Trial Outcomes & Findings for Impact of Hypoglycaemia in Patients With Diabetes Mellitus Type 2 on Platelet Activation (NCT NCT03460899)

Last Updated: 2019-11-18

Results Overview

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)

Recruitment status

COMPLETED

Study phase

Target enrollment

14 participants

Primary outcome timeframe

Measurement during different levels of hypoglycaemia as well as 1 and 7 days after the clamp experiment

Results posted on

2019-11-18

Participant Flow

Recruitment period: Approximately 3 Months (End of February until beginning of May 2018) Recruitmet process: Subjects were recruited by using a local recruitment registry.

Participant milestones

Participant milestones
Measure	Clamp Arm 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 insuline (Actrapid) will be used to reach certain plasma glucose levels. Euglycaemic Clamp: 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) Hyperinsulinaemic/Hypoglycaemic Clamp: 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)
Euglycaemic Clamp STARTED	14
Euglycaemic Clamp COMPLETED	14
Euglycaemic Clamp NOT COMPLETED	0
Hyperinsulinaemic/Hypoglycaemic Clamp STARTED	14
Hyperinsulinaemic/Hypoglycaemic Clamp COMPLETED	14
Hyperinsulinaemic/Hypoglycaemic Clamp NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Clamp Arm n=14 Participants 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 insuline (Actrapid) will be used to reach certain plasma glucose levels. Euglycaemic Clamp: 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) Hyperinsulinaemic/Hypoglycaemic Clamp: 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)
Age, Continuous	55 years STANDARD_DEVIATION 7 • n=14 Participants
Sex: Female, Male Female	10 Participants n=14 Participants
Sex: Female, Male Male	4 Participants n=14 Participants
Body Mass Index (BMI)	28.9 kg/m² STANDARD_DEVIATION 3.3 • n=14 Participants
Weight	86.4 kg STANDARD_DEVIATION 15.1 • n=14 Participants
Systolic Blood Pressure (SBP)	133 mmHg STANDARD_DEVIATION 13 • n=14 Participants
Diastolic Blood Pressure (DBP)	83 mmHg STANDARD_DEVIATION 8 • n=14 Participants
Fasting plasma glucose	7.2 mmol/L STANDARD_DEVIATION 0.9 • n=14 Participants
Triglycerides	2.02 mmol/L STANDARD_DEVIATION 1.33 • n=14 Participants
Cholesterol	5.22 mmol/L STANDARD_DEVIATION 1.19 • n=14 Participants
High-density lipoprotein-cholesterol (HDL-C)	1.19 mmol/L STANDARD_DEVIATION 0.36 • n=14 Participants
Low-density lipoprotein-cholesterol (LDL-C)	3.13 mmol/L STANDARD_DEVIATION 1.01 • n=14 Participants
Diabetes duration	5 years STANDARD_DEVIATION 4 • n=14 Participants
Daily metformin dose	1336 mg STANDARD_DEVIATION 599 • n=14 Participants
HbA1c	51 mmol/mol STANDARD_DEVIATION 7 • n=14 Participants
Angiotensin-converting-enzyme inhibitors	4 Participants n=14 Participants
Angiotensin-II receptor antagonists	5 Participants n=14 Participants
Calcium antagonists	3 Participants n=14 Participants
Diuretics	1 Participants n=14 Participants
Statins	4 Participants n=14 Participants

PRIMARY outcome

Timeframe: Measurement during different levels of hypoglycaemia as well as 1 and 7 days after the clamp experiment

Outcome measures

Outcome measures
Measure	Clamp Arm n=14 Participants 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 insuline (Actrapid) will be used to reach certain plasma glucose levels. Euglycaemic Clamp: 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) Hyperinsulinaemic/Hypoglycaemic Clamp: 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)
Changes in Platelet Activation Marker Adenosin Diphosphate (%) Timepoint 0	63 percentage of ADP Standard Deviation 14.3
Changes in Platelet Activation Marker Adenosin Diphosphate (%) Timepoint 1	64.4 percentage of ADP Standard Deviation 16.7
Changes in Platelet Activation Marker Adenosin Diphosphate (%) Timepoint 2	64.4 percentage of ADP Standard Deviation 13.4
Changes in Platelet Activation Marker Adenosin Diphosphate (%) Timepoint 3	61.1 percentage of ADP Standard Deviation 15.1
Changes in Platelet Activation Marker Adenosin Diphosphate (%) Follow up 1	67.7 percentage of ADP Standard Deviation 11.3
Changes in Platelet Activation Marker Adenosin Diphosphate (%) Follow up 2	70.4 percentage of ADP Standard Deviation 7.3

SECONDARY outcome

Timeframe: Measurement during different levels of hypoglycaemia as well as 1 and 7 days after the clamp experiment

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)

Outcome measures

Outcome measures
Measure	Clamp Arm n=14 Participants 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 insuline (Actrapid) will be used to reach certain plasma glucose levels. Euglycaemic Clamp: 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) Hyperinsulinaemic/Hypoglycaemic Clamp: 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)
Quantification of Platelet Function and Activation PAC1CD62PCD63POS (%) Timepoint 0	0.023 percentage of PAC1CD62PCD63POS Standard Deviation 0.019
Quantification of Platelet Function and Activation PAC1CD62PCD63POS (%) Timepoint 1	0.027 percentage of PAC1CD62PCD63POS Standard Deviation 0.028
Quantification of Platelet Function and Activation PAC1CD62PCD63POS (%) Timepoint 2	0.032 percentage of PAC1CD62PCD63POS Standard Deviation 0.032
Quantification of Platelet Function and Activation PAC1CD62PCD63POS (%) Timepoint 3	0.031 percentage of PAC1CD62PCD63POS Standard Deviation 0.033
Quantification of Platelet Function and Activation PAC1CD62PCD63POS (%) Follow up 1	0.085 percentage of PAC1CD62PCD63POS Standard Deviation 0.071
Quantification of Platelet Function and Activation PAC1CD62PCD63POS (%) Follow up 2	0.094 percentage of PAC1CD62PCD63POS Standard Deviation 0.087

SECONDARY outcome

Timeframe: Measurement during different levels of hypoglycaemia as well as 1 and 7 days after the clamp experiment

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)

Outcome measures

Outcome measures
Measure	Clamp Arm n=14 Participants 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 insuline (Actrapid) will be used to reach certain plasma glucose levels. Euglycaemic Clamp: 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) Hyperinsulinaemic/Hypoglycaemic Clamp: 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)
Markers of Coagulation Plasminogen Activator Inhibitor-1 (ng/mL) Timepoint 0	14.14 ng/mL Standard Deviation 9.06
Markers of Coagulation Plasminogen Activator Inhibitor-1 (ng/mL) Timepoint 1	11.32 ng/mL Standard Deviation 7.69
Markers of Coagulation Plasminogen Activator Inhibitor-1 (ng/mL) Timepoint 2	12.08 ng/mL Standard Deviation 8.50
Markers of Coagulation Plasminogen Activator Inhibitor-1 (ng/mL) Timepoin 3	13.50 ng/mL Standard Deviation 9.87
Markers of Coagulation Plasminogen Activator Inhibitor-1 (ng/mL) Follow up 1	26.26 ng/mL Standard Deviation 15.14
Markers of Coagulation Plasminogen Activator Inhibitor-1 (ng/mL) Follow up 2	25.35 ng/mL Standard Deviation 14.38

SECONDARY outcome

Timeframe: Measurement during different levels of hypoglycaemia as well as 1 and 7 days after the clamp experiment

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)

Outcome measures

Outcome measures
Measure	Clamp Arm n=14 Participants 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 insuline (Actrapid) will be used to reach certain plasma glucose levels. Euglycaemic Clamp: 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) Hyperinsulinaemic/Hypoglycaemic Clamp: 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)
Changes in Coagulation Marker Fibrinogen (g/L) Timepoint 2	2.64 g/L Standard Deviation 0.45
Changes in Coagulation Marker Fibrinogen (g/L) Timepoint 0	2.49 g/L Standard Deviation 0.40
Changes in Coagulation Marker Fibrinogen (g/L) Timepoint 1	2.54 g/L Standard Deviation 0.43
Changes in Coagulation Marker Fibrinogen (g/L) Timepoint 3	2.49 g/L Standard Deviation 0.41
Changes in Coagulation Marker Fibrinogen (g/L) Follow up 1	2.90 g/L Standard Deviation 0.50
Changes in Coagulation Marker Fibrinogen (g/L) Follow up 2	2.93 g/L Standard Deviation 0.53

Adverse Events

Clamp Arm

Serious events: 1 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Clamp Arm n=14 participants at risk 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 insuline (Actrapid) will be used to reach certain plasma glucose levels. Euglycaemic Clamp: 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) Hyperinsulinaemic/Hypoglycaemic Clamp: 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)
Hepatobiliary disorders Abdominal pain	7.1% 1/14 • Number of events 1 • Each participant was assessed for Adverse Events from successful Screening until Visit 5 Minimum timeframe for AE assessment: 18 days Maximum timeframe for AE assessment: 42 days

Other adverse events

Adverse event data not reported

Additional Information

Assoc.-Prof. Harald Sourij, MD

Medical University of Graz

Phone: 0043 316 385

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place