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

Sponsor
University Hospital, Basel, Switzerland (Other)
Overall Status
Recruiting
CT.gov ID
NCT05174507
Collaborator
(none)
26
1
6
9
2.9

Study Details

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
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
Anticipated 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).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
Anticipated Study Start Date :
Jul 1, 2022
Anticipated Primary Completion Date :
Apr 1, 2023
Anticipated Study Completion Date :
Apr 1, 2023

Arms and Interventions

Arm Intervention/Treatment
Other: 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).

Other: 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).

Other: 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).

Other: 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).

Other: 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).

Other: 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 [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 [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) [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 [at baseline and 60 min after ingestion of the mixed meal]

    Change in proinsulin to insulin ratio in serum

  4. Change in inflammatory state [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 [at baseline and 60 min after ingestion of the mixed meal]

    Change in RNAseq in peripheral PBMC

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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

Site City State Country Postal Code
1 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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
University Hospital, Basel, Switzerland
ClinicalTrials.gov Identifier:
NCT05174507
Other Study ID Numbers:
  • 2020-01287; me20Donath
First Posted:
Dec 30, 2021
Last Update Posted:
Apr 20, 2022
Last Verified:
Apr 1, 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
Additional relevant MeSH terms:

Study Results

No Results Posted as of Apr 20, 2022