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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT02315300
Other study ID # 14-030
Secondary ID
Status Completed
Phase N/A
First received December 1, 2014
Last updated June 14, 2016
Start date November 2014
Est. completion date May 2016

Study information

Verified date May 2016
Source RWTH Aachen University
Contact n/a
Is FDA regulated No
Health authority Germany: Ethics Committee
Study type Interventional

Clinical Trial Summary

Patients with insulin-dependent diabetes mellitus (DM) and chronic kidney disease (CKD) exhibit an excessive risk for cardiac arrhythmias, in particular sudden cardiac death (SCD). Hypoglycemia is a frequent problem in insulin-treated patients, especially in those with CKD, and various studies have shown that hypoglycemic episodes are strong predictors of cardiovascular mortality in both type 1 and type 2 diabetic patients. Experimental data and small clinical studies link hypoglycemia with ECG changes and SCD, but little is known about the direct association of hypoglycemic events and/or rapid swings in blood glucose with arrhythmias in this high risk population. Ideally, an algorithm should help to identify patients at risk for hypoglycemia-associated arrhythmias and SCD, but hitherto systematic analyses of blood glucose values and 12-channel ECGs are lacking in these patients.


Description:

Patients with diabetes mellitus (DM), especially those with a long duration of diabetes, insulin treatment and chronic kidney disease (CKD) are vulnerable patients exhibiting a high risk for cardiac arrhythmias and sudden cardiac death (SCD) [1, 2]. Various factors such as the presence of coronary heart disease, diabetic cardiomyopathy as well autonomic neuropathy are underlying pathologies associated with the development of potentially fatal arrhythmias in these patients while hypoglycemic events are considered to directly trigger these arrhythmias. In 1991, Tattersall and colleagues were the first to describe the phenomenon of sudden nocturnal death in young patients with type 1 diabetes and reported that many of these patients had recent nocturnal hypoglycemia episodes [3]. Therefore it has been postulated that severe hypoglycemia may lead to cardiac arrhythmias, later summarized as the "dead in bed" syndrome [4]. In addition, recent data from large cardiovascular outcome trials in patients with type 2 diabetes suggest that severe hypoglycemia is associated with an increased risk of cardiovascular events and cardiovascular related death [5]. Moreover, CKD markedly increases the risk for hypoglycemia and even a moderate impairment of kidney function (eGFR < 60 ml/min) is associated with a significant increase in SCD [6].

Various pathophysiological mechanisms may contribute to the increased cardiovascular mortality after hypoglycemia including hypoglycemia-induced release of catecholamines, pro-arrhythmogenic ECG alterations, inflammatory changes, direct effects in the vascular wall such as impaired endothelial function as well as abnormalities in coagulation and platelet function [7, 8].

Morphological and functional alterations of the heart occurring in CKD further contribute to these mechanisms. Several small studies performing simultaneous glucose monitoring and ECG recordings addressed the question whether spontaneous hypoglycemic events in patients with diabetes directly lead to cardiac arrhythmias [9-11], but hitherto no clear association has been found. These studies were limited by a short duration of glucose and ECG monitoring and by the fact that only 3 lead Holter-ECGs were used, thus not allowing the assessment of more sophisticated ECG abnormalities such as QT dispersion, T-wave alternans, or late potentials. Therefore no clear data exist to predict arrhythmias and SCD and its relation to hypoglycemia in patients with diabetes. Ideally, a SCD risk score could identify and characterize high-risk patients but to date little is known about hypoglycemia-associated ECG markers for the identification of patients at risk for arrhythmias and SCD.

In the general population, various ECG risk markers for SCD have been identified such as heart rate, cardiac rhythm abnormalities, AV block, QT length, QT dispersion, heart-rate variability (HRV), T-wave alternans, late potentials, as well as left- (LBBB) or right-bundle branch block (RBBB) (reviewed in [12]). In patients with diabetes hypoglycemia, diabetic cardiomyopathy, as well as the presence of autonomic neuropathy may lead to such ECG abnormalities. Under experimental conditions some of these ECG surrogate parameters have been studied in patients with diabetes in association with hypoglycemia. As such, clamp studies revealed that hypoglycemia prolongs the QT interval and increases QT dispersion (difference between the longest and shortest QT interval in a 12-lead Holter ECG) [10, 13], which in conjunction with an increased release of catecholamines during hypoglycemia may promote ventricular arrhythmias. In addition, controlled hypoglycemia in patients with type 1 diabetes alters cardiac repolarization by changing the T-wave amplitude [11]. Sparse data exist on the effect of spontaneous hypoglycemic episodes and changes in ECG parameters with only a small study in patients with type 1 diabetes demonstrating that nocturnal hypoglycemia is associated with a decrease in the low-frequency component of heart rate variability [14]. To date, more sophisticated markers such as QT dispersion (difference between the longest and shortest QT interval in a 12-lead Holter ECG), late potentials, or T-wave alternans (periodic beat-to-beat variation in the morphology, amplitude or timing of the T waves in ECGs) were not examined in a "real-life setting", most likely because these markers require a 12 lead ECG registration of longer duration.

However, for the establishment of a risk algorithm for the prediction of hypoglycemia-associated arrhythmias it is mandatory to perform long duration simultaneous glucose monitoring and 12 lead ECG registration to capture these ECG risk markers for SCD.


Recruitment information / eligibility

Status Completed
Enrollment 62
Est. completion date May 2016
Est. primary completion date May 2016
Accepts healthy volunteers No
Gender Both
Age group 18 Years and older
Eligibility Inclusion Criteria:

1. Insulin-treated diabetes mellitus (type 1 or 2)

2. CKD with eGFR < 40 ml/min (determined using the MDRD formula)

3. Stable anti-diabetic and cardiac medication prior to inclusion

4. Male or female aged > 18 years

5. Written informed consent prior to study participation

Exclusion Criteria:

1. Pregnancy or women without sufficient contraception, adapted specifically to amenorrhoic hemodialysis patients

2. Life expectancy below 6 months

3. Participation in another clinical trial within the previous 2 months

4. History of any other illness, which, in the opinion of the investigator, might pose an unacceptable risk when administering study medication

5. Any current or past medical condition and/or required medication to treat a condition that could affect the evaluation of the study

6. Alcohol or drug abuse

7. Patient has been committed to an institution by legal or regulatory order

8. Expected non-compliance

9. Patients unwilling or unable to give informed consent, or with limited ability to comply with instructions for this study

10. Participation in a parallel interventional clinical trial

Study Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention


Intervention

Device:
medilog® DARWIN FD12

Continuous Glucose Monitoring


Locations

Country Name City State
Germany Medizinische Klinik I Aachen North Rhine Westphalia

Sponsors (1)

Lead Sponsor Collaborator
RWTH Aachen University

Country where clinical trial is conducted

Germany, 

Outcome

Type Measure Description Time frame Safety issue
Primary heart rate Changes of ECG parameters during 7 days long term ECG not a single event or change of the parameter will be assessed after 18 months patterns of this parameter during a 7 days long-term ECG will screened for potential correlation with hypoglycaemic events No
Primary cardiac rhythm abnormalities Changes of ECG parameters during 7 days long term ECG not a single event or change of the parameter will be assessed after 18 months patterns of this parameter during a 7 days long-term ECG will screened for potential correlation with hypoglycaemic events No
Primary AV block Changes of ECG parameters during 7 days long term ECG not a single event or change of the parameter will be assessed after 18 months patterns of this parameter during a 7 days long-term ECG will screened for potential correlation with hypoglycaemic events No
Primary QT length Changes of ECG parameters during 7 days long term ECG not a single event or change of the parameter will be assessed after 18 months patterns of this parameter during a 7 days long-term ECG will screened for potential correlation with hypoglycaemic events No
Primary QT dispersion Changes of ECG parameters during 7 days long term ECG not a single event or change of the parameter will be assessed after 18 months patterns of this parameter during a 7 days long-term ECG will screened for potential correlation with hypoglycaemic events No
Primary heart-rate variability Changes of ECG parameters during 7 days long term ECG not a single event or change of the parameter will be assessed after 18 months patterns of this parameter during a 7 days long-term ECG will screened for potential correlation with hypoglycaemic events No
Primary T-wave alternans Changes of ECG parameters during 7 days long term ECG not a single event or change of the parameter will be assessed after 18 months patterns of this parameter during a 7 days long-term ECG will screened for potential correlation with hypoglycaemic events No
Primary late potentials Changes of ECG parameters during 7 days long term ECG not a single event or change of the parameter will be assessed after 18 months patterns of this parameter during a 7 days long-term ECG will screened for potential correlation with hypoglycaemic events No
Primary left or right bündle branch blocks Changes of ECG parameters during 7 days long term ECG not a single event or change of the parameter will be assessed after 18 months patterns of this parameter during a 7 days long-term ECG will screened for potential correlation with hypoglycaemic events No
Primary Glucose Levels < 65 mg/dl Changes of ECG parameters during 7 days long term ECG not a single event or change of the parameter will be assessed after 18 months patterns of this parameter during a 7 days long-term ECG will screened for potential correlation with hypoglycaemic events No
Secondary Association anf temporal coincidence of glycemic variability as assessed by changes in glucose excursion as well as mean amplitude of glycemic excursion (MAGE) occurence of clinically relevant hypoglycemia
occurence of symptomatic hypotension
occurence of hypertensive urgency & emergency
18 months No
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