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Glucagon's Cardiovascular Effects With and Without Beta-blocker-induced Cardioinhibition (GLUCAGON)

Primary Purpose

Drug Overdose, Overdose of Beta-adrenergic Blocking Drug

Status
Completed
Phase
Phase 4
Locations
Denmark
Study Type
Interventional
Intervention
Glucagon
Esmolol
Physiologic saline - glucagon dummy
Physiologic saline - esmolol dummy
Sponsored by
University Hospital Bispebjerg and Frederiksberg
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Drug Overdose focused on measuring Glucagon, Beta-adrenergic antagonist, poisoning

Eligibility Criteria

18 Years - 40 Years (Adult)MaleAccepts Healthy Volunteers

Inclusion Criteria:

  • Healthy male determined by investigator, based upon physical examination, medical history, ECG, vital signs and laboratory results
  • Body mass index (BMI) ≥ 18.5 and ≤ 29.9 kg/m2 and body weight between 50 and 100 kg, inclusive, at screening visit.

Exclusion Criteria:

  • Abnormal blood levels of sodium, potassium, creatinine, alanine transaminase (ALT), alkaline phosphatase, albumin, bilirubin, hemoglobin, HbA1c, cholesterol fractions.
  • Bradycardia (<45 beats per minute)
  • Hypotension (systolic blood pressure < 100 mmHg)
  • Second or third degree atrioventricular conduction delay
  • Sick sinus syndrome
  • Any heart disease or hypertension
  • Pheochromocytoma
  • Allergy to any active or inactive ingredient contained in investigatory medicines or tools.
  • Raynaud's syndrome
  • Prinzmetal's angina
  • Diabetes
  • Pulmonary disease
  • Pheochromocytoma
  • Any contraindication against investigatory medicines or tools.

Sites / Locations

  • University Hospital Bispebjerg

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Esmolol-placebo+glucagon 1 placebo (A)

Esmolol+glucagon 1 placebo (B)

Esmolol+glucagon 1 (C)

Esmolol-placebo+glucagon 2 (D)

Esmolol-placebo+glucagon 1 (E)

Arm Description

Physiologic saline - esmolol dummy (10 mg esmolol/ml) is administered as a loading dose at baseline (time= -15 minutes) (corresponding to 0.125 ml/kg/min of saline). Continuous infusion (0.05-0.075 ml/kg/min) of saline is then administered until T=30 minutes. + Physiologic saline - glucagon dummy bolus 50 ml at time=0.

Esmolol intravenous solution (10 mg/ml esmolol hydrochloride) is administered as a loading dose (1.25 mg/kg/min esmolol) at baseline (time= -15 minutes). Continuous infusion (500-750 micrograms/kg/min) of esmolol/placebo is then administered until T=30 minutes. + Physiologic saline - glucagon dummy bolus (50 ml) at time=0.

Esmolol intravenous solution (10 mg/ml esmolol hydrochloride) is administered as a loading dose (1.25 mg/kg/min esmolol) at baseline (time= -15 minutes). Continuous infusion (500-750 micrograms/kg/min) of esmolol/placebo is then administered until T=30 minutes. +Glukagon 1 (50 μg/kg bolus - over 1-3 min from time=0 min in 50 ml isotonic fluid)

Physiologic saline - esmolol dummy (10 mg esmolol/ml) is administered as a loading dose at baseline (time= -15 minutes) (corresponding to 0.125 ml/kg/min of saline). Continuous infusion (0.05-0.075 ml/kg/min) of saline is then administered until T=30 minutes. +Glukagon 2 (50 μg/kg bolus - over 30 min in 50 ml isotonic fluid from time=0 min)

Physiologic saline - esmolol dummy (10 mg esmolol/ml) is administered as a loading dose at baseline (time= -15 minutes) (corresponding to 0.125 ml/kg/min of saline). Continuous infusion (0.05-0.075 ml/kg/min) of saline is then administered until T=30 minutes. + Glukagon 1 (50 μg/kg bolus - over 1-3 min from time=0 min in 50 ml isotonic fluid)

Outcomes

Primary Outcome Measures

Heart rates on the esmolol+glucagon-day compared to the esmolol+placebo-day (2 minute average)
Arterial catheter connected to a pressure transducer records heart rate (beats per minute).

