E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Functional constipation in paediatric subjects |
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E.1.1.1 | Medical condition in easily understood language |
Functional constipation in Infants, toddlers and children |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 15.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10010774 |
E.1.2 | Term | Constipation |
E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
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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 |
To evaluate the efficacy of prucalopride compared to placebo for the treatment of functional constipation in a paediatric population, aged ≥6 months to <18 years. |
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E.2.2 | Secondary objectives of the trial |
1. Investigation of the individual symptoms defined by the Rome III criteria: bowel frequency, faecal incontinence, retentive posturing or excessive volitional stool retention, defecation pain, stool consistency,
occurrence of large diameter stools. In addition use of rescue medication, abdominal pain and toilet training*.
2. Pharmacokinetics: sparse blood sampling at single dose and steady state to enable population pharmacokinetic
modelling.
3. Safety and tolerability: evaluation of prucalopride treatment up to 24 weeks.
*Only for older children after acquisition of toileting skills (as standard of care). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Boys and girls, aged ≥6 months to <18 years
2. Subjects with a confirmed diagnosis of functional constipation as defined by the Rome III criteria in the following way: Subjects should have ≤2 spontaneous‡ defecations per week together with at least 1 out of 5 of the following symptoms during one month (for <4 years of age) or two months (for ≥4 years of age) prior to the selection:
1) at least one episode of faecal incontinence per week (after the acquisition of toileting skills)
2) history of retentive posturing or excessive volitional stool retention
3) history of painful or hard bowel movements (BMs)
4) presence of large faecal mass in the rectum, and 5) history of large diameter stools.
3. Subject and/or parent(s) or legally authorised representative agree to stop laxative use and agree to use the
rescue medication according to the rescue rule.
4. Subject and/or parent(s) or legally authorised representative agree to stop the use of disallowed medication.
‡A spontaneous bowel movement (SBM) is defined as a non-laxative induced BM, i.e. not preceded within a period of 24 hours by the intake of a laxative agent or by the use of an enema. |
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E.4 | Principal exclusion criteria |
1. Children with underlying GI abnormalities and causes for defecation disorders such as Hirschsprung’s disease, spina bifida occulta, cystic fibrosis, GI malformations, or significant developmental delays that are associated with musculoskeletal or neurological conditions affecting the GI tract.
2. Children who are breast fed.
3. Subjects suffering from secondary causes of chronic constipation, e.g.: Endocrine disorders, Metabolic disorders, Neurological disorders, Organic disorders, Surgery, Hernia, Autoimmune disorders. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The proportion of responders, defined as subjects with an average spontaneous‡ defecation frequency of ≥3 times/week AND an average number of ≤ 1 episode of faecal incontinence/2 weeks# (as calculated over week 5 to 8 of the double-blind treatment phase).
‡A spontaneous bowel movement (SBM) is defined as a non-laxative induced BM, i.e. not preceded within a period of 24 hours by the intake of a laxative agent or by the use of an enema.
#Faecal incontinence will only be taken into account in children after acquisition of toileting skills. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
According to the study design, primary endpoint will be evaluated on double-blind placebo controlled data; safety up to 24 weeks will make use of double-blind and open-label data.The first two weeks of the double-blind treatment phase will not be used for the primary efficacy analysis because of a possible effect of the use of an enema or oral laxative agent during run-in to remove the impaction. For evaluation of dose adjustment week 3 and 4 will be used. At the week 4 visit a possible dose adjustment might occur, the endpoint will therefore be determined from week 5 to 8.
Analysis including the first weeks will also be performed to evaluate the possible impact. |
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E.5.2 | Secondary end point(s) |
Secondary endpoints following individual Rome III3 criteria:
• The proportion of subjects with an average spontaneous defecation frequency of
≥3 times/week
• Number of faecal incontinence episodes/week
• Weekly frequency of retentive posturing or excessive volitional stool retention
• Frequency of defecation pain (6-point scale; only in subjects of 3 years or older)
• Stool consistency/week (4-point scale for children wearing diapers or 7-point Bristol scale for children without diapers )
• Weekly number of large stools
Other secondary endpoints:
• Time to first SBM
• Number of SBMs/week, BMs/week and change from baseline
• Amount of rescue medication used/week
• Abdominal pain score/week (6-points scale; only in subjects of 3 years or older)
• Global assessment of severity of constipation
• Global assessment of efficacy of treatment
• Weekly frequency of toilet training (only for subjects after acquisition of toileting skills) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Diary secondary endpoints are evaluated on a weekly basis. Global assessments are done at every visit. |
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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 | No |
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 | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
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 | Yes |
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 | Yes |
E.8.1.7.1 | Other trial design description |
Double-blind placebo controlled phase followed by an open-label PEG |
|
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.8.2.3.1 | Comparator description |
PEG 4000 (Forlax Junior® <8 years and Forlax® ≥8 |
|
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |