E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Intestinal failure with an underlying aetiology of short bowel |
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E.1.1.1 | Medical condition in easily understood language |
Intestinal failure due to short bowel is defined as a condition whereby a patient has insufficient intestinal length to absorb enough fuilds and/or nutrients to sustain life without IV supplementation |
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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 | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10049416 |
E.1.2 | Term | Short-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 | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Is the GLP-1 agonist liraglutide effective in the reduction in parenteral support requirements for patients with short bowel? |
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E.2.2 | Secondary objectives of the trial |
Is there an improvement in quality of life of the patients while they are on liraglutide?
Is there an change in levels of plasma citrulline (a marker of the small intestinal cell mass) together with gut hormone levels GLP-1, Peptide YY (PYY) and IGF-1?
What is the duration of the response of liraglutide? i.e. the proportion of subjects who maintain reduction in weekly PN volume from baseline at week 20.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion criteria 1. Short bowel with jejunostomy (≤200cm) as a result of major intestinal resection (e.g. due to injury, volvulus, vascular disease, Crohn’s disease). 2. 12 continuous months of parenteral support (PS) dependency prior to enrolment. 3. PS required at least 3 times per week to meet their caloric, fluid or electrolyte needs due to on-going malabsorption. 4. Stable PS for at least 4 consecutive weeks immediately prior to randomisation. Stability is described as: a. Actual PS usage should match prescribed PS; b. Baseline 48-hour urine output is 1-2 L/24 hours. 5. Body mass index ≥ 19.5 kg/m2. 6. Adequate hepatic and renal function: a. Total bilirubin within the normal range; b. Alanine aminotransferase (ALT) ≤ 2.5x upper limit of normal; c. Serum creatinine ≤1.5x upper limit of normal. 7. Stable dosage for > 4 weeks, prior to baseline evaluations, of anti-motility and anti-diarrhoeal agents, H2 antagonists, proton pump inhibitors, bile sequestering agents and oral rehydration solutions.
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E.4 | Principal exclusion criteria |
Exclusion criteria • Patients < 18 years of age • Pregnancy (Female subjects who are not surgically sterile or post menopausal (defined as aged 55 years or older and/or at least 2 years have elapsed since the last menses) or who are not using medically acceptable methods of birth control during and for 30 days after the treatment period) • Active malignancy • Previous malignancy within the past 5 years • History of multiple endocrine neoplasia type 2 (MEN 2) • Personal history or family history of medullary thyroid cancer Raised Serum Calcitonin (a biomarker for medullar thyroid cancer) at beginning of trial period Concurrent use of octeotride History of cardiac failure
• Concurrent use of diuretics • Previous history of pancreatitis • Recent use of other incretin based therapy in the previous 3 months • Type 1 or Type 2 diabetes • Alcohol or drug abuse in last year • > 4 hospitalisations related to short bowel or its treatment over the previous year • Any hospitalisation 30 days prior to screening • Introduction or dose adjustment of immunosuppressant for inflammatory bowel disease within 3 months, or treatment with biologics within the past 6 months (systemic corticosteroids, methotrexate, cyclosporine, tacrolimus, sirolimus, MMF, infliximab, adalimumab, vedolizumab) • BMI < 19 kg/m2 or > 27kg/m2 (An upper cut-off BMI of > 27kg/m2 has been chosen, as in these patients, there is often a desire to reduce BMI which will conflict with the study design by adding another variable) • Scleroderma/radiation enteritis/coeliacs disease/refractory or tropical sprue • Liver and renal function outside the inclusion range 2.3.4 Subject withdrawal criteria • Participants may withdraw at any point in time during the trial and for any reason. If a patient withdraws, the reason for withdrawal will be documented. • If a participant has weight loss during the study such that the BMI drops below 19 kg/m2 or there is a 10% reduction in weight between clinic appointments the patient will be withdrawn. • If a participant becomes pregnant during the study they will be withdrawn. • Development of any of the following criteria that would interfere with the analysis of study results (i.e. compromise PN) o Significant active, uncontrolled diseases e.g. cardiovascular, renal, cancer that would put the subject at undue risk or prevent completion of the study o Major surgical interventions e.g. abdominal, vascular o Cohn’s disease flare up • Occurrence of a serious adverse event (SAE) thought to be study drug related • Death of a patient • Investigator decision (i.e. subject non compliance with study procedures) • Significant adverse event (AE) or medical decision that precludes the subject from adhering to study requirements Discontinued subjects will not be replaced. |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Reduction in parenteral nutrition volume at 20 weeks from start of liraglutide
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
20 weeks from start of liraglutide |
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E.5.2 | Secondary end point(s) |
• Change in plasma citrulline, GLP-1, IGF-1 and PYY concentrations • Improvement in quality of life score • Duration of response i.e. proportion of subjects who maintain reduction in weekly PN volume from baseline at week 20. . Nights no longer requiring parenteral support |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
20 weeks from start of liraglutide |
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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 |
Alternative use of drug (new development plan) |
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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 | 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 | No |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | No |
E.8.5 | The trial involves multiple Member States | No |
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 | 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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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 | 8 |
E.8.9.1 | In the Member State concerned days | 8 |