Linaclotide Safety and Efficacy in 2 to 5-Year-Old Participants With Functional Constipation

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Sequential, Ascending, Multidose Study to Evaluate the Safety and Efficacy of Linaclotide in Pediatric Participants (Age 2 to 5 Years) With Functional Constipation

Conditions
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Functional Constipation

Intervention / Treatment
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* Drug: Linaclotide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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: History of retentive posturing or excessive volitional stool retention History of painful or hard bowel movements (BMs) Presence of a large fecal mass in the rectum History of large diameter stools that may obstruct the toilet 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: Improvement with defecation Onset associated with a change in frequency of stool 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: Surgery to remove a segment of the GI tract at any time before Screening (Visit 1) Surgery of the abdomen, pelvis, or retroperitoneal structures during the 6 months before the Screening Visit An appendectomy or cholecystectomy during the 60 days before Screening (Visit 1) 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: 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 (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. Anatomic malformations (eg, imperforate anus, anal stenosis, anterior displaced anus) Intestinal nerve or muscle disorders (eg, Hirschprung disease, visceral myopathies, visceral neuropathies) Neuropathic conditions (eg, spinal cord abnormalities, neurofibromatosis, tethered cord, spinal cord trauma) Lead toxicity, hypercalcemia 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.) Inflammatory bowel disease Childhood functional abdominal pain syndrome Childhood functional abdominal pain Poorly treated or poorly controlled psychiatric disorders that might influence his or her ability to participate in the study Lactose intolerance that is associated with symptoms which could confound the assessments in this study 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

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 5 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: Randomized
Intervention Model: Sequential Assignment
Interventional 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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 (Linaclotide 18 μg)<br>Linaclotide 18 microgram (μg), capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period. | Drug: Linaclotide<br>* Linaclotide, capsules, mixed with water and administered orally, once daily in fasted state.<br>|
| Experimental: Cohort 2 (Linaclotide 36 μg)<br>Linaclotide 36 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period. | Drug: Linaclotide<br>* Linaclotide, capsules, mixed with water and administered orally, once daily in fasted state.<br>|
| Experimental: Cohort 3 (Linaclotide 72 μg)<br>Linaclotide 72 μg, capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period. | Drug: Linaclotide<br>* Linaclotide, capsules, mixed with water and administered orally, once daily in fasted state.<br>|
| Experimental: Final Cohort (Linaclotide 72 μg)<br>Linaclotide at the highest dose tested/determined to be safe (72 μg), capsules, mixed with water and administered orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period. | Drug: Linaclotide<br>* Linaclotide, capsules, mixed with water and administered orally, once daily in fasted state.<br>|
| Placebo Comparator: Placebo Pooled<br>Matching placebo, orally, once daily in fasted state (30 minutes before any meal) for the 4-week Study Intervention Period pooled from Cohorts 1, 2, 3, and Final Cohort. | Drug: Placebo<br>* Matching placebo, capsules, mixed with water and administered orally, once daily in fasted state<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in 4-week Overall Spontaneous Bowel Movement (SBM) Frequency Rate (SBMs/Week) During the Study Intervention Period of Each Cohort | A SBM was defined as a bowel movement (BM) that occurred in the absence of laxative, suppository, or enema use on the calendar day of the BM or the calendar day before the BM. Each day the caregiver recorded the number of SBMs in the last 24 hours in an electronic diary (eDiary). The SBM frequency rate (SBMs/week) during the analysis period for each participant was calculated as [(total number of SBMs in the analysis period/number of days in the analysis period)*7]. Baseline value was based on values collected 14 days before randomization up to randomization. Change from Baseline was calculated as the SBM frequency rate during the 4-week treatment period - SBM frequency rate at Baseline. A positive change from Baseline indicates improvement. | Baseline (14 days prior to randomization) to Day 29 | 
| Change From Baseline in 4-week Stool Consistency Reported by the Caregiver During the Study Intervention Period of Each Cohort | The caregiver rated and recorded in an eDiary the consistency of the stool for each bowel movement using the Bristol Stool Form 7-point scale where: 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; 7=Watery, no solid pieces. Entirely liquid. Baseline value was based on values collected 14 days before randomization up to randomization. A participant's stool consistency score for the treatment period was the average of the nonmissing consistency scores from the BMs recorded by the caregiver during the 4-week treatment period. | Baseline (14 days prior to randomization) to Day 29 | 
| Change From Baseline in 4-week Straining Reported by the Caregiver During the Study Intervention Period of Each Cohort | The caregiver rated and recorded in an eDiary the amount of straining they observed when the child passed the BM (1=Not at all; 2=Yes a little; 3=Yes a lot; I don't know). Baseline value was based on values collected 14 days before randomization up to randomization. A participant's straining score for the treatment period was the average of the nonmissing straining scores from the BMs recorded by the caregiver during the 4-week treatment period. A negative change from Baseline indicates improvement. | Baseline (14 days prior to randomization) to Day 29 | 
| Percentage of Days With Fecal Incontinence During the Study Intervention Period (for Participants Who Have Acquired Toileting Skills During the Daytime and Nighttime or Acquired Toileting Skills During Daytime Only) Within Each Cohort | Each day the caregiver recorded in an eDiary if the child had a bowel movement accident (Yes; No; I don't know). The percentage of days with fecal incontinence for the treatment period was the average of the nonmissing incidences of fecal incontinence recorded by the caregiver during the 4-week treatment period. | 29 Days | 
| Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | An Adverse Event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease. A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that: results in death, is immediately life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, and/or causes a congenital anomaly/birth defect. A TEAE is an AE that begins or worsens after receiving study drug. Safety Population included all participants in the Randomized Population who received at least 1 dose of double-blind study intervention. | First dose of study drug intervention to within 1 week of last dose (Up to 45 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Functional constipation in children, LINZESS