A Study of Prucalopride For Functional Constipation in Children and Teenagers

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Constipation

Intervention / Treatment
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* Drug: Prucalopride
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Low Dose Group<br>Participants weighing less than (<) 50 kilograms (kg) will receive a daily dose of 0.04 milligrams per kilogram (mg/kg) prucalopride oral solution (will draw the required volume from one bottle of 0.4 milligram per milliliter [mg/mL] and one bottle of placebo oral solution to account for the daily dose assigned) once daily (QD) or participants weighing greater than or equal to (>=) 50 kg will receive a single dose of 2 milligram (mg) prucalopride oral tablet during 12 weeks of treatment period. Volume of the oral solution will be based on the participants body weight (BW) at the randomization visit. | Drug: Prucalopride<br>* Participants will receive 0.04 mg/kg or 0.08 mg/kg oral solution or 2 mg oral tablet of prucalopride QD.<br>* Other names: Prucalopride succinate;|
| Experimental: Part A: High Dose Group<br>Participants weighing < 50 kg will receive a daily dose of 0.08 mg/kg prucalopride oral solution (will draw the required volume from two bottle of 0.4 mg/mL to account for the daily dose assigned) QD or participants weighing >= 50 kg will receive a two dose of 2 mg prucalopride oral tablet during 12 weeks of treatment period. Volume of the oral solution will be based on the participants BW at the randomization visit. | Drug: Prucalopride<br>* Participants will receive 0.04 mg/kg or 0.08 mg/kg oral solution or 2 mg oral tablet of prucalopride QD.<br>* Other names: Prucalopride succinate;|
| Placebo Comparator: Part A: Placebo<br>Participants weighing < 50 kg will draw equal volumes from two bottles of matching placebo oral solution to account for the daily dose assigned or participants weighing >= 50 kg will receive two daily dose of matching placebo oral tablet during 12 weeks of treatment period. | Other: Placebo<br>* Participants will receive matching placebo of oral solution or tablet QD.<br>|
| Experimental: Part B: Low Dose Group<br>Participants weighing < 50 kg will receive a daily dose of 0.04 mg/kg prucalopride oral solution (will draw the required volume from one bottle of 0.4 mg/mL and one bottle of placebo oral solution to account for the daily dose assigned) QD or participants weighing >= 50 kg will receive a single dose of 2 mg prucalopride oral tablet during 36 weeks of treatment period. Volume of the oral solution will be based on the participants BW at the randomization visit. | Drug: Prucalopride<br>* Participants will receive 0.04 mg/kg or 0.08 mg/kg oral solution or 2 mg oral tablet of prucalopride QD.<br>* Other names: Prucalopride succinate;|
| Experimental: Part B: High Dose Group<br>Participants weighing < 50 kg will receive a daily dose of 0.08 mg/kg prucalopride oral solution (will draw the required volume from two bottle of 0.4 mg/mL to account for the daily dose assigned) QD or participants weighing >= 50 kg will receive two dose of 2 mg prucalopride oral tablet during 36 weeks of treatment period. Volume of the oral solution will be based on the participants BW at the randomization visit. | Drug: Prucalopride<br>* Participants will receive 0.04 mg/kg or 0.08 mg/kg oral solution or 2 mg oral tablet of prucalopride QD.<br>* Other names: Prucalopride succinate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Average Change From Baseline in Number of Spontaneous Bowel Movements (SBMs) per Week | Spontaneous bowel movements is defined as a bowel movement that is 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 (diary) data over 12 weeks, in toilet-trained participants who are at least 3 years of age collected during the placebo-controlled part (Part A) will be assessed. | Baseline up to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Average Change From Baseline in Participants' Stool Consistency Based on Bristol Stool Form Scale (BSFS) Score During Week 12 | Stool consistency will be assessed by typical stool form based on BSFS Score: 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. The average change from baseline in stool consistency (based on BSFS score), assessed as the weekly average during the 12-week double-blind, placebo-controlled treatment phase will be assessed. | Baseline up to Week 12 | 
| Part A: Average Change From Baseline in Straining During Week 12 | Straining will be assessed based on a 3-point Likert scale: (0=none, 1=mild, 2=moderate). The average change from baseline in straining (based on a 3-point Likert scale, assessed as the weekly average during the 12-week double-blind, placebo-controlled treatment phase will be assessed. | Baseline up to Week 12 | 
| Part A: Percentage of Responders With Increase of Greater Than or Equal to (>=) 1 and >= 3 Spontaneous Bowel Movements (SBMs) Per Week | Responder is 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 will be assessed. | Up to Week 12 | 
| Part A: Percentage of Participants With Fecal Incontinence per Week | Fecal incontinence is 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. Proportion of participants with fecal incontinence per week during the 12-week treatment period will be assessed. | Up to Week 12 |