
capsule at the visits listed in Section 2.1. Subjects will be trained on how to prepare the appropriate 
dose and instructed to take prepared dose at approximately the same time each day 15 - 30 minutes 
before a meal; subjects may eat 15 - 30 minutes after dosing. 
Linaclotide (or matching placebo for Part 2 only) will be provided by AbbVie. Sites are responsible for 
obtaining or prescribing any protocol permitted rescue medications to dispensed as outlined in 
Section 2.1. 
Study drug dose preparation and administration instructions will be provided separately. 
Study drug must not be dispensed without contacting the IRT system. Study drug may only be dispensed 
to subjects enrolled in the study through the IRT system. At the end of the Treatment Period or at the 
Premature D/C visit, the site will contact the IRT system to provide visit date information and study drug 
return information for each kit. 
6.2 Packaging and Labeling 
Linaclotide and matching placebo capsules will be supplied in bottles with quantities sufficient to 
accommodate the study design. Each kit will be labeled per local requirements and this label must 
remain affixed to the kit. All blank spaces should be completed by site staff prior to dispensing to the 
subject. Each kit will contain a unique kit number. This kit number is assigned to a subject via IRT and 
encodes the appropriate study drug to be dispensed at the subject's corresponding study visit. 
6.3 Storage and Disposition of Study Drug 
Study drug must be stored at room temperature (20° to 25°C [68° to 77°F], with permitted excursions 
15° to 30°C [59° to 86°F]). 
The investigational products are for investigational use only and are to be used only within the context 
of this study. The study drug supplied for this study must be maintained under adequate security and 
stored under the conditions specified on the label until dispensed for subject use or destroyed on site as 
appropriate. 
Sites are responsible for maintaining the investigational study drug according to the storage conditions 
specified on the clinical label and monitoring for temperature excursions with the use of a 
Page 70 of 76

 
 
 
 
p. 23 of 26 
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21 862 Version 2.0 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
calibrated continuous temperature monitoring device (for example, chart recorders and/or acceptable 
calibrated min/max thermometers) or continuous monitoring systems. Specific guidance on appropriate 
temperature monitoring and temperature excursions reporting requirements will be 
provided separately. 
6.4 Method of Assigning Subjects to Treatment Groups 
This study consists of 2 Parts that include 4 cohorts in total. Part 1 has three open label cohorts 
(Cohorts 1-3), and Part 2 has a double-blind cohort. Part 1 cohorts will enroll sequentially and receive 
open-label linaclotide in ascending doses. A linaclotide dose will be chosen for Part 2 based on the 
overall benefit-risk profile of the open label cohorts in Part 1. Part 2 will include a double-blind cohort to 
assess efficacy of linaclotide vs placebo.  
In Part 1, for Cohort 1, linaclotide will be administered at the dose of 9 µg; for Cohort 2, linaclotide will 
be administered at the dose of 18 µg; and for Cohort 3, linaclotide will be administered at the dose of 36 
µg. In Part 1, the study investigator and the legally authorized representative (LAR)/parent/guardian will 
be given the option for the subject to continue in the next higher cohort (dose escalation) if the safety 
profile favors a trial cohort at a higher dose. Part 2 will include additional subjects at the dose of 
linaclotide (either the 9, 18, or to 36 µg dose) that exhibited the best benefit-risk profile from Part 1; and 
subjects receiving matching placebo at a 1:1 randomization ratio. 
At the screening visit, all subjects will be assigned a unique subject number using the IRT system. For 
subjects who do not meet the study selection criteria, the site personnel must contact the IRT system 
and identify the subject as a screen failure. 
Subjects who are enrolled will retain their subject number assigned at the screening visit throughout the 
study. Upon receipt of study drug, the site will acknowledge receipt in the IRT system. 
Contact information and user guidelines for IRT use will be provided to each site. 
6.5 Selection and Timing of Dose for Each Subject 
One capsule of linaclotide (or placebo for Part 2 only) will be dosed orally as a prepared solution once 
daily. All subjects should take the study drug 15 - 30 minutes before any meal around the same time 
each day. Separate dosing instructions will be provided to the LAR/parent/guardian. Study drug will be 
prepared by LAR/parent/guardian at the site after instructions for how to prepare IP solution have been 
explained and video reviewed. 
7 REFERENCES 
1. Agostoni C, Riva E, Giovannini M. Dietary Fiber in Weaning Foods of Young Children. Pediatrics. 
1995;96(5):1002-5. 
2. Davidsson L, Mackenzie J, Kastenmayer P, et al. Dietary fiber in weaning cereals: a study of the 
effect on stool characteristics and absorption of energy, nitrogen, and minerals in healthy infants. J 
Pediatr Gastroenterol Nutr. 1996;22(2):167-79. 
Page 71 of 76

 
 
 
 
p. 24 of 26 
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21 862 Version 2.0 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
APPENDIX A. EDIARY COMPLETION 
During this study, LAR/parent/guardian/caregiver will complete daily and weekly entries in an eDiary: 
• 
Daily: The daily eDiary will be completed by the LAR/parent/guardian/caregiver during the 
Preintervention Period through the 1-week postintervention visit in the evening except on the 
day of the preintervention visit and the day of the enrollment/randomization visit. The modified 
daily eDairy will be completed in the evenings of the preintervention visit and the 
enrollment/randomization visit. 
• 
Weekly: Assessments of global change in symptoms and global severity of symptoms will be 
completed weekly in the eDiary. The global severity items will be completed beginning at the 
Preintervention Period through the 1-week postintervention visit, and the global change items 
will be completed from 1 week after enrollment/randomization through the 1-week 
postintervention visit. 
 
In addition, a clinic eDiary will be completed in the clinic before administration of first dose of study 
intervention on the day of enrollment/randomization.  
Page 72 of 76

 
 
 
 
p. 25 of 26 
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21 862 Version 2.0 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
APPENDIX B. ACCEPTABLE PROTOCOL MODIFICATIONS 
Due to unforeseen circumstance (e.g., natural disasters, pandemics, geopolitical conflict such as the 
conflict in Ukraine and surrounding impacted regions), it is possible that additional protocol 
modifications not outlined in this protocol may become necessary. If this situation arises, in addition to 
the study informed consent, additional temporary verbal consent from the parent/guardian/LAR may be 
obtained prior to these adaptations or substantial changes in study conduct in accordance with local 
regulations. An appropriately signed and dated informed consent form should be obtained from the 
parent/guardian/LAR afterwards, as soon as possible. 
Protocol Activities by Visit 
if it is not possible for all study procedures to be performed as specified due to travel restrictions or 
other reasons, the following modifications are allowed: 
• 
Some study visits and/or activities may be performed by a local clinic/hospital/laboratory. These 
are indicated by a plus sign (+) in the appropriate visit tables in Section 2. All procedures 
performed at local facilities must be performed by appropriately qualified personnel. See 
Section 3.15 for additional details specific to clinical laboratory assessments. 
 
ECGs 
The Sponsor and investigator will discuss availability of resources for ECG collection in the event of 
unforeseen circumstances in conjunction with severe diarrhea AESI. 
Dispense Study Drug 
Study drug may be shipped from the study site directly to the study subject's home if all the following 
criteria are met: 
• 
Direct-to-patient (DTP) shipment of study drug is allowed by local regulations and the relevant 
IRBs or ethics committees 
• 
Study drug can be administered by the subject's LAR/parent/guardian at home 
• 
Subject's LAR/parent/guardian agrees to have the study drug shipped directly to their home 
• 
Shipments may also include other study supplies (e.g., drug dosing diaries, paper copies of 
the ObsROs). Instructions will be provided by AbbVie as to how a study site can initiate a 
DTP shipment using Marken, a global vendor selected by AbbVie to provide this service 
when necessary. Shipments of study drugs from the study site to a subject's home will be 
appropriately temperature controlled (qualified shipper or temperature monitoring) within 
the labeled storage conditions. Signature is required upon delivery; due to COVID-19- 
related social distancing, this may be provided by the courier after delivery. Documentation 
of the shipment is to be retained by the clinical site. 
• 
AbbVie will not receive subject identifying information related to these shipments, as the 
site will work directly with the courier. 
 
