Empagliflozin and Anakinra for the Treatment of Postprandial Hypoglycemia in Patients With Prediabetes (Hypo-PrEA)

• ClinicalTrials.gov Identifier: NCT05174507
• Recruitment Status: Active, not recruiting
• First Posted: December 30, 2021
• Last Update Posted: December 1, 2022
• Sponsor: University Hospital, Basel, Switzerland
• Information provided by (Responsible Party): University Hospital, Basel, Switzerland

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Postprandial Hypoglycemia	Drug: empagliflozin; Drug: anakinra; Other: saline subcutaneous (s.c.) (placebo); Other: tablet per oral (p.o.) (placebo)	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 26 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention 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 (Participant, Care Provider, Investigator)
• Masking Description: Participants, investigators and study nurses will be blinded to the study drug.
• Primary Purpose: Treatment
• Official Title: Empagliflozin and Anakinra for the Treatment of Postprandial Hypoglycemia in Patients With Prediabetes: a Randomized, Placebo-controlled Study
• Actual Study Start Date: June 24, 2022
• Estimated Primary Completion Date: May 2024
• Estimated Study Completion Date: May 2024

Arms and Interventions

Arm	Intervention/treatment
Group 1 (anakinra; placebo; empagliflozin); Group 1: study day 1: anakinra; study day2: placebo; study day 3: empagliflozin	Drug: empagliflozin; 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).; Drug: anakinra; 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).; Other: saline subcutaneous (s.c.) (placebo); 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).; Other: tablet per oral (p.o.) (placebo); 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).
Group 2 (placebo; anakinra; empagliflozin); study day 1: placebo; study day2: anakinra; study day 3: empagliflozin	Drug: empagliflozin; 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).; Drug: anakinra; 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).; Other: saline subcutaneous (s.c.) (placebo); 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).; Other: tablet per oral (p.o.) (placebo); 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).
Group 3 (empagliflozin; placebo; anakinra); study day 1: empagliflozin; study day2: placebo; study day 3: anakinra	Drug: empagliflozin; 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).; Drug: anakinra; 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).; Other: saline subcutaneous (s.c.) (placebo); 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).; Other: tablet per oral (p.o.) (placebo); 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).
Group 4 (empagliflozin; anakinra; placebo); study day 1: empagliflozin; study day2: anakinra; study day 3: placebo	Drug: empagliflozin; 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).; Drug: anakinra; 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).; Other: saline subcutaneous (s.c.) (placebo); 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).; Other: tablet per oral (p.o.) (placebo); 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).
Group 5 (placebo; empagliflozin; anakinra); study day 1: placebo; study day2: empagliflozin; study day 3: anakinra	Drug: empagliflozin; 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).; Drug: anakinra; 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).; Other: saline subcutaneous (s.c.) (placebo); 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).; Other: tablet per oral (p.o.) (placebo); 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).
Group 6 (anakinra; empagliflozin; placebo); study day 1:anakinra; study day2: empagliflozin; study day 3: placebo	Drug: empagliflozin; 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).; Drug: anakinra; 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).; Other: saline subcutaneous (s.c.) (placebo); 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).; Other: tablet per oral (p.o.) (placebo); 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).

Outcome Measures

Primary Outcome Measures :

1. Number of symptomatic hypoglycemia [ Time Frame: up to 3 hours after ingestion of the liquid mixed-meal ]
   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).

Secondary Outcome Measures :

1. Severity of symptoms of hypoglycemia according to the Edinburgh Hypoglycemia Scale [ Time Frame: up to 3 hours after ingestion of the liquid mixed-meal ]

   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
2. Nadir plasma glucose (mmol/l) [ Time Frame: up to 3 hours after ingestion of the liquid mixed-meal ]
   Nadir plasma glucose (mmol/l)
3. Change in proinsulin to insulin ratio in serum [ Time Frame: at baseline and 60 min after ingestion of the mixed meal ]
   Change in proinsulin to insulin ratio in serum
4. Change in inflammatory state [ Time Frame: at baseline and 60 min after ingestion of the mixed meal ]
   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)
5. Change in RNA sequencing (RNAseq) in peripheral PBMC [ Time Frame: at baseline and 60 min after ingestion of the mixed meal ]
   Change in RNAseq in peripheral PBMC

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

Switzerland

Department of Endocrinology, Diabetes and Metabolism, University Hospital Basel

Basel, Switzerland, 4031

Sponsors and Collaborators

University Hospital, Basel, Switzerland

Investigators

• Principal Investigator: Marc Y. Donath, Prof. Dr. med.; Division of Endocrinology, Diabetes and Metabolism, University Hospital Basel

More Information

• Responsible Party: University Hospital, Basel, Switzerland
• ClinicalTrials.gov Identifier: NCT05174507
• Other Study ID Numbers: 2020-01287; me20Donath
• First Posted: December 30, 2021
• Last Update Posted: December 1, 2022
• Last Verified: November 2022

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University Hospital, Basel, Switzerland:

SGLT2-inhibitor empagliflozin; IL-1 receptor antagonist anakinra; prediabetes; insulin clearance; proinsulin

Additional relevant MeSH terms:

Hypoglycemia; Prediabetic State; Glucose Intolerance; Glucose Metabolism Disorders; Metabolic Diseases; Diabetes Mellitus; Endocrine System Diseases; Hyperglycemia; Empagliflozin; Interleukin 1 Receptor Antagonist Protein; Sodium-Glucose Transporter 2 Inhibitors; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; Physiological Effects of Drugs; Antirheumatic Agents