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

Primary Purpose

Postprandial Hypoglycemia

Status

Active

Phase

Phase 2

Locations

Switzerland

Study Type

Interventional

Intervention

empagliflozin

anakinra

saline subcutaneous (s.c.) (placebo)

tablet per oral (p.o.) (placebo)

About this trial

This is an interventional treatment trial for Postprandial Hypoglycemia focused on measuring SGLT2-inhibitor empagliflozin, IL-1 receptor antagonist anakinra, prediabetes, insulin clearance, proinsulin

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Department of Endocrinology, Diabetes and Metabolism, University Hospital Basel

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Other

Arm Label

Group 1 (anakinra; placebo; empagliflozin)

Group 2 (placebo; anakinra; empagliflozin)

Group 3 (empagliflozin; placebo; anakinra)

Group 4 (empagliflozin; anakinra; placebo)

Group 5 (placebo; empagliflozin; anakinra)

Group 6 (anakinra; empagliflozin; placebo)

Arm Description

Group 1: study day 1: anakinra; study day2: placebo; study day 3: empagliflozin

study day 1: placebo; study day2: anakinra; study day 3: empagliflozin

study day 1: empagliflozin; study day2: placebo; study day 3: anakinra

study day 1: empagliflozin; study day2: anakinra; study day 3: placebo

study day 1: placebo; study day2: empagliflozin; study day 3: anakinra

study day 1:anakinra; study day2: empagliflozin; study day 3: placebo

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

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

Nadir plasma glucose (mmol/l)

Change in proinsulin to insulin ratio in serum

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)

Change in RNA sequencing (RNAseq) in peripheral PBMC

Change in RNAseq in peripheral PBMC

Full Information

NCT ID

NCT05174507

First Posted

December 13, 2021

Last Updated

November 30, 2022

Sponsor

University Hospital, Basel, Switzerland

1. Study Identification

Unique Protocol Identification Number

NCT05174507

Brief Title

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

Acronym

Hypo-PrEA

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

November 2022

Overall Recruitment Status

Active, not recruiting

Study Start Date

June 24, 2022 (Actual)

Primary Completion Date

May 2024 (Anticipated)

Study Completion Date

May 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University Hospital, Basel, Switzerland

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Postprandial Hypoglycemia

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Crossover Assignment

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

ParticipantCare ProviderInvestigator

Masking Description

Participants, investigators and study nurses will be blinded to the study drug.

Allocation

Randomized

Enrollment

26 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Group 1 (anakinra; placebo; empagliflozin)

Arm Type

Other

Arm Description

Group 1: study day 1: anakinra; study day2: placebo; study day 3: empagliflozin

Arm Title

Group 2 (placebo; anakinra; empagliflozin)

Arm Type

Other

Arm Description

study day 1: placebo; study day2: anakinra; study day 3: empagliflozin

Arm Title

Group 3 (empagliflozin; placebo; anakinra)

Arm Type

Other

Arm Description

study day 1: empagliflozin; study day2: placebo; study day 3: anakinra

Arm Title

Group 4 (empagliflozin; anakinra; placebo)

Arm Type

Other

Arm Description

study day 1: empagliflozin; study day2: anakinra; study day 3: placebo

Arm Title

Group 5 (placebo; empagliflozin; anakinra)

Arm Type

Other

Arm Description

study day 1: placebo; study day2: empagliflozin; study day 3: anakinra

Arm Title

Group 6 (anakinra; empagliflozin; placebo)

Arm Type

Other

Arm Description

study day 1:anakinra; study day2: empagliflozin; study day 3: placebo

Intervention Type

Drug

Intervention Name(s)

empagliflozin

Intervention Description

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).

Intervention Type

Drug

Intervention Name(s)

anakinra

Intervention Description

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).

Intervention Type

Other

Intervention Name(s)

saline subcutaneous (s.c.) (placebo)

Intervention Description

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).

Intervention Type

Other

Intervention Name(s)

tablet per oral (p.o.) (placebo)

Intervention Description

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).

Primary Outcome Measure Information:

Title

Number of symptomatic hypoglycemia

Description

Time Frame

up to 3 hours after ingestion of the liquid mixed-meal

Secondary Outcome Measure Information:

Title

Severity of symptoms of hypoglycemia according to the Edinburgh Hypoglycemia Scale

Description

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

Time Frame

up to 3 hours after ingestion of the liquid mixed-meal

Title

Nadir plasma glucose (mmol/l)

Description

Nadir plasma glucose (mmol/l)

Time Frame

up to 3 hours after ingestion of the liquid mixed-meal

Title

Change in proinsulin to insulin ratio in serum

Description

Change in proinsulin to insulin ratio in serum

Time Frame

at baseline and 60 min after ingestion of the mixed meal

Title

Change in inflammatory state

Description

Time Frame

at baseline and 60 min after ingestion of the mixed meal

Title

Change in RNA sequencing (RNAseq) in peripheral PBMC

Description

Change in RNAseq in peripheral PBMC

Time Frame

at baseline and 60 min after ingestion of the mixed meal

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Marc Y. Donath, Prof. Dr. med.

Organizational Affiliation

Division of Endocrinology, Diabetes and Metabolism, University Hospital Basel

Official's Role

Principal Investigator

Facility Information:

Facility Name

Department of Endocrinology, Diabetes and Metabolism, University Hospital Basel

City

Basel

ZIP/Postal Code

4031

Country

Switzerland

12. IPD Sharing Statement

Learn more about this trial

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

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