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

Functional constipation (FC) is a common healthcare problem in children of all
ages, with a worldwide prevalence ranging between 0.7% and 29.6%. Symptoms
include infrequent, hard stools, and painful defecation, and affected children
may have abdominal pain and fecal incontinence, which is usually the result of
fecal impaction leading to overflow incontinence. These symptoms can have a
severe impact on a child*s quality of life and may lead to school absenteeism
and substantial costs related to healthcare utilization. Initial non-
pharmacological interventions include education, behavioral modifications, and
keeping a bowel diary. Despite these interventions, many children require
pharmacological interventions. Treatment consists of dis-impaction (ie, removal
of the rectal fecal mass), followed by maintenance treatment and eventually a
weaning phase. Multiple pharmacological agents are available for the treatment
of FC in children. Despite chronic pharmacological treatment, approximately 40%
of children with FC referred to a pediatric gastroenterologist remain
symptomatic after 5 years and 20% of children still have symptoms after 10
years. In some cases, symptoms may persist into adolescence or adulthood
despite medical treatment. Potential reasons for ineffectiveness of treatment
include suboptimal dosage regimens, poor compliance with treatment, or the use
of drugs with action mechanisms that do not address the underlying
pathophysiological etiology.

Irritable bowel syndrome (IBS) is characterized by symptoms of abdominal
discomfort or pain associated with altered bowel movement characteristics. In
adults, Rome III criteria has classified IBS with constipation (IBS-C), IBS
with diarrhea, mixed IBS, and unsubtyped IBS, depending on the stool
consistency. In children, although IBS subtypes are encountered in clinical
practice, a classification based on stool consistency had not been specified at
the time the Phase 2 dose ranging study (LIN -MD-63) was originally developed.
Such classification is important as the management will, in part, depend on the
presenting stool pattern.

The overall prevalence of IBS in the pediatric population is low. IBS
prevalence in children across the United States, based on parental reports,
ranges from 1.2% to 2.9%, while school - based studies in Colombia and Sri
Lanka found a prevalence of IBS of 4.9% and 5.4%, respectively. In adults,
although not life-threatening, because of its chronic relapsing course, IBS is
associated with impaired quality of life and high direct and indirect medical
costs such as absenteeism from work. In children and adolescents, IBS has been
associated with significant impairment as increased rates of school
absenteeism, health-care utilization and family disruption are common

The objective of this study is to assess the long-term safety of linaclotide in
pediatric participants with FC (total exposure with linaclotide for 24 weeks)
or IBS-C (total exposure with linaclotide for 52 weeks) who have completed
study intervention in Study LIN-MD-62, LIN-MD-63, or LIN-MD-64.

LIN-MD-66 is a Phase 3 open-label study with 24 weeks (FC participants) or 52
weeks (IBS-C participants) of linaclotide exposure that will enroll pediatric
participants (6-17 years of age) with FC or IBS-C who completed study
intervention in Study LIN-MD-62, LIN-MD-63, or LIN-MD-64 based on the
individual study criteria.

Participants will receive open-label linaclotide 72 µg or 145 µg once daily for
24 weeks (FC participants) or open-label linaclotide 72 µg, 145 µg, or 290 µg
once daily for 52 weeks (IBS-C participants) as follows based on their age
and/or weight at the time of enrollment into LIN-MD-66. Participants will be
instructed to take their assigned dose orally as a single daily dose at
approximately the same time each day, 30 minutes prior to any meal, except for
the Day 1 Visit, at which the linaclotide dose will be administered in the
clinic.

There will be a total of 6 study visits and 1 phone call with the study doctor
over a period of 6 months. During the visits, the following will take place:
personal questions, health and medication questions, vital signs, physical
examination, fecal impaction assessment, blood sample, urine sample,
electrocardiogram and pregnancy testing (if applicable).
Functional constipation (FC) is a common healthcare problem in children of all
ages.Many children require pharmacological treatments, however, the available
treatments are not always effective.There are currently no approved treatments
for FC in children. Linaclotide is not currently approved for use in people
younger than 18 years old, and the effects on children are still being studied.
In an earlier study in children (6-17 years of age) with FC who took
linaclotide, the side effects were similar to those reported by adults who took
linaclotide to treat constipation. Some of the most commonly reported side
effects in adults are: diarrhea and loose stools; upper or lower stomach pain;
gas; bloating; common cold; sinus infection; headache; stomach flu. Diarrhea
and loose stools are the most common side effects. In an earlier study of
linaclotide in children aged 6-17 years, side effects that occurred in more
than 1 patient included: diarrhea; a hardened mass of stool in the colon or
rectum; headache.