| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| functional constipation in paediatric patients |
|
| E.1.1.1 | Medical condition in easily understood language |
| constipation in children and adolescents |
|
| 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 | 18.0 |
| 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 |
|
| 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 efficacy, safety, and pharmacokinetics of oral lubiprostone 12 or 24 mcg capsules dosed twice daily (BID) (based on subject body weight at baseline) as compared to matching placebo BID, when administered orally for 12 weeks in paediatric subjects with functional constipation |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent obtained from subject or parent/legal guardian (and assent from subject where applicable).
2. Subject is at least 6 years of age but less than 18 years of age at the time of randomisation.
3. Subject is capable of and willing to swallow capsules.
4. Subject fulfills the Rome III Diagnostic Criteria for Childhood Functional Constipation (Child/Adolescent; Section H3a) as follows:
Must include two or more of the following in a child with a developmental age of at least 4 years with insufficient criteria for diagnosis of irritable bowel syndrome (IBS)*:
• Two or fewer defecations in the toilet per week
• At least one episode of faecal incontinence per week
• History of retentive posturing or excessive volitional stool retention
• History of painful or hard bowel movements
• Presence of a large faecal mass in the rectum
• History of large diameter stools which may obstruct the toilet
* Criteria fulfilled at least once per week for at least 2 months prior to diagnosis.
5. If subject is taking a concomitant medication (prescribed or over-the-counter) that affects gastrointestinal motility, he/she must discontinue use at the time of the Screening Visit (Visit 1); 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; and/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 Screening Visit and not likely to change during the study.
6. 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.
7. If subject is taking a fibre supplement (e.g., Metamucil®, PerDiem®, Fybogel), usage must have been at a stable dose and schedule for at least 30 days prior to the Screening Visit (Visit 1) and not likely to change during the study.
8. Subject and his/her parent/legal guardian must be willing and able to fill out his/her own diary.
9. Subject daily diary is at least 70% compliant for evening/end-of-day assessments during the Screening period.
10. Subject daily diary indicates an average of less than 3 spontaneous bowel movements (SBMs) per week during the Screening period.
11. Subject has at least one of the following for at least 25% of SBMs during each week of the screening period (as reported in the daily diary):
• Modified Bristol Stool Scale Type 1 or 2; and/or
• Some or extreme straining associated with SBMs.
Note: For subjects with no reported SBMs during the Screening Period, it is not necessary to meet criteria for bowel movement characteristics, e.g., hard or very hard stools.
Additional Eligibility Criteria for Dual-energy X-ray Absorptiometry (DXA) Evaluation Subgroup:
1. Subject is 6 to 9 years or 14 to 17 years of age at time of informed consent.
2. Subject has a bone mineral density (BMD) Z-score (normalized for age and gender) greater than -2.0, as assessed by DXA. |
|
| E.4 | Principal exclusion criteria |
1. Subject’s constipation is known to be attributed to any of the following:
a. Physical/Mental/Cognitive – any condition, other than functional constipation, that in the Investigator’s opinion would interfere with meaningful study participation or evaluation.
b. Anatomic – associated with a mechanical bowel obstruction (tumour, hernia, obstructive polyps, etc.), or pseudo-obstruction.
c. Neurological – associated with spinal cord disorder, congenital disorder, or Guillain-Barre syndrome.
d. Endocrine/Metabolic – associated with hypothyroidism, diabetes, hypercalcaemia, or hypokalaemia.
e. Inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis, celiac disease).
f. Medication – associated with the use of medication known to cause constipation.
2. Subject is a candidate for, or undergone abdominal surgery including bowel resection, colectomy, gastric bypass surgery (exceptions: appendectomy, cholecystectomy, benign polypectomy and inguinal hernia).
3. Subject has any gastrointestinal (GI) condition, other than constipation, affecting GI motility or defecation.
4. Subject has Hirschsprung’s disease.
5. Subject reports episodes of faecal incontinence that are not associated with retention of stool (e.g., non-retentive faecal incontinence as defined by the Rome III Diagnostic Criteria).
6. Subject has current evidence of untreated faecal impaction at the time of screening.
7. Subject has experienced an unexplained significant weight loss.
8. Subject has a medical/surgical condition that might interfere with the absorption, distribution, metabolism, or excretion of the study medication.
9. Subject has an uncontrolled cardiovascular, liver or lung disease, neurologic or psychiatric disorder, or other systemic disease, which the Investigator feels is clinically significant and would limit the subject’s ability to participate in the trial.
10. Subject is currently using an indwelling peritoneal catheter.
11. Subject has impaired renal function identified at the Screening Visit (i.e., serum creatinine concentration > 1.5 times the median of normal range).
12. Subject has 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.
13. Subject has current evidence of, or has been treated for, cancer within the past 5 years.
14. Subject (female of childbearing potential) has a positive pregnancy test or refuses/unwilling to undergo pregnancy testing, and / or does not agree to use protocol specified contraception measures for the duration of the study.
15. Subject or parent/legal guardian demonstrates a potential for non-compliance with study protocol (i.e., dosing schedule, visit schedule, diary completion, or study procedures).
16. Subject has received an investigational medication within 30 days prior to the Screening Visit (Visit 1), or plans to participate in another clinical trial during the study period.
17. Subject has received AMITIZA, lubiprostone, SPI-0211, or RU-0211 at any time prior to participation in this study.
Additional Eligibility Criteria for Dual-energy X-ray Absorptiometry (DXA) Evaluation Subgroup:
1. Subject has serum 25(OH) vitamin D level <20 ng/mL.
2. Subject has a history of bone disorders (e.g., rickets, osteogenesis imperfecta, rheumatoid arthritis, severe scoliosis), back surgery/injuries, endocrine disorders, anorexia nervosa, and/or use of corticosteroids, anticonvulsants, bisphosphonates, or Depo-Provera.
3. Subject has a history of chronic use of inhaled/oral corticosteroids within 6 months prior to the Screening Visit (Visit 1), or plans to initiate use of inhaled/oral corticosteroids at any point during the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Overall SBM response
o An overall responder is defined as a subject who qualifies as a weekly responder for 9 out of 12 weeks during the treatment period, with durability demonstrated by at least 3 of the responder weeks occurring in the last 4 weeks of the 12-week study period.
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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Throughout the entire 12 week treatment period (e-diary) |
|
| E.5.2 | Secondary end point(s) |
• Overall change from baseline in SBM frequency across the 12-week treatment period
• Monthly SBM responder rates as based on primary response definition requiring a monthly responder to achieve 3 of 4 weeks as a weekly responder during the given month.
• Overall change from baseline in BM and SBM frequency at each treatment week and each treatment month
• Time to first SBM following the first study medication administration
• Percentage of subjects with an SBM within 4, 8, 12, 24 and 48 hours of first study medication administration
• Overall, weekly, and monthly assessments of the average degree of and changes from baseline in:
o Straining associated with SBMs
o Stool consistency of SBMs
o Abdominal pain
o Constipation severity
o Treatment effectiveness
• Overall health-related quality of life (PedsQL™)
• Treatment response defined as those subjects who remained on treatment for at least 4 weeks, did not drop out due to lack of efficacy, and reported ≥ 1 or more SBMs over baseline and ≥ 3 weekly SBMs for 75% of observed treatment weeks overall and for at least 3 of the 4 final weeks of treatment
• Change from baseline in incontinence episodes frequency overall, during each treatment week, and during each treatment month (analysis performed for subset of subjects presenting with incontinence at baseline)
• Change from baseline in the production of large diameter stool (a stool that clogs the toilet) frequency overall, during each treatment week, and during each treatment month
• Frequency of faecal impaction overall, during each treatment week, and during each treatment month
• Proportion of BMs and SBMs in toilet overall, during each treatment week, and during each treatment month
• Frequency of retentive posturing or excessive volitional stool retention overall, during each treatment week, and during each treatment month |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| throughout the entire 12 week treatment period (e-diary) |
|
| 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 | 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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 | 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 |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
|
| 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 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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