E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Functional Constipation (FC) |
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E.1.1.1 | Medical condition in easily understood language |
FC is a condition that manifests with symptoms of infrequent, hard stools, and painful defecation. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
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 safety and efficacy of 12 weeks of linaclotide therapy in comparison with placebo in pediatric participants aged 6 to 17 years who fulfill modified Rome III Criteria for Child/Adolescent FC. |
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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.Age and Weight 1.01: Male and female participants must be ages 6 to 17 years (inclusive) at the time the participant provides assent for the study and parent/guardian/legally authorized representative (LAR) has provided signed consent 1.02: Participant weighs ≥18 kg at the time the participant provides assent and the parent/guardian/LAR has provided signed consent 2.01: Participants who meet the modified Rome III criteria for Child/Adolescent FC. For at least 2 months before the Screening Visit, the participant has had 2 or fewer defecations (with each defecation occurring in the absence of any laxative, suppository, or enema use during the preceding 24 hours) in the toilet per week. In addition, participant meets one or more of the following criteria at least once per week for at least 2 months before the screening visit: - History of retentive posturing or excessive volitional stool retention - History of painful or hard BMs - History of large diameter stools that may obstruct the toilet - Presence of a large fecal mass in the rectum - At least 1 episode of fecal incontinence per week 2.02: Participant is willing to discontinue any laxatives used before the Preintervention Visit in favor of the protocol-permitted rescue medicine 2.03: Participant has an average of fewer than 3 SBMs per week during the 14 days before the randomization day and up to the randomization (including the morning eDiary assessments reported before administration of first dose of double-blind study intervention on the randomization day). An SBM is defined as a BM that occurs in the absence of laxative, enema, or suppository use on the calendar day of the BM or the calendar day before the BM 2.04: Participant or parent/guardian/LAR or caregiver is compliant with eDiary requirements by completing both the morning and evening assessments for 10 out of the 14 days immediately preceding the Randomization Visit 3.Contraceptives 3.01: Female participants of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at the Randomization Visit prior to dosing 3.02: Female participants who have had their first menstrual period and are sexually active must agree to use a reliable form of contraception. Reliable contraception is defined in Section 10.7 Appendix 7. 4.Informed Consent 4.01: Participant must provide written or verbal informed assent and the parent/guardian/LAR and caregiver must provide written informed consent before the initiation of any study-specific procedures 4.02: Participant is able to read and/or understand the assessments in the eDiary device. If the participant is 6 to 11 years of age and does not meet this criterion, the interviewer-administered version of the eDiary must be used and the parent/guardian/LAR or caregiver who will be administering the interviewer- administered version of the eDiary must undergo training 5.Other 5.01: Participant must have acquired toilet training skills |
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E.4 | Principal exclusion criteria |
1.Medical Conditions 1.01: Participant meets Rome III criteria for Child/Adolescent IBS: At least once per week for at least 2 months before the Screening Visit, the participant has experienced abdominal discomfort (an uncomfortable sensation not described as pain) or pain associated with 2 or more of the following at least 25% of the time: - Improvement with defecation - Onset associated with a change in frequency of stool - Onset associated with a change in form (appearance) of stool 1.02: Participant reports having more than 1 loose, mushy stool (eDiary-recorded stool consistency of 6 on the Pediatric Bristol Stool Form Scale [p-BSFS]) or any watery stool (eDiary-recorded stool consistency of 7 on the p-BSFS) with any SBM that occurred in the absence of laxative use on the calendar day of the BM or the calendar day before the BM during the 14 days before the randomization day and up to the randomization (including the morning eDiary assessments reported before administration of first dose of double-blind study intervention on the randomization day) 1.03: Participant has a history of non-retentive fecal incontinence 1.04: Participant has (a) fecal impaction at Visit 2 and after failing outpatient clean-out during the Screening Period or (b) fecal impaction at Visit 3 1.05: Participant has required manual disimpaction any time prior to randomization 1.06: Participant currently has both unexplained and clinically significant alarm symptoms (lower GI bleeding [rectal bleeding or heme-positive stool], iron deficiency anemia, or any unexplained anemia, or weight loss) and systemic signs of infection or colitis, or any neoplastic process 1.07: Participant has clinically significant findings on a physical examination, ECG, or clinical laboratory test as determined by the investigator based on consideration of whether the finding could represent a safety concern or a condition that would be exclusionary, could prevent the participant from performing any protocol assessments, or could confound study assessments. 1.08: Participant has a history of drug or alcohol abuse. 1.09: Participant has any of the following conditions: a.Celiac disease, or positive serological test for celiac disease and the condition has not been ruled out by endoscopic biopsy b.Cystic fibrosis c.Hypothyroidism that is untreated or treated with thyroid hormone at a dose that has not been stable for at least 3 months prior to the Screening Visit d.Down's syndrome or any other chromosomal disorder e.Active anal fissure (Note: History of anal fissure is not an exclusion) f.Anatomic malformations (eg, imperforate anus, anal stenosis, anterior displaced anus) g.Intestinal nerve or muscle disorders (eg, Hirschprung disease, visceral myopathies, visceral neuropathies) h.Neuropathic conditions (eg, spinal cord abnormalities, neurofibromatosis, tethered cord, spinal cord trauma) i.Lead toxicity, hypercalcemia j.Neurodevelopmental disabilities (early-onset, chronic disorders that share the essential feature of a predominant disturbance in the acquisition of cognitive, motor, language, or social skills, which has a significant and continuing impact on the developmental progress of an individual) producing a cognitive delay that precludes comprehension and completion of the daily eDiary or other study related questionnaires (Note: Participants are excluded if the person who will be completing the daily eDiary or other study-related questionnaires meets this criterion.) k.Inflammatory bowel disease l.Childhood functional abdominal pain syndrome m.Childhood functional abdominal pain n.Poorly treated or poorly controlled psychiatric disorders that might influence his or her ability to participate in the study o.Lactose intolerance that is associated with abdominal pain or discomfort and could confound the assessments in this study p.History of cancer other than treated basal cell carcinoma of the skin. (Note: Participants with a history of cancer are allowed provided that the malignancy has been in a complete remission for at least 5 years before the Randomization Visit. A complete remission is defined as the disappearance of all signs of cancer in response to treatment.) q.History of diabetic neuropathy All exclusion criteria cannot be listed in this field. Please refer to the protocol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in 12-week SBM frequency rate (SBMs/week) during the study intervention period. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary Endpoint for FC participants: At week 12 |
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E.5.2 | Secondary end point(s) |
- Change from baseline in 12-week stool consistency during the study intervention period - Safety and tolerability assessments |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary Endpoint for FC participants: At Week 12 |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
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 | 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 | 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 | 3 |
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 | 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 |
Bulgaria |
Canada |
Estonia |
Germany |
Hungary |
Israel |
Italy |
Netherlands |
Poland |
Serbia |
Spain |
Ukraine |
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 | 0 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 10 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 15 |