Postprandial Hypoglycemia in Patients After Bariatric Surgery With Empagliflozin and Anakinra - The Hypo-BEAR-Study

Study Overview
=================
Brief Summary
-----------------
The purpose of the study is to investigate whether hypoglycaemia observed after food intake in bariatric patients can be either influenced by an SGLT2 inhibitor, empagliflozin, or via inhibition of inflammation with an human interleukin-1 receptor antagonist (IL1-RA, anakinra).

Detailed Description
-----------------
Postprandial hypoglycemia also referred as late-dumping after bariatric surgery can be clinically asymptomatic but also life-threatening. The exact mechanisms leading to postprandial hypoglycemia are not fully understood and therapeutic options are limited and often accompanied with reduced life-quality and weight gain. In this study, prospective, randomly selected and double-blinded treatment is performed to investigate the effect on postprandial hypoglycemia. A total of 12 subjects participate in the study. After a screening date, three study dates will be performed. Participation in the study usually takes two weeks, but can also be extended to three weeks in individual cases. The University Hospital Basel will be the only test center in this study. In order to check whether the increase in blood glucose after food intake and subsequent excessive reaction of the body followed by hypoglycaemia patients receive either anakinra as a subcutaneous injection 3h or empagliflozin as a tablet 2 h before a liquid standardized test meal. On one study day only subcutaneous and oral placebo control will be used. At the beginning of each study date as well as at the time of the test meal several blood samples will be taken to evaluate blood glucose and blood glucose-influencing parameters (insulin / C-peptide, intestinal hormones, inflammatory parameters such as C-reactive protein, IL1beta and IL1-receptor agonist as well as macrophage and t-lymphocyte subpopulations) will be controlled. Questionnaires for dumping symptoms (Dumping Rating scale, Sigstad Score) and hypoglycemia testing with mini-mental test, stanford sleepiness scale and Edinburgh Hypoglycemia Scale will be performed repetitively.

Official Title
-----------------
Postprandial Hypoglycemia in Patients After Bariatric Surgery With Empagliflozin and Anakinra - The Hypo-BEAR-Study

Conditions
-----------------
Postprandial Hypoglycemia, Bariatric Surgery, Late Dumping Syndrome

Intervention / Treatment
-----------------
* Drug: Empagliflozin
* Drug: Anakinra
* Other: oral placebo (winthrop tablet)
* Other: subcutaneous placebo (0.67 ml of 0.9% sodium chloride)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients after roux-y-gastric bypass or biliopancreatic diversion with documented hypoglycemia, i. e. ≤ 2.5 mmol/l and hypoglycaemic symptoms. For subjects with reproductive potential, willingness to use contraceptive measures adequate to prevent the subject or the subject's partner from becoming pregnant during the study Exclusion Criteria: Signs of current infection Use of any investigational drug in the last four weeks prior to enrolment Use of any anti-diabetic drugs adrenal insufficiency and/or substitution with glucocorticoids Neutropenia (leukocyte count < 1.5 × 109/L or absolute neutrophil count (ANC) < 0.5 × 109/L) Anemia (hemoglobin < 11 g/dL for males, < 10 g/dL for females) Clinically significant kidney or liver disease (creatinine > 1.5 mg/dL, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 2 × ULN, alkaline phosphatase > 2 × ULN, or total bilirubin [tBili] > 1.5 × ULN) Current immunosuppressive treatment or documented immunodeficiency Uncontrolled congestive heart failure Uncontrolled malignant disease Currently pregnant or breastfeeding known lactose intolerance

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo-Placebo<br>subcutaneous placebo (0.67 ml of 0.9% sodium chloride) 3 hours before the test meal and an oral placebo (winthrop tablet) 2 hours before the test meal will be administered by an Independent nurse to the blinded patient | Other: oral placebo (winthrop tablet)<br>* subcutaneous placebo (0.67 ml of 0.9% sodium chloride) 3 hours before the test meal and an oral placebo (winthrop tablet) 2 hours before the test meal will be administered by an Independent nurse to the blinded patient<br>Other: subcutaneous placebo (0.67 ml of 0.9% sodium chloride)<br>* subcutaneous placebo (0.67 ml of 0.9% sodium chloride) will be administered in arm 'Placebo-Placebo' and arm 'drug: Empagliflozin'<br>|
| Active Comparator: Investigational Drug A Empagliflozin<br>subcutaneous placebo (0.67 ml of 0.9% sodium chloride) 3 hours before the test meal and an 10mg of empagliflozin 2 hours before the test meal will be administered by an independent nurse to the blinded patient | Drug: Empagliflozin<br>* Glucose lowering effect of empagliflozin for reducing the counter-regulatory glucose-lowering response<br>Other: subcutaneous placebo (0.67 ml of 0.9% sodium chloride)<br>* subcutaneous placebo (0.67 ml of 0.9% sodium chloride) will be administered in arm 'Placebo-Placebo' and arm 'drug: Empagliflozin'<br>|
| Active Comparator: Investigational Drug B Anakinra<br>subcutaneous injection of 100mg anakinra 3 hours before the test meal and an oral placebo (winthrop tablet)before the test meal will be administered by an Independent nurse to the blinded patient | Drug: Anakinra<br>* IL-1Beta blockage effect on insulin secretion and thereby influencing postprandial glucose level<br>Other: oral placebo (winthrop tablet)<br>* subcutaneous placebo (0.67 ml of 0.9% sodium chloride) 3 hours before the test meal and an oral placebo (winthrop tablet) 2 hours before the test meal will be administered by an Independent nurse to the blinded patient<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Postprandial hypoglycemia in patients after bariatric surgery | To assess whether empagliflozin or anakinra compared to placebo reduce the severity of hypoglycemia (i.e. change of blood glucose level in mmol/l) following a mixed-meal in patients after bariatric surgery. | 6 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change of C-peptide | plasma level of c-peptide with anakinra or empagliflozin in comparison to placebo | 6 hours | 
| plasma level of IL-1Beta | plasma level of IL-1Beta with anakinra or empagliflozin in comparison to placebo | 6 hours | 
| plasma level of Glucagon-like Peptide1 (GLP1) | plasma level of GLP1 with anakinra or empagliflozin in comparison to placebo | 6 hours | 
| change of glucagon level | plasma level of glucagon with anakinra or empagliflozin in comparison to placebo | 6 hours | 
| changes in Edinburgh Hypoglycemia Scale | changes in Edinburgh Hypoglycemia Scale with anakinra or empagliflozin in comparison to placebo | 6 hours | 
| amount of glucose needed for restoring normoglycemia | amount (gramme) of glucose needed for restoring normoglycemia with anakinra or empagliflozin in comparison to placebo | 6 hours | 
| length of time needed for restoring normoglycemia | length of time (minutes) needed for restoring normoglycemia with anakinra or empagliflozin in comparison to placebo | 6 hours | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
postprandial hypoglycemia, bariatric surgery, late dumping syndrome, empagliflozin, SGLT2 inhibitor, IL-1Beta, IL1, anakinra