Linaclotide Safety and Efficacy in 2 to 5-Year-Old Participants With Functional Constipation
Condition: Functional Constipation
MeSH terms: Constipation
Intervention: Linaclotide; Placebo
Intervention description: Linaclotide, capsules, mixed with water and administered orally, once daily in fasted state.; Matching placebo, capsules, mixed with water and administered orally, once daily in fasted state
Intervention MeSH terms: Linaclotide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Sequential Assignment
Intervention model description: There are 3 cohorts with ascending doses and an additional final cohort to repeat the highest dose determined to be safe
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 35.0
Sex: All
Minimum age: 2 Years
Maximum age: 5 Years
Healthy volunteers: No
Keywords: Functional constipation in children; LINZESS

Summary:

      The purpose of this study is to evaluate the dose response, safety, and efficacy of
      linaclotide when compared with placebo in pediatric participants, 2 to 5 years of age, with
      Functional Constipation.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participant weighs ≥10 kilograms (kg) at the time the parent/guardian/legally
             authorized representative (LAR) has provided signed consent

          -  Participant meets modified Rome III criteria for FC: For at least 2 months before
             Screening (Visit 1) (for participants aged ≥ 4 years old), or for at least 1 month
             before Screening (Visit 1) (for participants aged < 4 years old), the participant has
             had 2 or fewer defecations (with each defecation occurring in the absence of any
             laxative, suppository, or enema use during the preceding 24 hours) per week.

        In addition, at least once per week, participant must meet 1 or more of the following:

          1. History of retentive posturing or excessive volitional stool retention

          2. History of painful or hard bowel movements (BMs)

          3. Presence of a large fecal mass in the rectum

          4. History of large diameter stools that may obstruct the toilet

          5. At least one episode of fecal incontinence per week after the acquisition of toileting
             skills

               -  Participant is willing to discontinue any laxatives used before the
                  Preintervention Visit in favor of the protocol-permitted rescue medicine

               -  Parent/guardian/LAR and caregiver must provide written informed consent before
                  the initiation of any study-specific procedures

               -  Caregiver who will be completing the eDiary is able to read and/or understand the
                  assessments in the eDiary device and must undergo training

        Exclusion Criteria:

          -  For participants aged ≥ 4 years old: Participant meets Rome III criteria for
             Child/Adolescent IBS: At least once per week for at least 2 months before Screening
             (Visit 1), the participant has experienced abdominal discomfort (an uncomfortable
             sensation not described as pain) or pain associated with 2 or more of the following at
             least 25% of the time:

               1. Improvement with defecation

               2. Onset associated with a change in frequency of stool

               3. Onset associated with a change in form (appearance) of stool

          -  Participant has required manual dis-impaction any time prior to randomization or
             dis-impaction during in-patient hospitalization within 1 year prior to randomization

          -  Participant currently has both unexplained and clinically significant alarm symptoms
             (lower 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

          -  Participant has had surgery that meets any of the following criteria:

               1. Surgery to remove a segment of the GI tract at any time before Screening (Visit
                  1)

               2. Surgery of the abdomen, pelvis, or retroperitoneal structures during the 6 months
                  before the Screening Visit

               3. An appendectomy or cholecystectomy during the 60 days before Screening (Visit 1)

               4. Other major surgery during the 30 days before Screening (Visit 1)

          -  Participant has a mechanical bowel obstruction or pseudo-obstruction.

          -  Participant has a known allergy or sensitivity to the study intervention or its
             components or other medications in the same drug class

          -  Participant has any of the following conditions:

               1. Celiac disease, or positive serological test for celiac disease or the condition
                  is suspected but has not been ruled out by endoscopic biopsy

               2. Cystic fibrosis

               3. 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)

               4. Down's syndrome or any other chromosomal disorder

               5. Active anal fissure (ie, participant reports having streaks of blood on the stool
                  or on toilet paper and/or 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 modified Rome III FC
                  criteria, the participant would not be eligible to participate in the study.

               6. Anatomic malformations (eg, imperforate anus, anal stenosis, anterior displaced
                  anus)

               7. Intestinal nerve or muscle disorders (eg, Hirschprung disease, visceral
                  myopathies, visceral neuropathies)

               8. Neuropathic conditions (eg, spinal cord abnormalities, neurofibromatosis,
                  tethered cord, spinal cord trauma)

               9. Lead toxicity, hypercalcemia

              10. Neurodevelopmental disabilities (early-onset, chronic disorders that share the
                  essential feature of a predominant disturbance in the acquisition of cognitive,
                  motor, language, or social skills, which has a significant and continuing impact
                  on the developmental progress of an individual) producing a cognitive delay that
                  precludes comprehension and completion of the daily eDiary or other study-related
                  questionnaires (Note: Participants are excluded if the person who will be
                  completing the daily eDiary or other study-related questionnaires meets this
                  criterion.)

              11. Inflammatory bowel disease

              12. Childhood functional abdominal pain syndrome

              13. Childhood functional abdominal pain

              14. Poorly treated or poorly controlled psychiatric disorders that might influence
                  his or her ability to participate in the study

              15. Lactose intolerance that is associated with symptoms which could confound the
                  assessments in this study

              16. History of cancer other than treated basal cell carcinoma of the skin. (Note:

        Participants with a history of cancer are allowed provided that the malignancy has been in
        a complete remission before the Randomization Visit. A complete remission is defined as the
        disappearance of all signs of cancer in response to treatment.)

          -  Participant received a study intervention during the 30 days before Screening (Visit
             1) or is planning to receive study intervention (other than that administered during
             this study)

          -  Participant's parent/guardian/LAR or caregiver has 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 participant,
             parent/guardian/LAR or caregiver who has a first-degree family member, significant
             other, or relative residing with him/her directly or indirectly who is involved in
             this study

          -  For participants aged ≥ 4 years old: Participant has a history of non-retentive fecal
             incontinence