E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Irritable Bowel Syndrome with Diarrhea (IBS-D)
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E.1.1.1 | Medical condition in easily understood language |
Abdominal pain / discomfort. Cramps, bloating , diarrhea and constipation. |
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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 | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10023003 |
E.1.2 | Term | Irritable bowel syndrome |
E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060845 |
E.1.2 | Term | Diarrhea predominant irritable bowel syndrome |
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 explore the therapeutic effect of eluxadoline in treating IBS-D in pediatric patients 12-17 years of age. - To evaluate the pharmacokinetics (PK) of eluxadoline in pediatric patients with IBS-D. - To evaluate the safety and tolerability of eluxadoline in pediatric patients with IBS-D. |
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E.2.2 | Secondary objectives of the trial |
The results of this dose-ranging study will allow the selection of an optimal dose(s) of eluxadoline to evaluate in the subsequent confirmatory efficacy study.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
To be eligible to participate in the study, patients must meet the following criteria: 1. Patient must provide written or verbal informed assent and the parent/guardian/LAR must provide written informed consent before the initiation of any study-specific procedures. 2. Patient is a male or female outpatient, 12 to 17 years of age inclusive, at the time the patient provides assent for the study and parent/guardian/LAR has provided signed consent. 3. Patient is able to read and understand the assessments in the eDiary. 4. Female patients of childbearing potential must have a negative serum pregnancy test at Visit 1 (screening) and a negative urine pregnancy test at Visit 3 (randomization) prior to dosing. 5. Female patients who have had their first menstrual period and are sexually active must agree to use a reliable form of contraception. Reliable contraception is defined as: a) Hormonal contraception (eg, oral contraceptive, contraceptive implant, or injectable hormonal contraceptive). b) Double-barrier method (eg, condom plus intrauterine device, diaphragm plus spermicide). 6. Patient has a diagnosis of IBS-D as defined by the modified Rome IV child/adolescent criteria*: Must include all of the following: 1. Abdominal pain at least 4 days per month over at least 2 months associated with one or more of the following: a. Related to defecation b. A change in frequency of stool c. A change in form (appearance) of stool 2. After appropriate evaluation, the symptoms cannot be fully explained by another medical condition 3. Patient has predominantly diarrheal stool symptoms defined as Bristol stool types 6 or 7 for >25% of bowel movements and Bristol stool types 1 or 2 for <25% of bowel movements that occur in the absence of laxatives *All criteria fulfilled for at least 2 months prior to Visit 1 (screening). 7. Patient has been compliant with the eDiary by completing both the morning and evening assessments for at least 8 out of the 14 days immediately preceding Visit 3 (randomization). 8. Patient has an average daytime abdominal pain score ≥2.0 over the 2 weeks prior to randomization. 9. Patient has at least 1 daytime bowel movement with a consistency of Type 6 or Type 7 on the pediatric Bristol Stool Form Scale (p-BSFS) on at least 2 days per week during the 2 weeks prior to randomization that occurs in the absence of laxatives. 10. Patient has no clinically significant findings on a physical examination, vital sign assessment, electrocardiogram (ECG), and clinical laboratory tests (clinical chemistry panel, liver biochemical tests, complete blood count, urine drug screen, urinalysis) after providing informed assent and after written consent is obtained, but before receiving the first dose of study treatment. (A central laboratory will be used to evaluate all urine [except urine pregnancy tests] and blood samples and will utilize reference ranges specific to a patient’s age and gender. ECGs will be performed and electronically transmitted to a central ECG laboratory for analysis by a pediatric cardiologist in accordance with the instructions provided by the central ECG laboratory. The Investigator will determine if a particular finding is clinically significant. [In making this determination, the Investigator will consider whether the particular finding could represent a condition that would exclude the patient from the study, could represent a safety concern if the patient participates in the study, or could confound the study-specific assessments of safety or efficacy.]) |
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E.4 | Principal exclusion criteria |
Patients who meet any of the following criteria will not be eligible to participate in the study: 1.has no gallbladder 2.has had any of the following surgeries: a)Any abdominal surgery within the 3 months prior to trial; b)A history of major gastric, hepatic, pancreatic, or intestinal surgery 3.has known or suspected biliary duct obstruction, or sphincter of Oddi disease or dysfunction 4.has a history of pancreatitis; structural diseases of the pancreas, known or suspected pancreatic duct obstruction 5.has a history of cholecystitis within 6months before trial. 6.has known or suspected bile acid malabsorption. 7.is a current regular alcohol drinker and/or binge drinker, and/or has a history of alcoholism, alcohol abuse, or alcohol addiction, and/or intends to consume alcohol during the trial. 8.has had chronic or severe constipation or sequelae from constipation, or known or suspected mechanical GI obstruction or pseudo obstruction. 9.has had or current diagnosis of constipation with encopresis. 10.meets the child/adolescent Rome IV criteria of IBS with constipation, IBS with constipation and diarrhea (mixed), unspecified IBS, or functional constipation. 11.has had intestinal obstruction, stricture, toxic megacolon, GI perforation, fecal impaction, gastric banding, bariatric surgery, adhesions, ischemic colitis, or impaired intestinal circulation. 12.has a history of hepatic impairment as defined by Child-Pugh Classification Grade A,B or C 13.has a history or current diagnosis of inflammatory or immune-mediated lower GI disorders including inflammatory bowel disease 14.has celiac disease,or a positive serological test for celiac disease and the condition has not been ruled out by endoscopic biopsy 15.has any congenital and/or acquired malabsorption syndrome 16.has a history of a microbiologically documented GI infection within 3months prior to trial 17.has a known lactose or fructose intolerance 18.has a history of diverticulitis within 3 months prior to trial 19.has had within 5 years prior to trial or current evidence of laxative abuse 20.has a history of either hypo-or hyperthyroidism that is untreated or treated with medication at a dose that has not been stable for at least 3months prior to trial. 21.Patient’s diarrhea is deemed by the Investigator to be caused by infectious 22.has had or current evidence of blood in the stool 23.currently has both unexplained and clinically significant alarm symptoms and systemic signs of infection or colitis, or any neoplastic process 24.has a history or current diagnosis of eosinophilic gastroenteritis 25.has Cystic Fibrosis, and or any other causes of pancreatic exocrine insufficiency 26.is receiving enteral tube feeding 27.has a history of a cardiovascular event, including stroke, myocardial infarction, congestive heart failure, or transient ischemic attack within 6months prior to trial 28.has an unstable renal, hepatic, metabolic, or hematologic condition 29.has a history of malignancy within 5 years before Screening, which includes any new diagnosis of malignancy or any treatment for or recurrence of a malignancy that was diagnosed 5 or more years prior. In order to be eligible for the study, patient must be malignancy free for the past 5years 30.has a history of immunodeficiency 31.has a history of drug abuse 32.has a positive urine drug result 33.has a weight and BMI less than the 3rd percentile. 34.has had an unintentional weight loss greater than or equal to 5% of his/her body weight within the last 3months 35.Female patients who are pregnant or nursing, or plan to become pregnant or nurse during the trial 36.has known allergies or hypersensitivity to opioids 37.used a prohibited medication or failed to meet the stabledose 38.is unable to tolerate the placebo oral tablets prior to randomization. 39.has any condition that, in the opinion of the Investigator, would contribute to the patient’s IBS-D symptoms or confound the evaluation of safety or efficacy of the IMP 40.has neurodevelopmental disabilities producing a cognitive delay that precludes comprehension and completion of the daily eDiary or other study-related questionnaires 41.has a poorly treated or poorly controlled psychiatric disorder that might influence the patient’s ability to participate in the study 42.has an acute or chronic condition that, in the Investigator's opinion, would limit the patients' ability to complete or participate in this clinical study 43.has any condition that, in the opinion of the Investigator, would compromise the well-being of the patient 44.received an investigational product during the 30 days before Visit1 or is planning to receive an IMP or use an investigational device at any time during the study 45. Patient’s parent/guardian/LAR has been directly or indirectly involved in the conduct and administration of this study as an Investigator, Sub-Investigator, Study Coordinator, or other study member |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy assessment will be the change from baseline in the 24‑ hour (combined daytime and nighttime) stool consistency averaged over the 4-week Treatment Period. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Throughout the study Over the 4-week period |
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E.5.2 | Secondary end point(s) |
The secondary efficacy parameters include change from baseline in the 4-week average for daily daytime and nighttime stool consistency scores during the Treatment Period, as well as change from baseline in the 4-week average for daytime, nighttime, and 24-hour (combined daytime and nighttime) abdominal pain, bowel movement frequency, urgency-free days in a week, and number of fecal incontinence-free days in a week during the Treatment Period.
The secondary change-from-baseline efficacy parameters will be analyzed in a similar way as the primary efficacy parameter using the ANCOVA model. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
throughout the study 4 week |
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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 | 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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | Yes |
E.8.1.7.1 | Other trial design description |
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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 | 4 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 66 |
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 |
Bulgaria |
Canada |
Germany |
Hungary |
Netherlands |
Poland |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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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The end of Trial is defined by the Last Patient Last visit |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |