A Study to Assess Adverse Events and Change in Disease Activity in Pediatric Participants (Age 6 Months to <2 Years) With Functional Constipation Who Are Treated With Linaclotide

• Linaclotide (Drug), also known as Linzess: Capsule; oral
• Placebo (Drug): Capsule; oral

Primary outcomes

• Change From Baseline in Overall Spontaneous Bowel Movement (SBM) Frequency Rate (SBMs/Week) During the Study Intervention Period [Baseline to Week 4]: An SBM is defined as a 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. The caregiver/parent/guardian/legally authorized representative (LAR) will complete the electronic diary (eDiary), providing data for the SBM frequency rate up to the last dose date equivalent to the 4-week SBM frequency rate.
• Change From Baseline in Stool Consistency (Bristol Stool Form Scale) During the Study Intervention Period [Baseline to Week 4]: The caregiver/parent/guardian/legally authorized representative (LAR) will rate and record in an eDiary the consistency of the stool for each BM using the Bristol Stool Form 7-point scale in which 1=Separate hard lumps, like nuts (hard to pass); 2=Sausage-shaped, but lumpy; 3=Like a sausage but with cracks on its surface; 4=Like a sausage or snake, smooth and soft; 5=Soft blobs with clear cut edges (easy to pass); 6=Fluffy pieces with ragged edges, a mushy stool; and 7=Watery, no solid pieces, entirely liquid.
• Change From Baseline in Straining During the Study Intervention Period [Baseline to Week 4]: Straining for each LAR/parent/guardian/caregiver-observed BM the child passes was collected daily in the eDiary device, using a 4-point scale (0 = No, not at all; 1 = Yes, a little; 2 = Yes, a lot; 3 = I don't know) based on two questions (did he/she grunt or make a face like he/she was straining). Lower value represents a better outcome and "I don't know" is considered as a missing response. The subject's average straining score for each caregiver-observed BM was derived based on the average of non-missing responses of the two straining questions. The participant's straining score in the 4-week Study Intervention Period was the average of the non-missing average straining scores from all caregiver-observed SBMs during the 4-week Study Intervention Period. If a subject had no caregiver-observed SBMs at baseline, then the baseline straining score reported by the caregiver was missing and, therefore, that subject was not included in the change from baseline straining analysis.
• Number of Participants With Adverse Events (AEs) [Up to Week 5]: An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. The investigator assesses the relationship of each event to the use of study.

Sex: All, ages: 6 Months to 23 Months

Inclusion Criteria:

* Individuals must be 6 months to less than 1 year and 11 months old, at the time the legally authorized representative (LAR)/parent/guardian signs the informed consent in alignment with local requirements.
* 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.
* Participant meets Rome IV criteria for functional constipation (FC): for at least 1 month before Screening (Visit 1), the participant must meet 2 or more of the following:

  * 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)
  * History of excessive stool retention
  * History of painful or hard bowel movements (BMs)
  * History of large-diameter stools
  * Presence of a large fecal mass in the rectum
* LAR/Parent/Guardian is willing to discontinue any laxatives used before the Preintervention Visit in favor of the protocol-permitted rescue medicine.

Exclusion Criteria:

* Participant has conditions that could interfere with drug absorption, including, but not limited to, short bowel syndrome.
* History of clinically significant medical conditions or any other reason that the investigator determines would interfere with the individual's participation in this study or would make the participant an unsuitable candidate to receive study drug.
* Participant has history of:

  * Celiac disease, or positive serological test for celiac disease or the condition is suspected but has not been ruled out by endoscopic biopsy
  * Cystic fibrosis
  * 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)
  * Down's syndrome or any other chromosomal disorder
  * Active anal fissure (investigator has confirmed an active anal fissure and participant 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 participant's Rome IV FC criteria, the subject would not be eligible to participate in the study.
  * Anatomic malformations (e.g., imperforate anus, anal stenosis, anterior displaced anus)
  * Intestinal nerve or muscle disorders (e.g., Hirschprung disease, visceral myopathies, visceral neuropathies)
  * Neuropathic conditions (e.g., spinal cord abnormalities, neurofibromatosis, tethered cord, spinal cord trauma)
  * Lead toxicity, hypercalcemia
  * Inflammatory bowel disease
  * Lactose intolerance that is associated with symptoms which could confound the assessments in this study
  * History of cancer. (Note: Participants 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)

Participant flow

Outcome results

• Change From Baseline in Overall Spontaneous Bowel Movement (SBM) Frequency Rate (SBMs/Week) During the Study Intervention Period (Primary), Mean, SBMs/Week: Open-Label Linaclotide 9 µg (Part 1) 3.181 +/- 0.9563; Double-Blind Placebo (Part 2) 2.503 +/- 1.3791; Double-Blind Linaclotide 9 µg (Part 2) 0.246 +/- 0.7035
• Change From Baseline in Stool Consistency (Bristol Stool Form Scale) During the Study Intervention Period (Primary), Mean, units on a scale: Open-Label Linaclotide 9 µg (Part 1) 0.845 +/- 2.1137; Double-Blind Placebo (Part 2) 1.062 +/- 0.8043; Double-Blind Linaclotide 9 µg (Part 2) 1.201 +/- 1.0192
• Change From Baseline in Straining During the Study Intervention Period (Primary), Mean, score on a scale: Open-Label Linaclotide 9 µg (Part 1) -1.087 +/- 0.6511; Double-Blind Placebo (Part 2) -0.821 +/- 0.9659; Double-Blind Linaclotide 9 µg (Part 2) -0.561 +/- 0.3779
• Number of Participants With Adverse Events (AEs) (Primary), Number, participants: Open-Label Linaclotide 9 µg (Part 1) 3; Double-Blind Placebo (Part 2) 1; Double-Blind Linaclotide 9 µg (Part 2) 3

Adverse events

Time frame: All-cause mortality and adverse event tables include events reported from the time of informed consent to the end of the study. The median time on follow-up was 72.5, 76.5, and 77 days for Double-Blind Placebo, Double-Blind Linaclotide 9 µg (Part 2), and Open-Label Linaclotide 9 µg (Part 1), respectively.

Other adverse events by term

• Study Protocol (PDF, 2024-11-25)
• Statistical Analysis Plan (PDF, 2023-05-17)

• ABBVIE INC., Study director, AbbVie