Secondary Outcome Measures

Change in heart rate from baseline compared between study days.
Arterial catheter connected to a pressure transducer records heart rate (beats per minute).
Change in stroke volume (ml) from baseline compared between study days.
Stroke volume (ml) derived from arterial pulse contour analysis.
Change in systolic, diastolic and mean arterial pressure (mmHg) from baseline compared between study days.
Arterial catheter connected to a pressure transducer records blood pressure in mm Hg.
Glucagon pharmacokinetics
Blood samples drawn for measurements of plasma glucagon
Effects of glucagon on blood glucose compared to placebo
Full blood glucose measured with a blood glucose meter
Adverse effects of glucagon
Nausea rated by a 4-point, verbal description scale (VDS) (no nausea=0, mild=1, moderate=2, severe=3).

Full Information

First Posted
March 9, 2018
Last Updated
October 16, 2019
Sponsor
University Hospital Bispebjerg and Frederiksberg
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1. Study Identification

Unique Protocol Identification Number
NCT03533179
Brief Title
Glucagon's Cardiovascular Effects With and Without Beta-blocker-induced Cardioinhibition
Acronym
GLUCAGON
Official Title
A Randomized, Participant-blinded Five-arm Crossover Study With Blinded Outcome Assessment Investigating Glucagon's Cardiovascular Effects With and Without Beta-blocker-induced Cardioinhibition.
Study Type
Interventional

2. Study Status

Record Verification Date
October 2019
Overall Recruitment Status
Completed
Study Start Date
June 1, 2018 (Actual)
Primary Completion Date
October 1, 2019 (Actual)
Study Completion Date
October 1, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University Hospital Bispebjerg and Frederiksberg

4. Oversight

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

5. Study Description

Brief Summary
This trial investigates effects of a glucagon bolus injection on heart rate, blood pressure and cardiac output during beta-blocker-induced cardiodepression. Furthermore, the effects of two different doses of intravenous glucagon on hemodynamic parameters are explored.
Detailed Description
This trial investigates effects of a glucagon bolus injection on heart rate, blood pressure and cardiac output during beta-blocker-induced cardiodepression. Furthermore, the effects of two different doses of intravenous glucagon on hemodynamic parameters are explored. Glucagon, administered as a 50 micrograms/kg bolus injection which can be repeated or followed by continuous infusion (50 -150 micrograms / kg / hour) is a well-accepted and recommended treatment of beta-blocker poisoned patients [1-4]. The evidence for the recommended glucagon dose is based on animal trials and human case studies suggesting beneficial effects. Theoretically, high-dose glucagon mimics effect of beta-receptor agonists (increasing heart rate and cardiac output) [5] via activation of cardiac glucagon receptors, which cannot be blocked by beta blockers [1,6]. Glucagon receptors in the heart muscle are seemingly activated only at high glucagon levels [7] (but could also theoretically be an off-target effect); therefore the recommended glucagon dose for beta-blocker poisonings is higher than that recommended for reversal of hypoglycemia. Despite some animal and human case data suggesting beneficial effects of glucagon, other data suggest that glucagon may actually be inferior to other therapies of cardiovascular collapse due to cardioinhibitory drug poisonings [2]. It is important to keep in mind that the knowledge about glucagon's effects in poisoning situations is derived from uncontrolled cohort studies and case reports as well as animal studies [3,8]. Thus, the recommended dose has never been studied in a controlled clinical trial in humans. Therefore, the overall level of evidence pertaining to glucagon in the management of beta-blocker overdoses is low. There is a need for clinical human data investigating the glucagon doses recommended for treatment of beta-blocker overdose. The purpose of this participant- and outcome assessor blinded, randomized placebo-controlled crossover clinical trial is to investigate the effects of intravenous glucagon on the circulation alone or during beta-blocker-induced heart (rate) suppression. The trial includes a total of six visits; a screening visit and five trial days as described under Arms and Interventions. At the screening visit, anthropometric data (weight, height, blood pressure and pulse) is measured. Additionally, blood samples are collected in accordance with in/exclusion criteria. A spot urine sample measuring the albumin/creatinine ratio is collected and an electrocardiogram (ECG) is recorded to verify normality of heart rhythm and electrical impulses. In addition, an investigator carries out a clinical examination. Based on the clinical examination, urine and blood tests and ECG measurement, an investigator assesses whether the trial participant meet all inclusion criteria and no exclusion criteria. After screening and inclusion, participants will be invited to five trial days at the trial site (days A-E). The participant is blinded to interventions. On each day, participants are required to be fasting for 8±2 hours. A peripheral venous line is inserted into each antecubital vein. An arterial catheter connected to a pressure transducer is inserted into the radial artery in the wrist. In randomized order, one of the five interventions are performed (see below). A 5 lead ECG connected to a computer is placed on the participant. At T=-15 minutes, esmolol intravenous solution (10 mg esmolol/ml esmolol hydrochloride) or matching placebo is administered as a loading dose at baseline (time= -15 min) (corresponding to 1,25 mg/kg/min esmolol) [9]. Continuous infusion (500-750 micrograms/kg/min) of esmolol/placebo is then administered until T=30 minutes. Infusion is halted if heart rate decreases below 30 bpm or >25% from baseline, the systolic blood pressure drops below 80 mm Hg, or the participant experiences subjective side effects. Esmolol/placebo infusion stops at T=30 minutes. Glucagon (GlucaGen injectable solution) or saline solution is administered at time=0 minutes as an intravenous bolus (50 micrograms /kg over 1-2 minutes) on days C & E or as a continuous infusion (50 micrograms/kg over 30 min on day D). One point five grams of acetaminophen administered as a disintegrating tablet dissolved in 100 ml of water with guar gum is given orally shortly before study start on each day [10]. Repeated ECG's are recorded and blood is drawn for measurements of secondary biochemical endpoints. A drop of blood is used to test glucose levels using a blood glucose meter. Cardiovascular parameters (heart rate, blood pressure and pulse contour curve/arterial pressure wave) are recorded via the arterial catheter and pressure transducer connected to a computer. The participant is closely monitored on site until T=60 minutes.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Drug Overdose, Overdose of Beta-adrenergic Blocking Drug
Keywords
Glucagon, Beta-adrenergic antagonist, poisoning

