A Study of Prucalopride For Functional Constipation in Children and Teenagers

Constipation Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04759833
• Other study ID #: TAK-555-3010
• Secondary ID: 2022-003221-22
• Status: Terminated
• Phase: Phase 3
• Start date: July 13, 2021
• Est. completion date: November 13, 2023

Study information

• Verified date: May 2024
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 175
• Est. completion date: November 13, 2023
• Est. primary completion date: November 13, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Months to 17 Years

Eligibility

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.

Related Conditions & MeSH terms

• Constipation

Intervention

Drug:
• Prucalopride
Prucalopride oral solution or oral tablets.

Other:
• Placebo
Prucalopride-matching placebo oral solution or oral tablets.

Locations

Country	Name	City	State
United States	Advanced Research Center, Inc.	Anaheim	California
United States	University of Colorado Denver	Aurora	Colorado
United States	Tekton Research, Inc.	Beaumont	Texas
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	The University of Chicago Medical Center	Chicago	Illinois
United States	Cleveland Clinic	Cleveland	Ohio
United States	Cedar Health Research	Dallas	Texas
United States	Pediatric Specialist of Virginia	Fairfax	Virginia
United States	Allure Health LLC	Friendswood	Texas
United States	Cyn3rgy Research & Development	Gresham	Oregon
United States	Direct Helpers Research Center	Hialeah	Florida
United States	Pediatric Associates	Houston	Texas
United States	Texas Children's Hospital	Houston	Texas
United States	Riley Hospital for Children at Indiana University Health	Indianapolis	Indiana
United States	Pediatric & Adult Research Center	Kissimmee	Florida
United States	GI For Kids	Knoxville	Tennessee
United States	Auzmer Research	Lakeland	Florida
United States	Le Bonheur Children's Hospital	Memphis	Tennessee
United States	Florida Research Center, Inc.	Miami	Florida
United States	Nicklaus Children's Hospital	Miami	Florida
United States	University of Miami - Miller School of Medicine	Miami	Florida
United States	Jersey Shore University Medical Center	Neptune	New Jersey
United States	CUMC Pediatrics-GI	New York	New York
United States	Children's Hospital of Orange County	Orange	California
United States	Orlando Health - APH Center for Digestive Health and Nutrition	Orlando	Florida
United States	GI Pediatric Subspecialty Clinic	Peoria	Illinois
United States	Methodist Medical Center of Illinois	Peoria	Illinois
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	Oregon Health & Science University	Portland	Oregon
United States	Pediatric Center	Richmond	Texas
United States	University of California, Davis Department of Pediatrics	Sacramento	California
United States	Cardinal Glennon Children's Medical Center	Saint Louis	Missouri
United States	University of Utah	Salt Lake City	Utah
United States	University of California	San Francisco	California
United States	Willis-Knighton Center for Pediatric Gastroenterology & Advanced Endoscopy	Shreveport	Louisiana
United States	Baystate Health	Springfield	Massachusetts
United States	Eclipse Clinical Research	Tucson	Arizona
United States	Novak Clinical Research	Tucson	Arizona
United States	Medstar Georgetown University Hospital	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Takeda	Takeda Development Center Americas, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Part A: Pharmacokinetic (PK) Plasma Concentrations of Prucalopride		1-3 hours post-dose at Baseline (Day 0), 14-26 hours post-dose at Weeks 4, 8 and 12
Primary	Part A: Change From Baseline in Average Number of Weekly Number of Spontaneous Bowel Movements (SBMs) at Week 12	Spontaneous bowel movement was defined as a bowel movement that was not preceded within a period of 24 hours by the intake of rescue medication. The average change from baseline in number of SBMs per week derived from the (e-diary) data, in toilet-trained participants who were at least 3 years of age collected during the placebo-controlled part (Part A) was assessed.	Baseline, Week 12
Primary	Parts A and B: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)	An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product that did not necessarily have a causal relationship with this treatment. A TEAE was defined as any event emerging or manifesting at or after the initiation of treatment with an investigational product (IP) or medicinal product or any existing event that worsens in either intensity or frequency following exposure to the IP or medicinal product. A serious adverse event (SAE) was any untoward medical occurrence (whether considered to be related to investigational product or not) that at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital abnormality/birth defect, is an important medical event.	From first dose of study drug up to Week 52