Page 73 of 76

 
 
 
 
p. 26 of 26 
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21 862 Version 2.0 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
The study site is responsible for meeting IRB/IEC reporting requirements related to DTP shipments of 
study drug, and for obtaining consent to provide delivery information to the courier and documenting 
this consent in source documents. 
Clinical Laboratory Tests 
If travel restrictions or other changes in local regulations prevent the subject from having blood drawn 
for laboratory testing at the study site, if possible, arrange for subjects to have laboratory work done at 
a local laboratory, hospital, or other facility. Local laboratory results should be obtained along with 
reference ranges and kept within the subjects' source documentation. The investigator should review 
local laboratory results as soon as possible. 
If laboratory samples cannot be obtained, study drug administration may be continued, provided the 
investigator has reviewed all prior laboratory results and confirms and discusses with the 
parent/guardian/LAR that there is no safety concern for the subject to continue use of the study drug in 
the absence of current laboratory results. The subject should be scheduled for laboratory draws as soon 
as feasible within the visit windows specified in Section 2 (i.e., Visit 4 + 2 days). 
Reporting Adverse Events and Intercurrent Illnesses 
Supplemental study case report form (CRF) should be completed in the event of COVID-19 related 
missed/virtual visits, study drug interruptions or discontinuations, or AEs (including capture of specific 
signs/symptoms of infection and testing results). 
COVID-19 infections should be captured as AEs. If the event meets the criteria for an SAE, then follow 
the SAE reporting directions per the protocol and above. The following COVID-19-related supplemental 
eCRFs should be completed (for both serious and nonserious events): 
• 
COVID-19 Supplemental Signs/ Symptoms 
• 
COVID-19 Status Form 
 
Reactions known to be associated with the SARS-CoV-2 vaccine should be reported as adverse events. If 
the event meets the criteria for an SAE, then follow the SAE reporting directions. All adverse events 
associated with the SARS-CoV-2 vaccine will be linked to the vaccine on the COVID-19 Vaccine eCRF. 
COVID 19 Pandemic Related Vaccination Guidance 
Given the ongoing COVID-19 pandemic, vaccines to prevent SARS-CoV-2 infection may be administered 
during screening, the treatment period, or follow-up, as long as components of the vaccine are not 
contraindicated. 
The decision to receive a locally available vaccine should be based on local guidance and an individual 
discussion between the treating physician and the subject. 
If vaccination is available, it should not interfere with eligibility. These recommendations may be subject 
to change based on the evolving knowledge around the use of SARS-CoV-2 vaccines in subjects with 
functional constipation and as more data are collected in real-world scenarios and clinical trials. Any 
SARS-CoV-2 vaccine information must be documented on the COVID-19 vaccine eCRF. 
Page 74 of 76

Document Approval
Study M21862 - A Phase 2 Dose Finding Study Evaluating the Safety and Efficacy of
Linaclotide in Pediatric Subjects 6 Months to Less Than 2 Years of Age with Functional
Constipation (FC) - Protocol Version 2-0 - EU CT 2022-501947-34-00 - 25Nov2024
Version: 1.0
Date: 02-Dec-2024
Company ID: 20241202-0900f9f688a6565f-1.0-en
Signed by:
Date:
Meaning of Signature:
02-Dec-2024 18:34 UTC
Approver
25-Nov-2024 22:56 UTC
Approver - Statistics
Page 76 of 76