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

• ClinicalTrials.gov Identifier: NCT04110145
• Recruitment Status: Completed
• First Posted: October 1, 2019
• Results First Posted: April 26, 2022
• Last Update Posted: April 26, 2022
• Sponsor: Allergan
• Collaborator: Ironwood Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Allergan

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Functional Constipation	Drug: Linaclotide; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 35 participants
• 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)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: October 14, 2019
• Actual Primary Completion Date: April 20, 2021
• Actual Study Completion Date: April 20, 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in 4-week Overall Spontaneous Bowel Movement (SBM) Frequency Rate (SBMs/Week) During the Study Intervention Period of Each Cohort [ Time Frame: Baseline (14 days prior to randomization) to Day 29 ]
   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.
2. Change From Baseline in 4-week Stool Consistency Reported by the Caregiver During the Study Intervention Period of Each Cohort [ Time Frame: Baseline (14 days prior to randomization) to Day 29 ]
   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.
3. Change From Baseline in 4-week Straining Reported by the Caregiver During the Study Intervention Period of Each Cohort [ Time Frame: Baseline (14 days prior to randomization) to Day 29 ]
   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.
4. 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 [ Time Frame: 29 Days ]
   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.
5. Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) [ Time Frame: First dose of study drug intervention to within 1 week of last dose (Up to 45 days) ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 5 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, Alabama

Central Research Associates, Inc

Birmingham, Alabama, United States, 35205

United States, Arkansas

HealthStar Research

Hot Springs, Arkansas, United States, 71913

Preferred Clinical Research Partners

Little Rock, Arkansas, United States, 72211

United States, California

Advanced Research Center

Anaheim, California, United States, 92805

Kindred Medical Institute for Clinical Trials, LLC

Corona, California, United States, 92879

Center for Clinical Trials, LLC

Paramount, California, United States, 90723

United States, Florida

Prohealth Research Center

Doral, Florida, United States, 33166

South Miami Medical & Research Group, Inc.

Miami, Florida, United States, 33155

United States, Georgia

River Birch Research Alliance, LLC

Blue Ridge, Georgia, United States, 30513

SleepCare Research Institute, Inc.

Stockbridge, Georgia, United States, 30281

United States, Maryland

Virgo Carter Pediatrics

Silver Spring, Maryland, United States, 20910

United States, Minnesota

Minnesota Gastroenterology PA

Minneapolis, Minnesota, United States, 55413

United States, Mississippi

David M. Headley, MD, P.A.

Port Gibson, Mississippi, United States, 39150

United States, New Jersey

Foundation Pediatrics Med Clinical Research Partners, LLC

East Orange, New Jersey, United States, 07108

United States, New York

Advantage Clinical Trials

Bronx, New York, United States, 10468

United States, South Carolina

Coastal Pediatric Research

Charleston, South Carolina, United States, 29414

Coastal Pediatric Research

Mount Pleasant, South Carolina, United States, 29464

United States, Virginia

Clinical Research Partners, LLC

Richmond, Virginia, United States, 23220

Sponsors and Collaborators

Allergan

Ironwood Pharmaceuticals, Inc.

Investigators

• Study Director: Anna Muslin; Allergan

  Study Documents (Full-Text)

Documents provided by Allergan:

Study Protocol  [PDF] May 4, 2020

Statistical Analysis Plan  [PDF] May 11, 2020

More Information

• Responsible Party: Allergan
• ClinicalTrials.gov Identifier: NCT04110145
• Other Study ID Numbers: LIN-MD-67; 2019-002126-75 ( EudraCT Number )
• First Posted: October 1, 2019
• Results First Posted: April 26, 2022
• Last Update Posted: April 26, 2022
• Last Verified: March 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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/.
• Supporting Materials: Study Protocol; Clinical Study Report (CSR)
• 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.
• 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.
• URL: http://www.allerganclinicaltrials.com/

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Allergan:

Functional constipation in children; LINZESS

Additional relevant MeSH terms:

Constipation; Signs and Symptoms, Digestive; Linaclotide; Guanylyl Cyclase C Agonists; Enzyme Activators; Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents