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Impact of Hypoglycaemia in Patients With Diabetes Mellitus Type 2 on Platelet Activation (Diaplate)

Primary Purpose

Diabetes Mellitus With Hypoglycemia, Diabetes Mellitus, Type 2, Hypoglycemia

Status
Completed
Phase
Not Applicable
Locations
Austria
Study Type
Interventional
Intervention
Euglycaemic Clamp
Hyperinsulinaemic/Hypoglycaemic Clamp
Sponsored by
Medical University of Graz
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Diabetes Mellitus With Hypoglycemia focused on measuring Hypoglycaemia, Platelet activity, Type 2 diabetes mellitus

Eligibility Criteria

18 Years - 64 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Male or female aged 18-64 years (both inclusive) at the time of signing informed consent
  • Subjects diagnosed with type 2 diabetes (diagnosed regarding world health organization [WHO] criteria) and on stable treatment for a period of 90 days prior to screening with metformin as monotherapy or diet only. Stable is defined as unchanged dose
  • Body mass index (BMI) between 20.0 and 35.0 kg/m2 (both inclusive)
  • HbA1c between 43 and 64 mmol/mol (6.0% - 8.0%) (both inclusive)
  • No use of platelet inhibiting therapy (e.g. aspirin, clopidogrel, ticagrelor, prasugrel)

Exclusion Criteria:

  • All other forms of diabetes (type 1 diabetes, gestational diabetes) than type 2 diabetes mellitus
  • Treatment with any glucose lowering agent(s) other than metformin in a period of 60 days before screening. An exception is short-term treatment (≤ 7 days in total) with insulin due to intercurrent illness
  • Impaired hypoglycaemic awareness determined at the discretion of the investigator
  • Medical history of arrhythmia as atrial fibrillation, atrial flutter, atrioventricular dissociation disorders or ventricular arrhythmias
  • Previously known cardiovascular disease and / or past cardiovascular events, or past episodes of a congestive heart failure syndrome (NYHA II - NYHA IV)
  • Severe hypoglycaemic event requiring third party help in the last 6 months
  • Known allergy to human insulin or dextrose solution
  • Clinically significant abnormal haematology, biochemistry, lipids, hormones, coagulation or urinalysis
  • Uncontrolled hypertension defined as resting blood pressure at screening (after resting for 5 min, measured in sitting position) outside the range of 90-160 mmHg for systolic or 50-100 mmHg for diastolic
  • Chronic liver failure with severe liver dysfunction as assessed by the investigator
  • Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) levels > 3x upper Limit of normal (ULN)
  • estimated Glomerular Filtration Rate (eGFR) <45 ml/min/1,73 m2
  • Any musculoskeletal disorders holding back from stay in bed in a lying position during the time of the clamp experiments
  • Treatment with beta-blockers, antiarrhythmic agents or neuroleptic drugs
  • Active smoker or intake of illicit substances
  • Regular intake of nonsteroidal anti-inflammatory drugs (NSAIDs)
  • Any mental disorders or psychiatric conditions which may interfere with understanding or conduction of study related procedures
  • Females of child bearing potential without adequate contraceptive methods (i.e. sterilisation, intrauterine device, vasectomised partner; or medical history of hysterectomy)

Sites / Locations

  • Medical University of Graz, Department for Internal Medicine

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Clamp Arm

Arm Description

All 14 subjects will undergo an Euglycaemic Clamp at Visit 2 as well as a Hyperinsulinaemic/Hypoglycaemic Clamp at Visit 3 with the Intervention of reaching certain plasma glucose levels for blood sampling regarding platelet activity parameters. Infusion of Dextrose and human soluble insulin (Actrapid) will be used to reach certain plasma glucose levels.

Outcomes

Primary Outcome Measures

Changes in Platelet Activation Marker Adenosin Diphosphate (%)
Changes in platelet activation measured by light transmittance aggregometry (LTA) on a Chronolog 700 Lumi-Aggregometer based on Adenosin Diphosphate (ADP %) activation. Visit 3, Hyperinsulinaemic/Hypoglycaemic clamp Experiment: Timepoint 0 (Baseline = Plasma Glucose 100mg/dL [5.5mmol/L]) Timepoint 1 (Hypoglycaemia Plateau 1 = Plasma Glucose 63mg/dL [3.5mmol/L]) Timepoint 2 (Hypoglycaemia Plateau 2 = Plasma Glucose 45mg/dL [2.5mmol/L]) Timepoint 3 (Recovery = Plasma Glucose 100mg/dL [5.5mmol/L] Follow up 1 (1 Day after the Clamp Experiment) Follow up 2 (7 +/- 1 day after the Clamp Experiment)

Secondary Outcome Measures

Quantification of Platelet Function and Activation PAC1CD62PCD63POS (%)
Quantification of platelet activation markers by flow cytometry in unstimulated blood samples (CD62P, CD63 and binding of PAC-1) using a BD LSRFortessa flow cytometer. Hyperinsulinaemic/Hypoglycaemic clamp Experiment: Timepoint 0 (Baseline = Plasma Glucose 100mg/dL [5.5mmol/L]) Timepoint 1 (Hypoglycaemia Plateau 1 = Plasma Glucose 63mg/dL [3.5mmol/L]) Timepoint 2 (Hypoglycaemia Plateau 2 = Plasma Glucose 45mg/dL [2.5mmol/L]) Timepoint 3 (Recovery = Plasma Glucose 100mg/dL [5.5mmol/L] Follow up 1 (1 Day after the Clamp Experiment) Follow up 2 (7 +/- 1 day after the Clamp Experiment)
Markers of Coagulation Plasminogen Activator Inhibitor-1 (ng/mL)
Effects on coagulation parameter plasminogen activator Inhibitor-1 (PAI-1) measured by Enzyme-linked immunosorbent assays. Visit 3, Hyperinsulinaemic/Hypoglycaemic clamp Experiment: Timepoint 0 (Baseline = PG 100mg/dL [5.5mmol/L]) Timepoint 1 (Hypoglycaemia Plateau 1 = PG 63mg/dL [3.5mmol/L]) Timepoint 2 (Hypoglycaemia Plateau 2 = PG 45mg/dL [2.5mmol/L]) Timepoint 3 (Recovery = PG 100mg/dL [5.5mmol/L] Follow up 1 (1 Day after the Clamp Experiment) Follow up 2 (7 +/- 1 day after the Clamp Experiment)
Changes in Coagulation Marker Fibrinogen (g/L)
Changes in coagulation marker Fibrinogen, measured on a Behring Coagulation System BCS XP Analyzer. Visit 3, Hyperinsulinaemic/Hypoglycaemic clamp Experiment: Timepoint 0 (Baseline = PG 100mg/dL [5.5mmol/L]) Timepoint 1 (Hypoglycaemia Plateau 1 = PG 63mg/dL [3.5mmol/L]) Timepoint 2 (Hypoglycaemia Plateau 2 = PG 45mg/dL [2.5mmol/L]) Timepoint 3 (Recovery = PG 100mg/dL [5.5mmol/L] Follow up 1 (1 Day after the Clamp Experiment) Follow up 2 (7 +/- 1 day after the Clamp Experiment)

Full Information

First Posted
February 22, 2018
Last Updated
November 15, 2019
Sponsor
Medical University of Graz
Collaborators
Merck Sharp & Dohme LLC
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1. Study Identification

Unique Protocol Identification Number
NCT03460899
Brief Title
Impact of Hypoglycaemia in Patients With Diabetes Mellitus Type 2 on Platelet Activation
Acronym
Diaplate
Official Title
Impact of Hypoglycaemia in Patients With Diabetes Mellitus Type 2 on Platelet Activation
Study Type
Interventional

2. Study Status

Record Verification Date
November 2019
Overall Recruitment Status
Completed
Study Start Date
February 12, 2018 (Actual)
Primary Completion Date
June 11, 2018 (Actual)
Study Completion Date
June 11, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Medical University of Graz
Collaborators
Merck Sharp & Dohme LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This experimental study is planned to investigate the impact of hypoglycaemia on platelet activation parameters (PAP) during a hyperinsulinaemic hypoglycaemic clamp study. The hypothesis that hypoglycaemia in patients with Diabetes Mellitus, Type 2 (T2DM) leads to increased platelet activation will be tested.
Detailed Description
Increased platelet activation is significantly involved in the pathophysiology of micro- and macrovascular diabetic complications. Previously performed studies suggested platelet activation in both, hyper- and hypoglycaemic states, leading to a potentially increased risk for thromboembolic complications. Hypoglycaemia, in particular severe hypoglycaemic episodes, has been associated with increased cardiovascular or overall mortality in previous studies. Potential mechanisms include arrhythmias or increased risk for thromboembolism, based on platelet activation and/or hypercoagulability. The aim of this experimental study is to investigate the impact of hypoglycaemia on platelet activation parameters (PAP) during a hyperinsulinaemic hypoglycaemic clamp study. We hypothesize that Hypoglycaemia in patients with T2DM leads to increased platelet activation. The primary objective is to investigate platelet activation during different levels of hypoglycaemia induced by a stepwise hyperinsulinaemic, hypoglycemic clamp experiment in patients with T2DM. Active study duration will be 5 days for each study participant. 14 subjects with T2DM without history of cardiovascular events or manifest atherosclerosis will be enrolled. During this monocentric, single arm, open, mechanistic trial platelet activation and recovery at one week after the clamp experiment, changes of pro-atherothrombotic markers during the hypoglycaemic clamp as well as counter regulatory hormone response during the clamp will be investigated.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetes Mellitus With Hypoglycemia, Diabetes Mellitus, Type 2, Hypoglycemia, Hypoglycemic Episode
Keywords
Hypoglycaemia, Platelet activity, Type 2 diabetes mellitus

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
14 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Clamp Arm
Arm Type
Experimental
Arm Description
All 14 subjects will undergo an Euglycaemic Clamp at Visit 2 as well as a Hyperinsulinaemic/Hypoglycaemic Clamp at Visit 3 with the Intervention of reaching certain plasma glucose levels for blood sampling regarding platelet activity parameters. Infusion of Dextrose and human soluble insulin (Actrapid) will be used to reach certain plasma glucose levels.
Intervention Type
Other
Intervention Name(s)
Euglycaemic Clamp
Intervention Description
All 14 subjects will undergo an euglycaemic clamp at Visit 2 with a plasma Glucose target of 5.5 mmol/L +/- 10% (4 timepoints for platelet activity parameter blood sampling)
Intervention Type
Other
Intervention Name(s)
Hyperinsulinaemic/Hypoglycaemic Clamp
Intervention Description
All 14 subjects will undergo a hypoglycaemic/hyperinsulinaemic clamp at Visit 3 with 4 timepoints for platelet activity Parameter blood sampling 30 minutes after reaching certain plasma glucose plateaus (5.5 mmol/L; 3.5 mmol/L; 2.5 mmol/L; after recovery again at 5.5 mmol/L)
Primary Outcome Measure Information:
Title
Changes in Platelet Activation Marker Adenosin Diphosphate (%)
Description
Changes in platelet activation measured by light transmittance aggregometry (LTA) on a Chronolog 700 Lumi-Aggregometer based on Adenosin Diphosphate (ADP %) activation. Visit 3, Hyperinsulinaemic/Hypoglycaemic clamp Experiment: Timepoint 0 (Baseline = Plasma Glucose 100mg/dL [5.5mmol/L]) Timepoint 1 (Hypoglycaemia Plateau 1 = Plasma Glucose 63mg/dL [3.5mmol/L]) Timepoint 2 (Hypoglycaemia Plateau 2 = Plasma Glucose 45mg/dL [2.5mmol/L]) Timepoint 3 (Recovery = Plasma Glucose 100mg/dL [5.5mmol/L] Follow up 1 (1 Day after the Clamp Experiment) Follow up 2 (7 +/- 1 day after the Clamp Experiment)
Time Frame
Measurement during different levels of hypoglycaemia as well as 1 and 7 days after the clamp experiment
Secondary Outcome Measure Information:
Title
Quantification of Platelet Function and Activation PAC1CD62PCD63POS (%)
Description
Quantification of platelet activation markers by flow cytometry in unstimulated blood samples (CD62P, CD63 and binding of PAC-1) using a BD LSRFortessa flow cytometer. Hyperinsulinaemic/Hypoglycaemic clamp Experiment: Timepoint 0 (Baseline = Plasma Glucose 100mg/dL [5.5mmol/L]) Timepoint 1 (Hypoglycaemia Plateau 1 = Plasma Glucose 63mg/dL [3.5mmol/L]) Timepoint 2 (Hypoglycaemia Plateau 2 = Plasma Glucose 45mg/dL [2.5mmol/L]) Timepoint 3 (Recovery = Plasma Glucose 100mg/dL [5.5mmol/L] Follow up 1 (1 Day after the Clamp Experiment) Follow up 2 (7 +/- 1 day after the Clamp Experiment)
Time Frame
Measurement during different levels of hypoglycaemia as well as 1 and 7 days after the clamp experiment
Title
Markers of Coagulation Plasminogen Activator Inhibitor-1 (ng/mL)
Description
Effects on coagulation parameter plasminogen activator Inhibitor-1 (PAI-1) measured by Enzyme-linked immunosorbent assays. Visit 3, Hyperinsulinaemic/Hypoglycaemic clamp Experiment: Timepoint 0 (Baseline = PG 100mg/dL [5.5mmol/L]) Timepoint 1 (Hypoglycaemia Plateau 1 = PG 63mg/dL [3.5mmol/L]) Timepoint 2 (Hypoglycaemia Plateau 2 = PG 45mg/dL [2.5mmol/L]) Timepoint 3 (Recovery = PG 100mg/dL [5.5mmol/L] Follow up 1 (1 Day after the Clamp Experiment) Follow up 2 (7 +/- 1 day after the Clamp Experiment)
Time Frame
Measurement during different levels of hypoglycaemia as well as 1 and 7 days after the clamp experiment
Title
Changes in Coagulation Marker Fibrinogen (g/L)
Description
Changes in coagulation marker Fibrinogen, measured on a Behring Coagulation System BCS XP Analyzer. Visit 3, Hyperinsulinaemic/Hypoglycaemic clamp Experiment: Timepoint 0 (Baseline = PG 100mg/dL [5.5mmol/L]) Timepoint 1 (Hypoglycaemia Plateau 1 = PG 63mg/dL [3.5mmol/L]) Timepoint 2 (Hypoglycaemia Plateau 2 = PG 45mg/dL [2.5mmol/L]) Timepoint 3 (Recovery = PG 100mg/dL [5.5mmol/L] Follow up 1 (1 Day after the Clamp Experiment) Follow up 2 (7 +/- 1 day after the Clamp Experiment)
Time Frame
Measurement during different levels of hypoglycaemia as well as 1 and 7 days after the clamp experiment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
64 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male or female aged 18-64 years (both inclusive) at the time of signing informed consent Subjects diagnosed with type 2 diabetes (diagnosed regarding world health organization [WHO] criteria) and on stable treatment for a period of 90 days prior to screening with metformin as monotherapy or diet only. Stable is defined as unchanged dose Body mass index (BMI) between 20.0 and 35.0 kg/m2 (both inclusive) HbA1c between 43 and 64 mmol/mol (6.0% - 8.0%) (both inclusive) No use of platelet inhibiting therapy (e.g. aspirin, clopidogrel, ticagrelor, prasugrel) Exclusion Criteria: All other forms of diabetes (type 1 diabetes, gestational diabetes) than type 2 diabetes mellitus Treatment with any glucose lowering agent(s) other than metformin in a period of 60 days before screening. An exception is short-term treatment (≤ 7 days in total) with insulin due to intercurrent illness Impaired hypoglycaemic awareness determined at the discretion of the investigator Medical history of arrhythmia as atrial fibrillation, atrial flutter, atrioventricular dissociation disorders or ventricular arrhythmias Previously known cardiovascular disease and / or past cardiovascular events, or past episodes of a congestive heart failure syndrome (NYHA II - NYHA IV) Severe hypoglycaemic event requiring third party help in the last 6 months Known allergy to human insulin or dextrose solution Clinically significant abnormal haematology, biochemistry, lipids, hormones, coagulation or urinalysis Uncontrolled hypertension defined as resting blood pressure at screening (after resting for 5 min, measured in sitting position) outside the range of 90-160 mmHg for systolic or 50-100 mmHg for diastolic Chronic liver failure with severe liver dysfunction as assessed by the investigator Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) levels > 3x upper Limit of normal (ULN) estimated Glomerular Filtration Rate (eGFR) <45 ml/min/1,73 m2 Any musculoskeletal disorders holding back from stay in bed in a lying position during the time of the clamp experiments Treatment with beta-blockers, antiarrhythmic agents or neuroleptic drugs Active smoker or intake of illicit substances Regular intake of nonsteroidal anti-inflammatory drugs (NSAIDs) Any mental disorders or psychiatric conditions which may interfere with understanding or conduction of study related procedures Females of child bearing potential without adequate contraceptive methods (i.e. sterilisation, intrauterine device, vasectomised partner; or medical history of hysterectomy)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Harald Sourij
Organizational Affiliation
Medical University of Graz, Division of Endocrinology and Diabetology
Official's Role
Principal Investigator
Facility Information:
Facility Name
Medical University of Graz, Department for Internal Medicine
City
Graz
ZIP/Postal Code
8036
Country
Austria

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
35596173
Citation
Eyileten C, Wicik Z, Keshwani D, Aziz F, Aberer F, Pferschy PN, Tripolt NJ, Sourij C, Prietl B, Pruller F, von Lewinski D, De Rosa S, Siller-Matula JM, Postula M, Sourij H. Alteration of circulating platelet-related and diabetes-related microRNAs in individuals with type 2 diabetes mellitus: a stepwise hypoglycaemic clamp study. Cardiovasc Diabetol. 2022 May 20;21(1):79. doi: 10.1186/s12933-022-01517-5.
Results Reference
derived

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Impact of Hypoglycaemia in Patients With Diabetes Mellitus Type 2 on Platelet Activation

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