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

NCT04110145 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: LIN-MD-672019-002126-75
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 18

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.

Conditions

Functional Constipation

Keywords

Functional constipation in children; LINZESS

Outcome Measures

Primary Outcomes (5)

• 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)

Study Arms (5)

Cohort 1 (Linaclotide 18 μg)

EXPERIMENTAL

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

Cohort 2 (Linaclotide 36 μg)

EXPERIMENTAL

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

Cohort 3 (Linaclotide 72 μg)

EXPERIMENTAL

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

Final Cohort (Linaclotide 72 μg)

EXPERIMENTAL

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

Placebo Pooled

PLACEBO COMPARATOR

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

Interventions

Linaclotide DRUG

Linaclotide, capsules, mixed with water and administered orally, once daily in fasted state.

Cohort 1 (Linaclotide 18 μg); Cohort 2 (Linaclotide 36 μg); Cohort 3 (Linaclotide 72 μg); Final Cohort (Linaclotide 72 μg)

Placebo DRUG

Matching placebo, capsules, mixed with water and administered orally, once daily in fasted state

Placebo Pooled

Eligibility Criteria

• Age: 2 Years - 5 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Allergan: lead
• Ironwood Pharmaceuticals, Inc.: collaborator

Study Sites (18)

Central Research Associates, Inc

Birmingham, Alabama, 35205, United States

Location

HealthStar Research

Hot Springs, Arkansas, 71913, United States

Location

Preferred Clinical Research Partners

Little Rock, Arkansas, 72211, United States

Location

Advanced Research Center

Anaheim, California, 92805, United States

Location

Kindred Medical Institute for Clinical Trials, LLC

Corona, California, 92879, United States

Location

Center for Clinical Trials, LLC

Paramount, California, 90723, United States

Location

Prohealth Research Center

Doral, Florida, 33166, United States

Location

South Miami Medical & Research Group, Inc.

Miami, Florida, 33155, United States

Location

River Birch Research Alliance, LLC

Blue Ridge, Georgia, 30513, United States

Location

SleepCare Research Institute, Inc.

Stockbridge, Georgia, 30281, United States

Location

Virgo Carter Pediatrics

Silver Spring, Maryland, 20910, United States

Location

Minnesota Gastroenterology PA

Minneapolis, Minnesota, 55413, United States

Location

David M. Headley, MD, P.A.

Port Gibson, Mississippi, 39150, United States

Location

Foundation Pediatrics Med Clinical Research Partners, LLC

East Orange, New Jersey, 07108, United States

Location

Advantage Clinical Trials

The Bronx, New York, 10468, United States

Location

Coastal Pediatric Research

Charleston, South Carolina, 29414, United States

Location

Coastal Pediatric Research

Mt. Pleasant, South Carolina, 29464, United States

Location

Clinical Research Partners, LLC

Richmond, Virginia, 23220, United States

Location

MeSH Terms

Interventions

linaclotide

Results Point of Contact

• Title: Therapeutic Area, Head
• Organization: Allergan

clinicaltrials@allergan.com

714-246-4500

Study Officials

• Anna Muslin

  Allergan

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: There are 3 cohorts with ascending doses and an additional final cohort to repeat the highest dose determined to be safe

Study Record Dates

• First Submitted: September 27, 2019
• First Posted: October 1, 2019
• Study Start: October 14, 2019
• Primary Completion: April 20, 2021
• Study Completion: April 20, 2021
• Last Updated: April 26, 2022
• Results First Posted: April 26, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, 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.

Locations

US (18)