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

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

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.

Study Overview

• Status: Completed
• Conditions: Functional Constipation
• Intervention / Treatment: Drug: Linaclotide; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35205
      • Central Research Associates, Inc
  • Arkansas
    • Hot Springs, Arkansas, United States, 71913
      • Healthstar Research
    • Little Rock, Arkansas, United States, 72211
      • Preferred Clinical Research Partners
  • California
    • Anaheim, California, United States, 92805
      • Advanced Research Center
    • Corona, California, United States, 92879
      • Kindred Medical Institute for Clinical Trials, LLC
    • Paramount, California, United States, 90723
      • Center for Clinical Trials, LLC
  • Florida
    • Doral, Florida, United States, 33166
      • Prohealth Research Center
    • Miami, Florida, United States, 33155
      • South Miami Medical & Research Group, Inc.
  • Georgia
    • Blue Ridge, Georgia, United States, 30513
      • River Birch Research Alliance, Llc
    • Stockbridge, Georgia, United States, 30281
      • SleepCare Research Institute, Inc.
  • Maryland
    • Silver Spring, Maryland, United States, 20910
      • Virgo Carter Pediatrics
  • Minnesota
    • Minneapolis, Minnesota, United States, 55413
      • Minnesota Gastroenterology PA
  • Mississippi
    • Port Gibson, Mississippi, United States, 39150
      • David M. Headley, MD, P.A.
  • New Jersey
    • East Orange, New Jersey, United States, 07108
      • Foundation Pediatrics Med Clinical Research Partners, LLC
  • New York
    • Bronx, New York, United States, 10468
      • Advantage Clinical Trials
  • South Carolina
    • Charleston, South Carolina, United States, 29414
      • Coastal Pediatric Research
    • Mount Pleasant, South Carolina, United States, 29464
      • Coastal Pediatric Research
  • Virginia
    • Richmond, Virginia, United States, 23220
      • Clinical Research Partners, LLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 5 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: SEQUENTIAL
• Masking: TRIPLE

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Cohort 1 (Linaclotide 18 μg); 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; Linaclotide, capsules, mixed with water and administered orally, once daily in fasted state.
EXPERIMENTAL: Cohort 2 (Linaclotide 36 μg); 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; Linaclotide, capsules, mixed with water and administered orally, once daily in fasted state.
EXPERIMENTAL: Cohort 3 (Linaclotide 72 μg); 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; Linaclotide, capsules, mixed with water and administered orally, once daily in fasted state.
EXPERIMENTAL: Final Cohort (Linaclotide 72 μg); 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; Linaclotide, capsules, mixed with water and administered orally, once daily in fasted state.
PLACEBO_COMPARATOR: Placebo Pooled; 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; Matching placebo, capsules, mixed with water and administered orally, once daily in fasted state

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Allergan
• Collaborators: Ironwood Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 14, 2019
• Primary Completion (ACTUAL): April 20, 2021
• Study Completion (ACTUAL): April 20, 2021

Study Registration Dates

• First Submitted: September 27, 2019
• First Submitted That Met QC Criteria: September 27, 2019
• First Posted (ACTUAL): October 1, 2019

Study Record Updates

• Last Update Posted (ACTUAL): April 26, 2022
• Last Update Submitted That Met QC Criteria: March 31, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Functional constipation in children; LINZESS
• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Constipation; Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents; Guanylyl Cyclase C Agonists; Enzyme Activators; Linaclotide
• Other Study ID Numbers: LIN-MD-67; 2019-002126-75 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Allergan will share de-identified patient-level data and study-level data including protocols and clinical study reports for phase 2 - 4 trials completed after 2008 that are registered to ClinicalTrials.gov or EudraCT, have received regulatory approval in the United States and/or the European Union in a given indication and the primary manuscript from the trial has been published. To request access to the data, the researcher must sign a data use agreement and any shared data is to be used for non-commercial purposes. More information can be found on http://www.allerganclinicaltrials.com/.
• IPD Sharing Time Frame: After having received regulatory approval in the United States and/or the European Union in a given indication and the primary manuscript from the trial has been published.
• IPD Sharing Access Criteria: To request access to the data, the researcher must sign a data use agreement and any shared data is to be used for non-commercial purposes.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No