Long-term Safety of Linaclotide in Pediatric Participants With FC or IBS-C

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

Official Title
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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)

Conditions
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Irritable Bowel Syndrome With Constipation, Functional Constipation

Intervention / Treatment
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* Drug: Irritable Bowel Syndrome with Constipation (IBS-C) participants (LIN-MD-63 completers)
* Drug: Functional Constipation (FC) participants (LIN-MD-62 and LIN-MD-64 completers)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant weighs ≥ 18 kg at the time the parent/guardian/LAR and/or caregiver has provided signed consent. Female participants who have had their first menstrual period and are sexually active must agree to use a reliable form of contraception. Participants must have completed study intervention in their lead-in study. Inclusion Criteria for Phase 2 LIN-MD-62 or Phase 2 LIN-MD-63 and Phase 3 LIN-MD-64 completers who enroll in LIN-MD-66 after >28 days from last study intervention: Female participants of childbearing potential must have a negative serum pregnancy test at the Screening Visit (Visit 1) and negative urine pregnancy test prior to the first dose on the Day 1 Visit (Visit 2). LIN-MD-63 completers only: Participants meet Rome III criteria for child/adolescent IBS: At least once per week for at least 2 months before the LIN-MD-66 Screening Visit (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: a) Improvement with defecation b) Onset associated with a change in frequency of stool c) Onset associated with a change in form (appearance) of stool Participants meet modified Rome III criteria for child/adolescent FC: For at least 2 months before the LIN-MD-66 Screening Visit (Visit 1), 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) in the toilet per week. In addition, at least once per week, participant meets 1 or more of the following: a) History of retentive posturing or excessive volitional stool retention b) History of painful or hard BMs c) Presence of a large fecal mass in the rectum d) History of large diameter stools that may obstruct the toilet e) At least 1 episode of fecal incontinence per week Exclusion Criteria: Participant has a known allergy or sensitivity to the study intervention or its components or other medications in the same drug class. Participant received an investigational drug, other than linaclotide, during the 30 days before the Screening Visit (Visit 1) or is planning to receive an investigational drug (other than that administered during this study) or use an investigational device at any time during the study. Female participants who are currently pregnant or nursing, or plan to become pregnant or nurse during the clinical study. Participant has required manual disimpaction any time prior to study intervention or disimpaction during in-patient hospitalization within 1 year prior to study intervention. Participant has any of the following conditions: a) Down's syndrome or any other chromosomal disorder b) Anatomic malformations (eg, imperforate anus, anal stenosis, anterior displaced anus) c) Intestinal nerve or muscle disorders (eg, Hirschprung disease, visceral myopathies, visceral neuropathies) d) Neuropathic conditions (eg, spinal cord abnormalities, neurofibromatosis, tethered cord, spinal cord trauma) e) 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 by the participant. Participant has a mechanical bowel obstruction or pseudo-obstruction. 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 an active anal fissure (Note: history of anal fissure is not an exclusion). Participant has had surgery that meets any of the following criteria: a) Bariatric surgery for treatment of obesity, or surgery to remove a segment of the GI tract at any time before the Screening Visit (Visit 1). b) Surgery of the abdomen, pelvis, or retroperitoneal structures during the 6 months before the Screening Visit (Visit 1) c) An appendectomy or cholecystectomy during the 60 days before the Screening Visit d) Other major surgery during the 30 days before the Screening Visit (Visit 1) Participant is receiving enteral tube feeding Participants who have positive urine drug screen results for cocaine, barbiturates, opiates, or cannabinoids will be excluded from study participation. Exclusion Criteria for LIN-MD-62, LIN-MD-63 and LIN-MD-64 Completers Who Enroll in LIN-MD-66 > 28 Days From Last Study Intervention: Participant has a history of nonretentive fecal incontinence For LIN-MD-62 and LIN-MD-64 completers only: 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: a) Improvement with defecation b) Onset associated with a change in the frequency of stool c) Onset associated with a change in form (appearance) of stool Participant has a history of drug or alcohol abuse Participant has any of the following conditions: a) Celiac disease, or positive serological test for celiac disease and the condition 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 the Screening (Visit 1) d) Lead toxicity, hypercalcemia e) Inflammatory bowel disease f) Childhood functional abdominal pain syndrome g) Childhood functional abdominal pain h) Poorly treated or poorly controlled psychiatric disorders that might influence his or her ability to participate in the study i) Lactose intolerance that is associated with abdominal pain or discomfort and could confound the assessments in this study j) 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 for at least 5 years before the Randomization Visit. A complete remission is defined as the disappearance of all signs of cancer in response to treatment.) k) History of diabetic neuropathy Participants who have positive urine drug screen results for cocaine, barbiturates, opiates, or cannabinoids.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 72 μg linaclotide<br>An oral capsule that is taken once daily. It may be taken whole or sprinkled into 1 teaspoonful of applesauce or 30mL of bottled water. | Drug: Irritable Bowel Syndrome with Constipation (IBS-C) participants (LIN-MD-63 completers)<br>* Participants whom are between the ages of 7-11 years old at their time of enrollment will be assigned a dose (72 μg or 145 μg) based on their weight. Randomized doses (145 μg or 290 μg) will be assigned to participants whom are 12-17 years old at the time of enrollment.<br>Drug: Functional Constipation (FC) participants (LIN-MD-62 and LIN-MD-64 completers)<br>* Participants whom are between the ages of 6-11 years old at their time of enrollment will be assigned a dose of 72 μg. Randomized doses (72 μg or 145 μg) will be assigned to participants whom are 12-17 years old at the time of enrollment.<br>|
| Active Comparator: 145 μg linaclotide<br>An oral capsule that is taken once daily. It may be taken whole or sprinkled into 1 teaspoonful of applesauce or 30mL of bottled water. | Drug: Irritable Bowel Syndrome with Constipation (IBS-C) participants (LIN-MD-63 completers)<br>* Participants whom are between the ages of 7-11 years old at their time of enrollment will be assigned a dose (72 μg or 145 μg) based on their weight. Randomized doses (145 μg or 290 μg) will be assigned to participants whom are 12-17 years old at the time of enrollment.<br>Drug: Functional Constipation (FC) participants (LIN-MD-62 and LIN-MD-64 completers)<br>* Participants whom are between the ages of 6-11 years old at their time of enrollment will be assigned a dose of 72 μg. Randomized doses (72 μg or 145 μg) will be assigned to participants whom are 12-17 years old at the time of enrollment.<br>|
| Active Comparator: 290 μg linaclotide<br>An oral capsule that is taken once daily. It may be taken whole or sprinkled into 1 teaspoonful of applesauce or 30mL of bottled water. | Drug: Irritable Bowel Syndrome with Constipation (IBS-C) participants (LIN-MD-63 completers)<br>* Participants whom are between the ages of 7-11 years old at their time of enrollment will be assigned a dose (72 μg or 145 μg) based on their weight. Randomized doses (145 μg or 290 μg) will be assigned to participants whom are 12-17 years old at the time of enrollment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment Emergent Adverse Events | Number of Participants With Treatment-Emergent Adverse Events (TEAEs). | 24 to 52 weeks |