Primary	Parts A and B: Number of Participants With Clinically Significant Abnormalities in Clinical Laboratory Parameters	Laboratory parameters included blood chemistry, hematology, and urinalysis. Clinically significant laboratory parameters assessment was based on investigator interpretation. Number of participants with clinically significant changes in laboratory parameters (included hematology, blood chemistry, and urinalysis) were reported.	From first dose of study drug up to Week 52
Primary	Parts A and B: Number of Participants With Clinically Significant Vital Sign Abnormalities	Vital signs included measurement of pulse rate, systolic, and diastolic blood pressure. Clinically significant vital signs assessment was based on investigator interpretation. Number of participants with clinically significant changes in vital signs were reported.	From first dose of study drug up to Week 52
Primary	Parts A and B: Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities	ECG included heart rhythm, heart rate, QRS intervals, QT intervals, RR intervals and corrected QT (QTc) intervals parameters measurement. Clinically significant ECG assessment was based on investigator interpretation. Number of participants with clinically significant changes in ECG were reported.	From first dose of study drug up to Week 52
Secondary	Part A: Change From Baseline in Participants' Weekly Stool Consistency Based on Bristol Stool Form Scale (BSFS) Score at Week 12 Categorized by Age	The Bristol Stool Form Scale is a 7-score visual scale to measure stool consistency, 1- Separate hard lumps, hard to pass, 2- Sausage-shaped, but lumpy, 3- Like a sausage but with cracks on the surface, 4- Like a sausage or snake, smooth and soft, 5- Soft blobs with clear-cut edges, 6- Fluffy pieces with ragged edges, a mushy stool, 7- Watery, no solid pieces, entirely liquid. A score of 1 or 2 indicates constipation while a score of 6 or 7 indicates diarrhea. A better score (score of 3 and 4 represent ideal stools as they are easy to defecate while not containing excess liquid, 5 indicates average consistency but lack of dietary fiber) would trend toward the middle of the scale (3 to 5). Daily scores were summed to obtain a weekly score ranging from 7 to 49 with higher scores indicating diarrhea. Data for this outcome measure is reported per age group bifurcation.	Baseline, Week 12
Secondary	Part A: Change From Baseline in Weekly Straining Score Based on a 3-point Likert Scale at Week 12	Straining was assessed based on a 3-point Likert scale: (1=not at all, 2=a little, 3=a lot). A higher score indicates a lot of straining i.e., worsening of the condition. Daily scores were summed to obtain a weekly score ranging from 7 to 21 with higher scores indicating a lot of straining.	Baseline, Week 12
Secondary	Part A: Percentage of Responders Based on Assessment of SBMs	Spontaneous bowel movement was defined as a bowel movement that was not preceded within a period of 24 hours by the intake of rescue medication. Responder was defined as a participant having an increase of =1 SBM per week compared to Baseline and =3 SBMs per week for at least 9 out of the 12 weeks of placebo-controlled part (Part A), including 3 of the last 4 weeks. Percentages are rounded off to the nearest single decimal place.	Baseline through Week 12
Secondary	Part A: Percentage of Participants With Fecal Incontinence at Week 12	Fecal incontinence was defined as unintentional smear or liquid stool in the underwear that is not due to poor wiping. Fecal incontinence can only occur in toilet-trained participants. Non-retentive fecal incontinence is diagnosed (must include at least a 1-month history in a child with a developmental age older than 4 years for all the following): (i) defecation in places inappropriate to the sociocultural context, (ii) no evidence of fecal retention, and (iii) after appropriate evaluation, the fecal incontinence cannot be explained by another medical condition. Percentages are rounded off to the nearest single decimal place.	Week 12

External Links

•   To obtain more information on the study, click here/on this link