Reduction by Pasireotide of the Effluent Volume in High-output Enterostomy in Patients Refractory to Usual Medical Treatment

Study Overview
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Brief Summary
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During rectal or complex digestive surgery with multiple digestive resections and anastomosis, the creation of enterostomy is a common procedure. In France, it is estimated that 20000 patients have an ileostomy and 16000 new digestive stomas are formed each year with approximately 30% of enterostomy. Enterostomy might sometimes give high-output not controlled with usual medical treatment (e.g loperamide ± codeine) and exposes the patients to important hydro-electrolytic loss leading to a risk for dehydration, electrolyte abnormalities and acute renal failure. This risk implies parenteral correction which may extend hospital stay and delay home return. Somatostatin analogues (octreotide, lanreotide and pasireotide) could reduce digestive secretions and decrease digestive peristalsis. Nevertheless, somatostatin analogues are not routinely used for the treatment of patients with high-output enterostomy and their efficacy in the indication (off-label) was only tested in small case series. Pasireotide (SOM230, SIGNIFOR®) is currently indicated for the treatment of patients with Cushing's disease for whom surgery is not an option or for whom surgery has failed. As the efficacity of pasireotide in patients with high-output enterostomy refractory to usual medical treatment associated with an oral fluid restriction has never been demonstrated before, there is a need to perform a pilot, double-blind, randomized, placebo-controlled trial evaluating its impact on reduction of the effluent volume.

Official Title
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Reduction by Pasireotide of the Effluent Volume in High-output Enterostomy in Patients Refractory to Usual Medical Treatment : Phase II Multicentric Randomized Double Bland Placebo Controlled Study

Conditions
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Enterostomy

Intervention / Treatment
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* Drug: Pasireotide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and Female patients ≥ 18 years old ; Patients who underwent an intestinal surgery with enterostomy repair in the three weeks preceding the inclusion ; Patients with high-output ileostomy or jejunostomy > 1000 ml/24h ; Patients with failure of treatment combining oral fluid restriction and loperamide (up to 8 capsules/24h) +/- codeine syrup (10 mg x 3/24h) during 5 days ; Patients who gave its written informed consent to participate to the study ; Patients affiliated to a social insurance regime. Exclusion Criteria: Male and Female patients < 18 years old ; Patients who did not give its written informed consent to participate to the study ; Patients who received somatostatin analogues during the month before inclusion ; Patients with symptomatic cholelithiasis or acute or chronic pancreatitis ; Patients with uncontrolled diabetes (with HbA1c (glycated hemoglobin) > 8%) ; Patients who are hypothyroid and not on adequate replacement therapy ; Patients who have congestive heart failure (NYHA (New York Heart Association) Class III or IV), unstable angina, sustained ventricular tachycardia, ventricular fibrillation, advanced heart block or a history of clinically significant bradycardia or acute myocardial infarction within the 6 months preceding randomization ; Patients with history of syncope or family history of idiopathic sudden death ; Patients with screening or baseline (predose) : QT interval corrected for heart rate using Fridericia's correction (QTcF) QTcF > 450 msec (male), QTcF > 460 msec (female) (QT interval corrected for heart rate using Fridericia's correction) ; Patients with not corrected hypokalaemia and/or hypomagnesaemia ; Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis, or patients with alanine transaminase/aspartate transaminase (ALT/AST) > 2 x Upper Limit of Normal (ULN), serum bilirubin > 2 x ULN ; Patients with Child-Pugh C cirrhosis ; Female patients who are pregnant or lactating, or are of childbearing potential and not practicing a medically acceptable method of birth control ; Patients with abnormal coagulation (PT and/or APTT elevated by 30% above normal limits) or patients receiving anticoagulants that affect PT (prothrombin time) or activated partial thromboplastin time (APTT) ; Patients with known hypersensitivity to somatostatin analogues or any other component of the pasireotide LAR ; Patients under guardianship ; Patients nonaffiliated to a social insurance regime.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pasireotide<br>Pasireotide 0.9 mg by subcutaneous injection twice a day during 3 days and 1 intramuscular injection of pasireotide Long Acting Release (LAR) 60mg on Day 4 morning. | Drug: Pasireotide<br>* Pasireotide 0.9 mg by subcutaneous injection twice a day during 3 days and 1 intramuscular injection of pasireotide Long Acting Release (LAR) 60mg on Day 4 morning.<br>* Other names: Pasireotide 0.9 mg (SIGNIFOR®) and Pasireotide 60mg Long Acting Release (LAR);|
| Placebo Comparator: Placebo<br>Placebo by subcutaneous injection twice a day during 3 days and 1 intramuscular injection of placebo on Day 4 morning. | Drug: Placebo<br>* Placebo by subcutaneous injection twice a day during 3 days and 1 intramuscular injection of placebo on Day 4 morning.<br>* Other names: Placebo of pasireotide 0.9 mg by subcutaneous injection twice a day during 3 days and 1 intramuscular injection of pasireotide LAR (Long Acting Release) 60mg on Day 4;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare the efficacy of pasireotide versus placebo in reduction of high-output | Decrease of enterostomy output (ml/24H)within the 72 hours after first injection of treatment | Evaluated 72 hours after first injection of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimate the success rate of pasireotide and placebo | Number of normal renal function patients in both arms with an enterostomy output than 800 millimeters (mL) /24h within a week after first injection of treatment allowing discontinuation of intravenous perfusion. | 1 week after first injection of treatment | 
| Compare the decrease in the length of hospitalization with pasireotide versus placebo | Duration of hospitalization in days in both arms | 1 month after the end of treatment | 
| Compare the incidence of premature closure of stoma due to high-output with pasireotide versus placebo | Rate of premature closure of stoma due to high-output (before 2 months after creation) in both arms | 2 months after enterostomy creation | 
| Evaluate the economic impact of pasireotide in this indication | Costs of taking care of patients from French Public Health Insurance perspective in both arms | 2 months from the inclusion of the patient in the study | 
| Incidence of treatment - Emergent Adverse Events | Nature, number and grade of adverse events observed throughout the study | during treatment (4 days), one week, two weeks, three weeks and one month after treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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High-Output Enterostomy, Pasireotide, Somatostatin Analogues