Clinical trial NCT02881060: The Late Effects of Ethanol Intake on the Glucose Response to Subcutaneous Glucagon in Type 1 Diabetes
Official title: The Late Effects of Ethanol Intake on the Glucose Response to Subcutaneous Glucagon in Type 1 Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hypoglycemia
Diabetes Mellitus, Type 1
Keywords: Glucagon
Ethanol
Lead sponsor: Hvidovre University Hospital
Sponsor class: OTHER
Collaborators: name: Danish Diabetes Academy
name: University of Copenhagen
First posted: 2016-08-26
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: Objective: Because many people with type 1 diabetes drink ethanol and because glucagon is used to treat mild hypoglycaemia, it is essential to determine whether ethanol will impair the effectiveness of glucagon to increase glucose, which may impair the effectiveness of the dual hormone treatment in preventing hypoglycaemia.

The purpose of this study is to determine, whether ethanol influences the glucose response to subcutaneous glucagon during mild hypoglycaemia.

The investigators hypothesize that prior evening ethanol consumption does not reduce the effect of a glucagon bolus to raise plasma glucose compared with no prior ethanol consumption.

The study aims:

1. To determine the late effects of ethanol on the efficacy of subcutaneous glucagon to restore plasma glucose after an episode of mild hypoglycemia.
2. To determine the late effects of ethanol on the counter-regulatory hormones and hypoglycaemia awareness during mild hypoglycaemia

A double-blinded placebo-controlled study will be conducted. Participants will serve as their own controls. Eligible participants will after an informed consent complete two study visits, one with and one without ethanol consumption, in a random order. On each study visit, participants are induced a insulin induced hypoglycemia, seven-eight hours after a meal with or without ethanol. Once plasma glucose is below 3.9 mmol/l, a subcutaneous injection of 100 mcg glucagon is administered. Two hours later a second bolus is administered.


Eligibility criteria: Inclusion Criteria:

* Age 18 - 70 years
* T1D ≥ 3 year
* BMI 20-28 kg/m2
* CSII ≥ 1 year
* Caucasian origin
* Hypoglycaemia awareness (assessed by Gold, Clarke and Pedersen-Bjergaard methods)
* Use of carbohydrate counting and the insulin pump bolus calculator for all meals
* Ethanol exposure once within 1 year consisting of at least 4 drinks (1 drink contains 12 gram ethanol) within four hours

Exclusion Criteria:

* Allergy or intolerance to lactose or Glucagen®(Novo Nordisk, Bagsværd, DK)
* Allergy for ethanol or any food ingredients that will be used in the study.
* Impaired renal function (eGFR \< 60 ml/min/1.73m2)
* Liver disease with ALAT \> 2.5 times the upper limit of the reference interval
* Gastropareses (beat-beat variation \< 10 beats per min and/or orthostatic systolic blood pressure \> 20 mmHg)
* Insomnia, sleep apnoea or any troubles with sleeping that according to the investigator's assessment makes the individual unsuitable for study participation.
* Aldehyde dehydrogenase deficiency as determined by a screening questionnaire
* Unable to refrain from the consumption of ethanol at least 24 hours prior to study start
* History of drinking problems or alcoholism, regardless of whether active or in remission.
* Use of benzodiazepines or barbiturates or opiates or other central nervous system depressant drugs that could act synergistically with ethanol to lower the level of consciousness
* History of drug abuse
* Current participation in another diabetes-related clinical trial that, in the judgment of the principle investigator, will compromise the results of the study or the safety of the subject.
* Use of anti-diabetic medicine (other than insulin), corticosteroids or other drugs affecting glucose metabolism during the study period or within 30 days prior to study start
* Use of medications that are known to cause QT interval prolongation
* Presence of pheochromocytoma
* Other concomitant medical or psychological condition that according to the investigator's assessment makes the individual unsuitable for study participation
* Females who are pregnant, breast-feeding or intend to become pregnant or are not using adequate contraceptive methods.
* Females who have different basal insulin pattern depending on their menstrual cycle.
* Inability to understand the individual information and to give informed consent.

Primary outcomes:
measure: Increase in plasma glucose
timeFrame: 0-120 min after the first glucagon injection
Secondary outcomes:
measure: Peak plasma glucose
timeFrame: 0-240 min after the first glucagon injection
measure: Increase in plasma glucose
timeFrame: 0-120 min after the second glucagon injection
measure: Total AUC(0-120)
timeFrame: 0-240 min after the first glucagon injection
measure: PI-AUC(0-120)
timeFrame: 0-240 min after the first glucagon injection
measure: Tmax
timeFrame: 0-240 min after the first glucagon injection
measure: Time above 4.0mM
timeFrame: 0-240 min after the first glucagon injection
measure: Time above baseline
timeFrame: 0-240 min after the first glucagon injection
measure: Rescue rates
timeFrame: 0-240 min after the first glucagon injection
measure: Hyperglycemia rates
timeFrame: 0-240 min after the first glucagon injection
measure: Changes in plasma ketone bodies, measured as area under the curve
timeFrame: 0-240 min after the first glucagon injection
measure: Changes in plasma ketone bodies, measured as incremental peak
timeFrame: 0-240 min after the first glucagon injection
measure: Changes in plasma glucagon, measured as area under the curve
timeFrame: 0-240 min after the first glucagon injection
measure: Changes in plasma glucagon, measured as incremental peak
timeFrame: 0-240 min after the first glucagon injection
measure: Changes in insulin, measured as area under the curve
timeFrame: 0-240 min after the first glucagon injection
measure: Changes in insulin, measured as incremental peak
timeFrame: 0-240 min after the first glucagon injection
measure: Changes in growth hormones, measured as area under the curve
timeFrame: 0-240 min after the first glucagon injection
measure: Changes in growth hormones, measured as incremental peak
timeFrame: 0-240 min after the first glucagon injection
measure: Changes in serum corticole, measured as area under the curve
timeFrame: 0-240 min after the first glucagon injection
measure: Changes in serum corticole, measured as incremental peak
timeFrame: 0-240 min after the first glucagon injection
measure: Changes in plasma ethanol, measured as area under the curve
timeFrame: 0-240 min after the first glucagon injection
measure: Changes in plasma ethanol, measured as incremental peak
timeFrame: 0-240 min after the first glucagon injection
measure: Changes in free fatty acids, measured as area under the curve
timeFrame: 0-240 min after the first glucagon injection
measure: Changes in free fatty acids, measured as incremental peak
timeFrame: 0-240 min after the first glucagon injection
measure: Changes in triglycerides, measured as area under the curve
timeFrame: 0-240 min after the first glucagon injection
measure: Changes in triglycerides, measured as incremental peak
timeFrame: 0-240 min after the first glucagon injection
measure: Average in blood pressure
timeFrame: 0-240 min after the first glucagon injection
measure: Average heart rate
timeFrame: 0-240 min after the first glucagon injection
measure: Intensity of hypoglycemia
timeFrame: 0-240 min after the first glucagon injection
measure: Cognitive impairment
timeFrame: 0-240 min after the first glucagon injection
measure: Side effects
timeFrame: 0-240 min after the first glucagon injection
measure: Incidence of vomiting
timeFrame: 0-240 min after the first glucagon injection
measure: Meal induced glucose excursion
timeFrame: 0-3 hours after meal
measure: Meal induced hormonal changes
timeFrame: 0-3 hours after meal
measure: Nocturnal changes in plasma glucose
timeFrame: 0-6 hours after start of sleep
measure: Nocturnal changes in corticol
timeFrame: 0-6 hours after start of sleep
measure: Nocturnal changes in growth hormone
timeFrame: 0-6 hours after start of sleep
measure: Nocturnal changes in ketones
timeFrame: 0-6 hours after start of sleep
measure: Nocturnal changes in ethanol
timeFrame: 0-6 hours after start of sleep
measure: Nocturnal changes in glucagon
timeFrame: 0-6 hours after start of sleep
measure: Difference between the first second glucagon injection and between both study visits in peak change plasma glucose
timeFrame: 0-240 min after the first glucagon injection
measure: Difference between glucagon injections on both study visits in positive incremental area under the glucose curve from 0-120 minutes
timeFrame: 0-240 min after the first glucagon injection
measure: Difference between glucagon injections on both study visits in total area under the glucose curve from 0-120 minutes
timeFrame: 0-240 min after the first glucagon injection
measure: Difference between glucagon injections on both study visits in time-to-peak glucose value
timeFrame: 0-240 min after the first glucagon injection
measure: Difference between glucagon injections on both study visits in duration of glucose above 4.0 mmol/l after first and second glucagon injection
timeFrame: 0-240 min after the first glucagon injection
measure: Difference between glucagon injections on both study visits in duration of glucose above baseline after first and second glucagon injection
timeFrame: 0-240 min after the first glucagon injection
measure: Difference in glucose sensor data on study night with alcohol vs. study night without alcohol - Mean absolute relative difference (MARD) values of glucose sensors compared with YSI from 7 PM- 8 AM.
timeFrame: 0-10 hours after meal
measure: Difference in glucose sensor data on study night with alcohol vs. study night without alcohol - Precision absolute relative difference (PARD) 120 min before and 120 after each glucagon injection.
timeFrame: 0-10 hours after meal
measure: Difference in glucose sensor data on study night with alcohol vs. study night without alcohol - MARD values between glucose sensors 0-120 minutes after each glucagon injection.
timeFrame: 0-10 hours after meal
measure: Difference in glucose sensor data within 2 days after study night with alcohol vs. study night without alcohol - Time in range (glucose sensor value =4.0-10.0mmol/l)
timeFrame: 0-2 days after the first glucagon injection
measure: Difference in glucose sensor data within 2 days after study night with alcohol vs. study night without alcohol - Time in hypoglycaemia (glucose sensor value < 4.0 mmol/l)
timeFrame: 0-2 days after the first glucagon injection
measure: Difference in glucose sensor data within 2 days after study night with alcohol vs. study night without alcohol - Time in hyperglycaemia (glucose sensor value >10.0mmol/l)
timeFrame: 0-2 days after the first glucagon injection
measure: Difference in glucose sensor data within 2 days after study night with alcohol vs. study night without alcohol - Number of hypoglycaemia episodes (glucose sensor value < 4.0 mmol/l)
timeFrame: 0-2 days after the first glucagon injection
measure: Difference in glucose sensor data between the study period with and without alcohol - Clarke- Error Grid analysis for both sensors compared with YSI during study visit
timeFrame: -2 to 4 days after study visits
measure: Difference in glucose sensor data between the study period with and without alcohol - PARD values from day 1-7
timeFrame: -2 to 4 days after study visits
measure: Difference in glucose sensor data between the study period with and without alcohol - PARD values <4.0 mmol/L from day 1-7
timeFrame: -2 to 4 days after study visits
measure: Difference in glucose sensor data between the study period with and without alcohol - PARD values 4.0-10.0 mmol/L from day 1-7
timeFrame: -2 to 4 days after study visits
measure: Difference in glucose sensor data between the study period with and without alcohol PARD values >10.0 mmol/L from day 1-7
timeFrame: -2 to 4 days after study visits
measure: Difference in glucose sensor data between the study period with and without alcohol - Number of hypoglycaemia episodes (glucose sensor value < 4.0 mmol/l)
timeFrame: -2 to 4 days after study visits
Other outcomes:
Locations:
city: Hvidovre
country: Denmark
facility: Hvidovre University Hospital
Study officials:
affiliation: Hvidovre University Hospital
name: Ajenthen Ranjan, MD
role: PRINCIPAL_INVESTIGATOR
References: