Efficacy and Safety of Plecanatide in Children 6 to <18 Years With Irritable Bowel Syndrome With Constipation (IBS-C)

This study is a randomized, double-blind, placebo-controlled, dose-ranging clinical trial designed to evaluate the safety, efficacy, and pharmacokinetics of plecanatide in pediatric patients aged 6 to <18 years with irritable bowel syndrome with constipation (IBS-C). IBS-C is a condition that causes abdominal pain and infrequent, hard bowel movements.

The study includes two age cohorts:

Group A: 6 to 11 years Group B: 12 to <18 years

Participants are randomly assigned to receive one of four plecanatide doses (0.5 mg, 1.0 mg, 2.0 mg, or 3.0 mg) or placebo. All treatments were taken orally once daily for 4 weeks following a 28-day screening/baseline period. After treatment, participants were followed for 2 weeks.

The primary objective is to determine whether plecanatide increases the number of spontaneous bowel movements (SBMs) compared to placebo.

Secondary objectives include:

Time to first bowel movement after starting treatment Changes in stool consistency Changes in abdominal pain and discomfort Overall safety and tolerability of plecanatide

Safety assessments include monitoring adverse events, laboratory tests, and treatment compliance. Participants recorded daily bowel habits and symptoms in an electronic diary and attended scheduled clinic visits for evaluations.

Inclusion criteria

A patient will be eligible for study participation if he or she meets all of the following criteria:

• Male or female child or adolescent age 6 to < 18;
• Meets ROME IV criteria for child/adolescent IBS-C defined as:

For at least 2 months before diagnosis the patient has had:

• Abdominal pain at least 4 days per month associated with one or more of the following:

• Related to defecation
• A change in frequency of stool
• A change in form (appearance) of stool;
• The pain does not resolve with resolution of the constipation (children in whom the pain resolves have functional constipation, not irritable bowel syndrome);
• After appropriate evaluation, the symptoms cannot be fully explained by another medical condition
• More than one-fourth (25%) of bowel movements with Bristol stool form types 1 or 2 and less than one-fourth (25%) of bowel movements with Bristol stool form types 6 or 7 on the BSFS or 4 or 5 on the mBSFS-C;

• Patient's parent/guardian/LAR is able to voluntarily provide written, signed, and dated consent and patient is able to voluntarily provide assent as per IRB guidance; 4. Patient and patient's parent/guardian/LAR demonstrates an understanding, ability, and willingness to fully comply with protocol requirements and study procedures (e.g., acceptance of venipuncture, acceptance of urine drug screen for opiates, visit schedule, complete daily electronic diary reporting).

Exclusion criteria

A patient will be excluded from the study if he or she meets any of the following criteria:

• The patient has a mental age <4 years in the investigator's opinion;
• The patient has previously been diagnosed with anorectal malformations, neurological deficits, or anatomical anomalies that would constitute a predisposition to constipation;
• The patient currently requires iron supplements, amitriptyline, or other tricyclic antidepressants for depression, opioid-containing medications or compounds for pain, or has other conditions that require medications known to cause constipation. A patient with an onset of constipation prior to the use of these medications and who has been on a stable dose for at least 8 weeks prior to Screening might be considered eligible for this study if the investigator deems these medications do not significantly contribute to the patient's constipation. Screening of these patients needs to be approved by the medical monitor and the sponsor;
• The patient is pregnant or lactating;
• Females age 12 to < 18 or females age 6 to 11 of childbearing potential (defined as post menarche) who does not agree to practice one of the following medically acceptable methods of birth control throughout the study;

• Hormonal methods such as oral, implantable, injectable, vaginal ring, or transdermal contraceptives for a minimum of 1 full cycle (based on the patient's usual menstrual cycle period) before study drug administration.
• Total abstinence from sexual intercourse (since the last menses before study drug administration
• Intrauterine device.
• Double-barrier method (condoms, sponge, or diaphragm with spermicidal jellies or cream.
• The patient follows a diet not considered normal by the investigator for the patient's age, relative to variety of food, caloric content, and quantity. The patient must have been on a stable diet for at least 30 days prior to Screening;
• The patient's mobility or normal exercise tolerance is compromised in the investigator's opinion;
• The patient has a history of an eating disorder;
• The patient has clinical or laboratory signs and symptoms of significant cerebral, respiratory, renal, hepatobiliary, pancreatic, intestinal (including acute appendicitis, inflammatory bowel disease, or undiagnosed abdominal pain), endocrinologic, or infectious disease that in the investigator's judgment could interfere with study assessments or completion of the study. (Note: A patient with a history of thyroid disease may be enrolled if he or she has normal T3 and T4 at Screening. If the patient is taking medication for active thyroid disease, his or her T3 and T4 level must be within normal limits and the dose of any medication used to treat it must be stable for at least 30 days prior to Screening);
• The patient has any other medical condition or is receiving concomitant medication or therapy that would in the investigator's opinion compromise his or her safety or compliance with the study protocol or compromise data collection;
• The patient has a history or evidence of drug or alcohol abuse in the 12 months before Screening;
• The patient has a hypersensitivity, allergy, or contraindication to plecanatide;
• The patient has received any experimental drug, including linaclotide and lubiprostone, or experimental therapy within 30 days of study start;
• The patient is unable to tolerate protocol-prescribed rescue medication (Dulcolax®), or unwilling to use it as the only laxative for the duration of the trial;
• The patient has taken a medication considered to be a protocol-defined prohibited prior or concomitant medication or supplement as defined in section 3.3.2;
• The patient and his or her caregiver are unable to communicate well with the study staff and comply with the study requirements (restrictions, appointments, and examination schedule). (The patient/caregiver must be able to complete required Daily BM and Symptom diary entries during the Screening/Baseline period and for the duration of the study. The patient/caregiver must also agree to provide contact information to receive daily reminders should the patient not complete the daily electronic diary entries or require password resets);
• The patient has been screened for or participated in this or another Synergy study in the past;
• The patient has a sibling that is currently participating or has participated in another Synergy study.

Exclusion criteria

Based on Baseline Diary Entries

• Patient reports having more than 1 loose, mushy stool (Diary-recorded stool consistency of 6 on the Bristol Stool Form Scale (BSFS or 4 on the modified Bristol Stool Form Scale for Children [mBSFSC]) or any watery stool (Diary-recorded stool consistency of 7 on the BSFS or 5 on the mBSFS-C) 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 each 7-day (week) period before the randomization day and up to the day of randomization;
• ≥ 3 CSBMs per week for either week of the 2-week baseline diary assessment immediately preceding the randomization visit;
• > 6 SBMs per week for either week of the 2-week baseline diary assessment immediately preceding the randomization visit;
• Patient reports worst abdominal pain intensity (WAPI) scores in the 2-week baseline diary that meet either of the following:

• WAPI score of 0 on the 11-point Numeric Rating Scale or Wong-Baker Faces® Pain Rating Scale for more than two days during each week of the 2-week baseline diary period.
• An average WAPI < 3 for either of the two weeks of the baseline diary;
• Completion of < 5 of the 7 required daily diary entries in each week of the 2-week baseline diary assessment immediately preceding the randomization visit;
• Use of rescue medication (Dulcolax®, bisacodyl) for more than 2 days during either of the two weeks of the 2-week baseline diary assessment immediately preceding the randomization visit.