E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
functional constipation in paediatric patients |
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E.1.1.1 | Medical condition in easily understood language |
constipation in children and adolescents |
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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 | 16.1 |
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 assess the long-term safety, efficacy, and pharmacokinetics of oral lubiprostone 12 or 24 mcg capsules dosed twice daily (BID) when administered orally for 36 weeks in paediatric subjects with functional constipation. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written informed consent obtained from subject and/or parent/legal guardian (and assent from subject where applicable).
2. Subject must have completed the entire 12-week treatment period from the preceding study (SAG/0211PFC-1131) prior to enrolment.
3. Subject must continue to abstain from taking concomitant medication (prescribed or over-the-counter) that affects gastrointestinal motility; these medications include:
a. Cholinesterase inhibitors; anti-spasmodic, anti-diarrheal, anti-constipation, or prokinetic agents; laxative agents (e.g., PEG 3350), including homeopathic remedies;
b. Tricyclic antidepressants; or
c. Any medication, at the discretion of the Investigator, known to cause constipation or constipation-related symptoms.
Exceptions: Treatment with anticholinergic agents, SSRIs, SNRIs, or MAO inhibitors is allowed if a stable dose has been used for at least 30 days prior to the Baseline Visit (of the preceding study SAG/0211PFC-1131) and not likely to change during the study.
4. Subject (and if necessary, parent/legal guardian) must be willing and able to use or administer recommended (rectal and/or oral) rescue medications if needed.
5. If subject is taking a fibre supplement (e.g., Metamucil®, PerDiem®, Fybogel), usage must have been at a stable dose not likely to change during the study.
6. Subject and his/her parent/legal guardian must be willing and able to fill out his/her own diary
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E.4 | Principal exclusion criteria |
1. Subject has current evidence of untreated faecal impaction.
2. Subject has experienced an adverse event during the SAG/0211PFC-1131 study which the Investigator considers to be clinically significant and would limit the subject’s ability to participate in the trial.
3. Subject has had a significant change in their medical status, newly diagnosed and uncontrolled cardiovascular, liver or lung disease, neurologic or psychiatric disorder, or other systemic disease, which the Investigator considers to be clinically significant and would limit the subject’s ability to participate in the trial.
4. Subject has developed abnormal laboratory test (haematology, urinalysis, or blood chemistry), which in the Investigator’s opinion is clinically significant, unexplained, and would limit the subject’s ability to participate in the trial.
5. Subject (female of childbearing potential) has a positive pregnancy test or refuses/is unwilling to undergo pregnancy testing, and/ does not agree to use protocol-specified contraceptive measures for the duration of the study.
6. Subject demonstrated non-compliance with study protocol (i.e., dosing schedule, visit schedule, diary completion, or study procedures) during the SAG/0211PFC-1131 study
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E.5 End points |
E.5.1 | Primary end point(s) |
The efficacy endpoints are as follows:
• Overall and monthly changes from baseline in BM and SBM frequency rate
• Overall and monthly assessments of the average degree of, and changes from baseline in:
o Stool consistency of SBMs
o Straining associated with SBMs
o Abdominal pain associated with SBMs
o Constipation severity
• Monthly SBM Response
o A monthly responder is defined as a subject who is a weekly responder for 3 of 4 weeks per month.
o A weekly responder is defined as a subject who has a frequency rate of ≥ 3 SBMs/week and an increase from baseline of ≥ 1 SBM/week for that week.
• Overall and monthly assessment of average treatment effectiveness rating
• Overall Health-related quality of life (PedsQL™)
• Overall and monthly change from baseline in incontinence episodes frequency (analysis performed for subset of subjects presenting with incontinence at baseline)
• Overall and monthly change from baseline in the production of large diameter stool (a stool that clogs the toilet) frequency
• Overall and monthly change from baseline in frequency of faecal impaction
• Overall and monthly change from baseline in proportion of BMs and SBMs in toilet overall
• Overall and monthly change from baseline in frequency of retentive posturing or excessive volitional stool retention
The safety endpoints are as follows:
• Incidence of adverse events grouped by MedDRA System Organ Class (SOC) and Preferred Term
• Changes from baseline in clinical laboratory parameters (haematology, serum chemistry, urinalysis)
• Changes from baseline in physical examination
• Changes from baseline in vital sign measurements, including height and weight
o Height will be measured using a wall-mounted stadiometer, if available
• For those subjects who were aged 6 to 9 or 14 to 17 at the time of enrolment into the SAG/0211PFC-1131 study, and who were qualified to participate and enrolled in the dual-energy X-ray absorptiometry (DXA) substudy:
o Percent changes from baseline in bone mineral density (BMD) and bone mineral content (BMC)
o Changes from baseline in BMD Z-scores and in height-adjusted Z-scores, as assessed by DXA for DXA Subgroup
o Changes from baseline in height and weight Z-scores for DXA Subgroup
o Incidence of clinical fractures
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
throughout the entire 36 weeks treatment period (e-diary) |
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E.5.2 | Secondary end point(s) |
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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 | 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 | 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 | No |
E.8.1.1 | Randomised | No |
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 | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 35 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Canada |
France |
Italy |
Netherlands |
Germany |
Spain |
Poland |
United Kingdom |
United States |
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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.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |