| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to evaluate the efficacy of prucalopride during the 12-week double-blind, placebo-controlled treatment phase and the long-term (48 weeks) safety and tolerability of prucalopride in toilet-trained subjects with functional constipation who are at least 3 years of age. |
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| E.2.2 | Secondary objectives of the trial |
The key secondary objective to evaluate the efficacy of prucalopride on signs and symptoms of functional constipation (stool consistency,
straining, and stool frequency responder index), during the 12-week double-blind, placebo-controlled treatment phase in toilet-trained subjects with functional constipation who are at least 3 years of age. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects 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: Subjects 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 subjects 3 years to 17 years of age, inclusive, or non-toilet-trained subjects 6 months to 17 years of age, inclusive.
Subject weighs greater than or equal to (>=) 5.5 kilograms (kg) (12 pounds [lbs]).
Male, or non-pregnant, non-lactating female subjects 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 subjects >= 12 years and/or female subjects lesser than (<) 12 years who have started menarche must have a negative serum pregnancy test at screening.
- Subject meets modified Rome IV criteria:
* For child/adolescent (aged > 4 years) functional constipation (H3a):
Subjects 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 Subjects 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 subject does not satisfy sufficient criteria for a diagnosis of irritable bowel syndrome (IBS) and, after appropriate evaluation, the subjects symptoms cannot be fully explained by another medical condition.
For infants/toddler (aged 6 months to <= 4 years) functional constipation (G7):
Subjects 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 - Subject 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:
Subject has an average of < 3 SBMs (defecations) per week during the screening period and prior to the disimpaction.
Subject or legally authorized representative (dependent on subject age) is compliant with completing the electronic diary for at least 7 consecutive days preceding the disimpaction. |
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| E.4 | Principal 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 subject 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).
Subjects with renal impairment:
Subjects <= 2 years of age with serum creatinine greater than normal (screening sample results using central laboratory pediatric reference ranges).
Subjects > 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.
Subject used prucalopride within 10 days prior to the first dose of the IP or has been unsuccessfully treated with prucalopride before.
Subject meets Rome IV criteria for other Child/Adolescent Functional Gastrointestinal Disorders (FGID) (H1 - H2 and H3b).
Subject with secondary causes of constipation:
Endocrine disorders (e.g., hypopituitarism, hypothyroidism, hypercalcemia, pheochromocytoma, glucagon-producing tumors) unless these are controlled by appropriate medical therapy. Subject 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 subjects with Gilbert's syndrome.
Any significant underlying liver disease.
Subject is not able to swallow the IP (liquid or tablet).
Subject is pregnant or planning to get pregnant during study period.
To be evaluated prior to randomization:
Subject has used other disimpaction medication in lieu of the protocol-provided medication.
Subject has used non-protocol approved medications to induce BMs during the screening period or disimpaction.
The Subject has failed the disimpaction based on the investigator's assessment.
Worsening of depression and emergence of suicidal thoughts. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
- Part A: Average Change From Baseline in Number of Spontaneous Bowel Movements (SBMs) per Week
- Number of Subjects With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
- Number of Subjects With Clinically Significant Changes in Clinical Laboratory Parameters, Electrocardiogram (ECG), Vital Signs and Physical Examination |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Baseline up to Week 12 (Endpoint: Part A: Average Change From Baseline in Number of SBMs per Week)
- From start of study treatment up to follow-up (52 weeks) (Endpoint: Number of Subjects With TEAEs and TESAEs)
- From start of study treatment up to Week 12 and 48 (Endpoint: Number of Subjects With Clinically Significant Changes in Clinical Laboratory Parameters, ECG, Vital Signs and Physical Examination) |
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| E.5.2 | Secondary end point(s) |
- Part A: Average Change From Baseline in Subjects' Stool Consistency Based on Bristol Stool Form Scale (BSFS) Score During
Week 12
- Part A: Average Change From Baseline in Straining During Week 12
- Part A: Percentage of Responders With Increase of Greater Than or Equal to (>=) 1 and >= 3 Spontaneous Bowel Movements (SBMs) Per Week
- Part A: Percentage of Subjects With Fecal Incontinence per Week
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 25 |
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