Empagliflozin and Anakinra for the Treatment of Postprandial Hypoglycemia in Patients With Prediabetes

Study Overview
=================
Brief Summary
-----------------
This study is to analyze whether the SGLT2-inhibitor empagliflozin or the IL-1 receptor antagonist anakinra may improve postprandial hypoglycemia in subjects with prediabetes.

Detailed Description
-----------------
Subjects with prediabetes may develop postprandial hypoglycemia. This is probably due to a dysfunction of the insulin producing β-cell characterized by a delayed and exaggerated insulin secretion leading to an initial peak in glycaemia followed by a rapid fall and eventually resulting in hypoglycemia. The latter occurring typically within 1 to 3 hours after food intake. In patients with gastric bypass surgery and postprandial hypoglycemia the SGLT2-inhibitor empagliflozin and the IL-1 receptor antagonist anakinra reduced postprandial insulin release and prevented hypoglycemia. This study is to analyze whether a similar therapeutic approach using empagliflozin and anakinra may also improve postprandial hypoglycemia in subjects with prediabetes.

Official Title
-----------------
Empagliflozin and Anakinra for the Treatment of Postprandial Hypoglycemia in Patients With Prediabetes: a Randomized, Placebo-controlled Study

Conditions
-----------------
Postprandial Hypoglycemia

Intervention / Treatment
-----------------
* Drug: empagliflozin
* Drug: anakinra
* Other: saline subcutaneous (s.c.) (placebo)
* Other: tablet per oral (p.o.) (placebo)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects with prediabetes defined by Glycosylated haemoglobin A1c (HbA1c) 5.7-6.4 % or fasting plasma glucose 6.1-6.9 mmol/l) or plasma glucose 2 h following 75 glucose ingestion of 7.8-11.0 mmol/l. Hypoglycemia occuring 1 to 3 h following ingestion of a standardized liquid mixed-meal (75 g carbohydrates) and fulfilling the Whipple's triad (glucose below 3.0 mmol/l). Age ≥ 18 years For subjects with reproductive potential, willingness to use contraceptive measures adequate to prevent the subject from becoming pregnant during the study Exclusion Criteria: Upper gastrointestinal surgery Diagnosis of any type of diabetes mellitus Signs of current infection Use of investigational drug up to one week prior to start of treatment phase Glucocorticoid therapy 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)/ALT > 2 × ULN, alkaline phosphatase > 2 × ULN, or total bilirubin [tBili] > 1.5 × ULN) Uncontrolled disease Currently pregnant or breastfeeding No subjects meeting the criteria for vulnerability Participation in another study with investigational drug within the 30 days preceding and during the present study.

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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Placebo controlled, double-blind, randomized, cross-over proof-of-concept study. Subjects will be randomized to either group 1-6 (ratio 1:1, in blocks of 4 participants).
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Group 1 (anakinra; placebo; empagliflozin)<br>Group 1: study day 1: anakinra; study day2: placebo; study day 3: empagliflozin | Drug: empagliflozin<br>* Empagliflozin (Jardiance®; Boehringer Ingelheim (Schweiz) GmbH) is a highly selective, reversible inhibitor of the sodium glucose co-transporter 2 (SGLT2). Treatment consists of a single oral tablet of 25 mg of empagliflozin (Jardiance®) two hours before ingestion of the mixed-meal (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes).<br>Drug: anakinra<br>* Anakinra (Kineret®; r-metHuIL-1ra, Swedish Orphan Biovitrum AB) is a recombinant, non-glycosylated form of the human interleukin-1 receptor antagonist (IL-1Ra) in a 100 mg/0.67ml solution for SC injection. Treatment consists of a single subcutaneous injection of 100 mg Anakinra (Kineret®) three hours before ingestion of the mixed-meal (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes).<br>Other: saline subcutaneous (s.c.) (placebo)<br>* Placebo for anakinra is 0.67 ml of sterile 0.9 % saline solution s. c. Treatment consists of a single subcutaneous injection of matched placebo (0.67 ml of 0.9 % saline) three hours before ingestion of the mixed-meal (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes).<br>Other: tablet per oral (p.o.) (placebo)<br>* Placebo for empagliflozin is Winthrop P® (Zentiva, Frankfurt/Main) lactose tablet. Treatment consists of a single oral tablet of matched placebo two hours before ingestion of the mixed-meal (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes).<br>|
| Other: Group 2 (placebo; anakinra; empagliflozin)<br>study day 1: placebo; study day2: anakinra; study day 3: empagliflozin | Drug: empagliflozin<br>* Empagliflozin (Jardiance®; Boehringer Ingelheim (Schweiz) GmbH) is a highly selective, reversible inhibitor of the sodium glucose co-transporter 2 (SGLT2). Treatment consists of a single oral tablet of 25 mg of empagliflozin (Jardiance®) two hours before ingestion of the mixed-meal (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes).<br>Drug: anakinra<br>* Anakinra (Kineret®; r-metHuIL-1ra, Swedish Orphan Biovitrum AB) is a recombinant, non-glycosylated form of the human interleukin-1 receptor antagonist (IL-1Ra) in a 100 mg/0.67ml solution for SC injection. Treatment consists of a single subcutaneous injection of 100 mg Anakinra (Kineret®) three hours before ingestion of the mixed-meal (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes).<br>Other: saline subcutaneous (s.c.) (placebo)<br>* Placebo for anakinra is 0.67 ml of sterile 0.9 % saline solution s. c. Treatment consists of a single subcutaneous injection of matched placebo (0.67 ml of 0.9 % saline) three hours before ingestion of the mixed-meal (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes).<br>Other: tablet per oral (p.o.) (placebo)<br>* Placebo for empagliflozin is Winthrop P® (Zentiva, Frankfurt/Main) lactose tablet. Treatment consists of a single oral tablet of matched placebo two hours before ingestion of the mixed-meal (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes).<br>|
| Other: Group 3 (empagliflozin; placebo; anakinra)<br>study day 1: empagliflozin; study day2: placebo; study day 3: anakinra | Drug: empagliflozin<br>* Empagliflozin (Jardiance®; Boehringer Ingelheim (Schweiz) GmbH) is a highly selective, reversible inhibitor of the sodium glucose co-transporter 2 (SGLT2). Treatment consists of a single oral tablet of 25 mg of empagliflozin (Jardiance®) two hours before ingestion of the mixed-meal (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes).<br>Drug: anakinra<br>* Anakinra (Kineret®; r-metHuIL-1ra, Swedish Orphan Biovitrum AB) is a recombinant, non-glycosylated form of the human interleukin-1 receptor antagonist (IL-1Ra) in a 100 mg/0.67ml solution for SC injection. Treatment consists of a single subcutaneous injection of 100 mg Anakinra (Kineret®) three hours before ingestion of the mixed-meal (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes).<br>Other: saline subcutaneous (s.c.) (placebo)<br>* Placebo for anakinra is 0.67 ml of sterile 0.9 % saline solution s. c. Treatment consists of a single subcutaneous injection of matched placebo (0.67 ml of 0.9 % saline) three hours before ingestion of the mixed-meal (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes).<br>Other: tablet per oral (p.o.) (placebo)<br>* Placebo for empagliflozin is Winthrop P® (Zentiva, Frankfurt/Main) lactose tablet. Treatment consists of a single oral tablet of matched placebo two hours before ingestion of the mixed-meal (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes).<br>|
| Other: Group 4 (empagliflozin; anakinra; placebo)<br>study day 1: empagliflozin; study day2: anakinra; study day 3: placebo | Drug: empagliflozin<br>* Empagliflozin (Jardiance®; Boehringer Ingelheim (Schweiz) GmbH) is a highly selective, reversible inhibitor of the sodium glucose co-transporter 2 (SGLT2). Treatment consists of a single oral tablet of 25 mg of empagliflozin (Jardiance®) two hours before ingestion of the mixed-meal (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes).<br>Drug: anakinra<br>* Anakinra (Kineret®; r-metHuIL-1ra, Swedish Orphan Biovitrum AB) is a recombinant, non-glycosylated form of the human interleukin-1 receptor antagonist (IL-1Ra) in a 100 mg/0.67ml solution for SC injection. Treatment consists of a single subcutaneous injection of 100 mg Anakinra (Kineret®) three hours before ingestion of the mixed-meal (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes).<br>Other: saline subcutaneous (s.c.) (placebo)<br>* Placebo for anakinra is 0.67 ml of sterile 0.9 % saline solution s. c. Treatment consists of a single subcutaneous injection of matched placebo (0.67 ml of 0.9 % saline) three hours before ingestion of the mixed-meal (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes).<br>Other: tablet per oral (p.o.) (placebo)<br>* Placebo for empagliflozin is Winthrop P® (Zentiva, Frankfurt/Main) lactose tablet. Treatment consists of a single oral tablet of matched placebo two hours before ingestion of the mixed-meal (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes).<br>|
| Other: Group 5 (placebo; empagliflozin; anakinra)<br>study day 1: placebo; study day2: empagliflozin; study day 3: anakinra | Drug: empagliflozin<br>* Empagliflozin (Jardiance®; Boehringer Ingelheim (Schweiz) GmbH) is a highly selective, reversible inhibitor of the sodium glucose co-transporter 2 (SGLT2). Treatment consists of a single oral tablet of 25 mg of empagliflozin (Jardiance®) two hours before ingestion of the mixed-meal (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes).<br>Drug: anakinra<br>* Anakinra (Kineret®; r-metHuIL-1ra, Swedish Orphan Biovitrum AB) is a recombinant, non-glycosylated form of the human interleukin-1 receptor antagonist (IL-1Ra) in a 100 mg/0.67ml solution for SC injection. Treatment consists of a single subcutaneous injection of 100 mg Anakinra (Kineret®) three hours before ingestion of the mixed-meal (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes).<br>Other: saline subcutaneous (s.c.) (placebo)<br>* Placebo for anakinra is 0.67 ml of sterile 0.9 % saline solution s. c. Treatment consists of a single subcutaneous injection of matched placebo (0.67 ml of 0.9 % saline) three hours before ingestion of the mixed-meal (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes).<br>Other: tablet per oral (p.o.) (placebo)<br>* Placebo for empagliflozin is Winthrop P® (Zentiva, Frankfurt/Main) lactose tablet. Treatment consists of a single oral tablet of matched placebo two hours before ingestion of the mixed-meal (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes).<br>|
| Other: Group 6 (anakinra; empagliflozin; placebo)<br>study day 1:anakinra; study day2: empagliflozin; study day 3: placebo | Drug: empagliflozin<br>* Empagliflozin (Jardiance®; Boehringer Ingelheim (Schweiz) GmbH) is a highly selective, reversible inhibitor of the sodium glucose co-transporter 2 (SGLT2). Treatment consists of a single oral tablet of 25 mg of empagliflozin (Jardiance®) two hours before ingestion of the mixed-meal (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes).<br>Drug: anakinra<br>* Anakinra (Kineret®; r-metHuIL-1ra, Swedish Orphan Biovitrum AB) is a recombinant, non-glycosylated form of the human interleukin-1 receptor antagonist (IL-1Ra) in a 100 mg/0.67ml solution for SC injection. Treatment consists of a single subcutaneous injection of 100 mg Anakinra (Kineret®) three hours before ingestion of the mixed-meal (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes).<br>Other: saline subcutaneous (s.c.) (placebo)<br>* Placebo for anakinra is 0.67 ml of sterile 0.9 % saline solution s. c. Treatment consists of a single subcutaneous injection of matched placebo (0.67 ml of 0.9 % saline) three hours before ingestion of the mixed-meal (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes).<br>Other: tablet per oral (p.o.) (placebo)<br>* Placebo for empagliflozin is Winthrop P® (Zentiva, Frankfurt/Main) lactose tablet. Treatment consists of a single oral tablet of matched placebo two hours before ingestion of the mixed-meal (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes).<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of symptomatic hypoglycemia | Incidence of symptomatic hypoglycemia following a standardized mixed-meal test defined by appearance of typical symptoms, blood glucose level below 3.0 mmol/l and relief of symptoms when the glucose level is raised (Whipple's triad). | up to 3 hours after ingestion of the liquid mixed-meal | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Severity of symptoms of hypoglycemia according to the Edinburgh Hypoglycemia Scale | The Edinburgh Hypoglycemia Scale is a classification of the 11 most common symptoms of hypoglycemia. Subjective intensity-grading: no symptoms 0 light symptoms 1 moderate symptoms 2 severe symptoms 3 | up to 3 hours after ingestion of the liquid mixed-meal | 
| Nadir plasma glucose (mmol/l) | Nadir plasma glucose (mmol/l) | up to 3 hours after ingestion of the liquid mixed-meal | 
| Change in proinsulin to insulin ratio in serum | Change in proinsulin to insulin ratio in serum | at baseline and 60 min after ingestion of the mixed meal | 
| Change in inflammatory state | Change in inflammatory laboratory parameters (Interleukin (IL)1ß, IL6, Tumor necrosis factor (TNF) α, IL-10, IL-1Ra) in supernatants of Lipopolysaccharide (LPS)-stimulated and unstimulated peripheral blood mononuclear cells (PBMC) | at baseline and 60 min after ingestion of the mixed meal | 
| Change in RNA sequencing (RNAseq) in peripheral PBMC | Change in RNAseq in peripheral PBMC | at baseline and 60 min after ingestion of the mixed meal | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
SGLT2-inhibitor empagliflozin, IL-1 receptor antagonist anakinra, prediabetes, insulin clearance, proinsulin