Clinical trial NCT04110145: Linaclotide Safety and Efficacy in 2 to 5-Year-Old Participants With Functional Constipation
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Functional Constipation
Keywords: Functional constipation in children
LINZESS
Lead sponsor: Allergan
Sponsor class: INDUSTRY
Collaborators: name: Ironwood Pharmaceuticals, Inc.
First posted: 2019-10-01
Enrollment: 35
Sex: ALL
Minimum age (years): 2
Maximum age (years): 5
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: There are 3 cohorts with ascending doses and an additional final cohort to repeat the highest dose determined to be safe
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Change From Baseline in 4-week Overall Spontaneous Bowel Movement (SBM) Frequency Rate (SBMs/Week) During the Study Intervention Period of Each Cohort
timeFrame: Baseline (14 days prior to randomization) to Day 29
measure: Change From Baseline in 4-week Stool Consistency Reported by the Caregiver During the Study Intervention Period of Each Cohort
timeFrame: Baseline (14 days prior to randomization) to Day 29
measure: Change From Baseline in 4-week Straining Reported by the Caregiver During the Study Intervention Period of Each Cohort
timeFrame: Baseline (14 days prior to randomization) to Day 29
measure: 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
timeFrame: 29 Days
measure: Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
timeFrame: First dose of study drug intervention to within 1 week of last dose (Up to 45 days)
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Central Research Associates, Inc
state: Alabama
city: Hot Springs
country: United States
facility: HealthStar Research
state: Arkansas
city: Little Rock
country: United States
facility: Preferred Clinical Research Partners
state: Arkansas
city: Anaheim
country: United States
facility: Advanced Research Center
state: California
city: Corona
country: United States
facility: Kindred Medical Institute for Clinical Trials, LLC
state: California
city: Paramount
country: United States
facility: Center for Clinical Trials, LLC
state: California
city: Doral
country: United States
facility: Prohealth Research Center
state: Florida
city: Miami
country: United States
facility: South Miami Medical & Research Group, Inc.
state: Florida
city: Blue Ridge
country: United States
facility: River Birch Research Alliance, LLC
state: Georgia
city: Stockbridge
country: United States
facility: SleepCare Research Institute, Inc.
state: Georgia
city: Silver Spring
country: United States
facility: Virgo Carter Pediatrics
state: Maryland
city: Minneapolis
country: United States
facility: Minnesota Gastroenterology PA
state: Minnesota
city: Port Gibson
country: United States
facility: David M. Headley, MD, P.A.
state: Mississippi
city: East Orange
country: United States
facility: Foundation Pediatrics Med Clinical Research Partners, LLC
state: New Jersey
city: Bronx
country: United States
facility: Advantage Clinical Trials
state: New York
city: Charleston
country: United States
facility: Coastal Pediatric Research
state: South Carolina
city: Mount Pleasant
country: United States
facility: Coastal Pediatric Research
state: South Carolina
city: Richmond
country: United States
facility: Clinical Research Partners, LLC
state: Virginia
Study officials:
affiliation: Allergan
name: Anna Muslin
role: STUDY_DIRECTOR
References: