Clinical trial NCT04759833: A Study of Prucalopride For Functional Constipation in Children and Teenagers
Official title: Phase 3, Multicenter, Randomized Study With 2 Different Doses of Prucalopride Administered to Male and Female Pediatric Subjects Aged 6 Months to 17 Years With Functional Constipation, Consisting of a 12-week Double-blind, Placebo-controlled Part (Part A) to Evaluate Efficacy and Safety Followed by a 36-week Double-blind Extension Part (Part B) to Document Long-term Safety up to Week 48
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Constipation
Lead sponsor: Takeda
Sponsor class: INDUSTRY
Collaborators: name: Takeda Development Center Americas, Inc.
First posted: 2021-02-18
Enrollment: 175
Sex: ALL
Minimum age (years): 6
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Functional constipation is a condition when it is very hard to pass a stool that is not due to any other health problem or to medicines being taken. This condition is more common in children and teenagers.

This study has 2 parts:

The main aim of the 1st part of the study is to learn if a medicine called prucalopride can improve bowel movements in children and teenagers with functional constipation. Another aim is to check for side effects from 2 different doses of prucalopride. The main aim of the 2nd part of the study is to continue to check for side effects from 2 different doses of prucalopride.

In the 1st part, at the first visit, the study doctor will check who can take part. Participants who take part will be picked for 1 of 3 treatments by chance.

* A low dose of prucalopride once a day.
* A higher dose of prucalopride once a day.
* A placebo once a day. In this study, a placebo will look like prucalopride but will not have any medicine in it. Participants will be treated with prucalopride or a placebo for 12 weeks.

Participants who took prucalopride will continue to the 2nd part of the study. They will have the same treatment as they did in the 1st part of the study. They will continue with their treatment for another 36 weeks. Participants who took placebo in the 1st part of the study will receive prucalopride in the 2nd part of the study. They will be picked for a low dose or a high dose of prucalopride by chance.

Participants will visit the clinic a few times during treatment. The clinic staff will also telephone the participants, or their parents or caregivers throughout treatment for a check-up 4 weeks after last treatment, the clinic staff will telephone the participants, or their parents or caregivers for a final check-up.

Detailed description: This study consists of a 12-week double-blind, placebo-controlled part (Part A) followed by a 36-week double-blind safety extension part (Part B). Participants aged 3 to 17 years are planned for randomization in a 1:1:1 ratio to the Low Dose Group, High Dose Group, or matching placebo (placebo-controlled part \[Part A\]). After completion of Part A, participants in the placebo group will be re-randomized in a 1:1 ratio to the Low Dose Group or the High Dose Group (safety extension part \[Part B\]). Randomization at study entry will be stratified by toilet-trained status.

Eligibility criteria: Inclusion Criteria:

* Participants and/or their parent(s)/caregiver(s)/legally authorized representative(s) have an understanding, ability, and willingness to fully comply with study procedures and restrictions.
* Ability to voluntarily provide written, signed, and dated (personally or via parent\[s\]/caregiver\[s\]/legally authorized representative\[s\]) informed consent/assent as applicable to participate in the study.

Note: Participants and/or parent(s)/caregiver(s)/legally authorized representative(s) (where appropriate depending on age and local regulation) can also provide consent/assent to the sparse Pharmacokinetic (PK) sampling in this study.

* Toilet-trained participants 3 years to 17 years of age, inclusive, or non-toilet-trained participants 6 months to 17 years of age, inclusive.
* Participant weighs greater than or equal to (\>=) 5.5 kilograms (kg) (12 pounds \[lbs\]).
* Male, or non-pregnant, non-lactating female participants who are sexually active and agree to comply with the applicable contraceptive requirements of the protocol or females of non-childbearing potential.

Note: All female participants \>= 12 years and/or female participants lesser than (\<) 12 years who have started menarche must have a negative serum pregnancy test at screening.

- Participant meets modified Rome IV criteria:

\* For child/adolescent (aged \> 4 years) functional constipation (H3a):

Participants must have lesser than or equal to (\<=) 2 defecations per week and 1 or more of the following occurring at least once per week for a minimum of 1 month:

* \>= 1 episode of fecal incontinence per week (only for participants after the acquisition of toileting skills).
* History of retentive posturing or excessive volitional stool retention.
* History of painful or hard bowel movements (BMs).
* Presence of large fecal mass in rectum.
* History of large diameter stools which can obstruct the toilet. In addition, the participant does not satisfy sufficient criteria for a diagnosis of irritable bowel syndrome (IBS) and, after appropriate evaluation, the participants symptoms cannot be fully explained by another medical condition.

For infants/toddler (aged 6 months to \<= 4 years) functional constipation (G7):

Participants must have \<= 2 defecations per week and \>= 1 month of at least 1 of the following:

* History of excessive stool retention
* History of painful or hard BMs
* History of large-diameter stools (in the diaper)
* Presence of a large fecal mass in the rectum

In toilet-trained children, the following additional criteria may be used:

* At least 1 episode/week of incontinence after the acquisition of toileting skills
* History of large-diameter stools which may obstruct the toilet - Participant and/or parent(s)/caregiver(s)/legally authorized representative(s) is willing to discontinue any laxatives during the screening period up to disimpaction and agrees to adhere to the protocol-specified disimpaction and rescue medication rules, if applicable.

To be evaluated prior to randomization:

* Participant has an average of \< 3 SBMs (defecations) per week during the screening period and prior to the disimpaction.
* Participant or legally authorized representative (dependent on participant age) is compliant with completing the electronic diary for at least 7 consecutive days preceding the disimpaction.

Exclusion Criteria:

* Current or recurrent disease that could affect the action, absorption, or disposition of the investigational product (IP), or clinical or laboratory assessments.
* Any clinically significant abnormal findings on the electrocardiogram (ECG) that indicates a dysrhythmia or conduction abnormalities (such as abnormal heart rate, PR, QRS, or QT).
* Major cardiovascular disease such as: cardiomyopathy, cardiac insufficiency, uncorrected congenital heart disease, symptomatic valve disorders, or septal defects.
* Current or relevant history of physical or psychiatric illness (e.g. severe autism, depression, etc.), any medical disorder that may require treatment or make the participant unlikely to fully complete the study, or any condition that presents undue risk from the IP or procedures.
* Non-retentive fecal incontinence.
* Intestinal perforation or obstruction due to structural or functional disorder of the gut wall, obstructive ileus, severe inflammatory conditions of the intestinal tract such as Crohn's disease, ulcerative colitis, and toxic megacolon/megarectum.
* Current use of any medication (including over-the-counter, herbal, or homeopathic preparations) that could affect (improve or worsen) the condition being studied (e.g. opioids), or could affect the action, absorption, or disposition of the IP, or clinical or laboratory assessment. (Current use is defined as use within the past 5 days).
* Participants with renal impairment:

  * Participants \<= 2 years of age with serum creatinine greater than normal (screening sample results using central laboratory pediatric reference ranges).
  * Participants \> 2 years of age with severe renal impairment or end stage renal disease (estimated glomerular filtration rate \[eGFR\] \<30 mL/min/1.73 m\^2).
* Known or suspected intolerance or hypersensitivity to the IP(s), closely-related compounds, or any of the stated ingredients.
* Known history of alcohol or other substance abuse within the last year.
* Within 30 days prior to the first dose of the IP in the current study:

  * Have used any IP.
  * Have been enrolled in a clinical study (including vaccine studies) that may or may not include the administration of an IP that, in the investigator's opinion, may impact this study.
* Participant used prucalopride within 10 days prior to the first dose of the IP or has been unsuccessfully treated with prucalopride before.
* Participant meets Rome IV criteria for other Child/Adolescent Functional Gastrointestinal Disorders (FGID) (H1 - H2 and H3b).
* Participant with secondary causes of constipation:

  * Endocrine disorders (e.g., hypopituitarism, hypothyroidism, hypercalcemia, pheochromocytoma, glucagon-producing tumors) unless these are controlled by appropriate medical therapy. Participant with uncontrolled diabetes mellitus is to be excluded
  * Metabolic disorders (e.g. porphyria, uremia, hypokalemia, hypothyroidism, amyloid neuropathy), unless controlled by appropriate medical therapy
  * Neurological disorders (e.g. cerebral tumors, cerebrovascular accidents, multiple sclerosis, meningocele, aganglionosis, hypoganglionosis, hyperganglionosis, autonomic neuropathy, spinal cord injury, Chagas disease
  * Organic disorders (known or suspected) of the large bowel (e.g. obstruction from any cause including biliary obstruction, malignancy, intestinal perforation, obstructive ileus, pseudo-obstruction, history of or current anorectal malformations, severe inflammation of the intestinal tract, such as Crohn's disease, ulcerative colitis or toxic megacolon/megarectum, Hirschsprung's disease)
  * Celiac disease, cow milk allergy
  * Surgery: history of gastrointestinal surgery related or possibly related to the presence of constipation
  * Lactose intolerance
* Any of the following clinically significant abnormalities of serum biochemistry:

  * Serum aspartate aminotransferase (AST) \>1.5 times upper limit of normal (ULN) at screening.
  * Serum alanine aminotransferase (ALT) \>1.5 times ULN at screening.
  * Total bilirubin outside the age-adjusted normal range, except for participants with Gilbert's syndrome.
* Any significant underlying liver disease.
* Participant is not able to swallow the IP (liquid or tablet).
* Participant is pregnant or planning to get pregnant during study period.

To be evaluated prior to randomization:

* Participant has used other disimpaction medication in lieu of the protocol-provided medication.
* Participant has used non-protocol approved medications to induce BMs during the screening period or disimpaction.
* The participant has failed the disimpaction based on the investigator's assessment.
* Worsening of depression and emergence of suicidal thoughts.

Primary outcomes:
measure: Part A: Change From Baseline in Average Number of Weekly Number of Spontaneous Bowel Movements (SBMs) at Week 12
timeFrame: Baseline, Week 12
measure: Parts A and B: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
timeFrame: From first dose of study drug up to Week 52
measure: Parts A and B: Number of Participants With Clinically Significant Abnormalities in Clinical Laboratory Parameters
timeFrame: From first dose of study drug up to Week 52
measure: Parts A and B: Number of Participants With Clinically Significant Vital Sign Abnormalities
timeFrame: From first dose of study drug up to Week 52
measure: Parts A and B: Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities
timeFrame: From first dose of study drug up to Week 52
Secondary outcomes:
measure: Part A: Change From Baseline in Participants' Weekly Stool Consistency Based on Bristol Stool Form Scale (BSFS) Score at Week 12 Categorized by Age
timeFrame: Baseline, Week 12
measure: Part A: Change From Baseline in Weekly Straining Score Based on a 3-point Likert Scale at Week 12
timeFrame: Baseline, Week 12
measure: Part A: Percentage of Responders Based on Assessment of SBMs
timeFrame: Baseline through Week 12
measure: Part A: Percentage of Participants With Fecal Incontinence at Week 12
timeFrame: Week 12
Other outcomes:
measure: Part A: Pharmacokinetic (PK) Plasma Concentrations of Prucalopride
timeFrame: 1-3 hours post-dose at Baseline (Day 0), 14-26 hours post-dose at Weeks 4, 8 and 12
Locations:
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Tucson
country: United States
facility: Novak Clinical Research
state: Arizona
city: Tucson
country: United States
facility: Eclipse Clinical Research
state: Arizona
city: Anaheim
country: United States
facility: Advanced Research Center, Inc.
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: Sacramento
country: United States
facility: University of California, Davis Department of Pediatrics
state: California
city: San Francisco
country: United States
facility: University of California
state: California
city: Aurora
country: United States
facility: University of Colorado Denver
state: Colorado
city: Washington
country: United States
facility: Medstar Georgetown University Hospital
state: District of Columbia
city: Hialeah
country: United States
facility: Direct Helpers Research Center
state: Florida
city: Kissimmee
country: United States
facility: Pediatric & Adult Research Center
state: Florida
city: Lakeland
country: United States
facility: Auzmer Research
state: Florida
city: Miami
country: United States
facility: University of Miami - Miller School of Medicine
state: Florida
city: Miami
country: United States
facility: Nicklaus Children's Hospital
state: Florida
city: Miami
country: United States
facility: Florida Research Center, Inc.
state: Florida
city: Orlando
country: United States
facility: Orlando Health - APH Center for Digestive Health and Nutrition
state: Florida
city: Chicago
country: United States
facility: The University of Chicago Medical Center
state: Illinois
city: Peoria
country: United States
facility: GI Pediatric Subspecialty Clinic
state: Illinois
city: Peoria
country: United States
facility: Methodist Medical Center of Illinois
state: Illinois
city: Indianapolis
country: United States
facility: Riley Hospital for Children at Indiana University Health
state: Indiana
city: Shreveport
country: United States
facility: Willis-Knighton Center for Pediatric Gastroenterology & Advanced Endoscopy
state: Louisiana
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Springfield
country: United States
facility: Baystate Health
state: Massachusetts
city: Saint Louis
country: United States
facility: Cardinal Glennon Children's Medical Center
state: Missouri
city: Neptune
country: United States
facility: Jersey Shore University Medical Center
state: New Jersey
city: New York
country: United States
facility: CUMC Pediatrics-GI
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Gresham
country: United States
facility: Cyn3rgy Research & Development
state: Oregon
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Knoxville
country: United States
facility: GI For Kids
state: Tennessee
city: Memphis
country: United States
facility: Le Bonheur Children's Hospital
state: Tennessee
city: Beaumont
country: United States
facility: Tekton Research, Inc.
state: Texas
city: Dallas
country: United States
facility: Cedar Health Research
state: Texas
city: Friendswood
country: United States
facility: Allure Health LLC
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Houston
country: United States
facility: Pediatric Associates
state: Texas
city: Richmond
country: United States
facility: Pediatric Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Fairfax
country: United States
facility: Pediatric Specialist of Virginia
state: Virginia
Study officials:
affiliation: Takeda
name: Medical Director
role: STUDY_DIRECTOR
References: