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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)
Sponsored by
University Hospital, Basel, Switzerland
About
Eligibility
Locations
Arms
Outcomes
Full info

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

Other

Other

Other

Other

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)
Nadir plasma glucose (mmol/l)
Change in proinsulin to insulin ratio in serum
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

First Posted
December 13, 2021
Last Updated
November 30, 2022
Sponsor
University Hospital, Basel, Switzerland
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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
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

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
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).
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
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)
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
No
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

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

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