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 4
Interventional Study Model
Crossover Assignment
Model Description
5-arm, participant and outcome-assessor blinded, randomized, placebo-controlled study.
Masking
ParticipantOutcomes Assessor
Masking Description
Interventions will be administered behind a curtain covering half the participant and thus the arm in which intervensions are administered. A list allocating participants to interventions are kept in an opaque envelope in a locked cabinet at the trial site. Outcome assessor will not have access to this list.
Allocation
Randomized
Enrollment
10 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Esmolol-placebo+glucagon 1 placebo (A)
Arm Type
Experimental
Arm Description
Physiologic saline - esmolol dummy (10 mg esmolol/ml) is administered as a loading dose at baseline (time= -15 minutes) (corresponding to 0.125 ml/kg/min of saline). Continuous infusion (0.05-0.075 ml/kg/min) of saline is then administered until T=30 minutes. + Physiologic saline - glucagon dummy bolus 50 ml at time=0.
Arm Title
Esmolol+glucagon 1 placebo (B)
Arm Type
Experimental
Arm Description
Esmolol intravenous solution (10 mg/ml esmolol hydrochloride) is administered as a loading dose (1.25 mg/kg/min esmolol) at baseline (time= -15 minutes). Continuous infusion (500-750 micrograms/kg/min) of esmolol/placebo is then administered until T=30 minutes. + Physiologic saline - glucagon dummy bolus (50 ml) at time=0.
Arm Title
Esmolol+glucagon 1 (C)
Arm Type
Experimental
Arm Description
Esmolol intravenous solution (10 mg/ml esmolol hydrochloride) is administered as a loading dose (1.25 mg/kg/min esmolol) at baseline (time= -15 minutes). Continuous infusion (500-750 micrograms/kg/min) of esmolol/placebo is then administered until T=30 minutes. +Glukagon 1 (50 μg/kg bolus - over 1-3 min from time=0 min in 50 ml isotonic fluid)
Arm Title
Esmolol-placebo+glucagon 2 (D)
Arm Type
Experimental
Arm Description
Physiologic saline - esmolol dummy (10 mg esmolol/ml) is administered as a loading dose at baseline (time= -15 minutes) (corresponding to 0.125 ml/kg/min of saline). Continuous infusion (0.05-0.075 ml/kg/min) of saline is then administered until T=30 minutes. +Glukagon 2 (50 μg/kg bolus - over 30 min in 50 ml isotonic fluid from time=0 min)
Arm Title
Esmolol-placebo+glucagon 1 (E)
Arm Type
Experimental
Arm Description
Physiologic saline - esmolol dummy (10 mg esmolol/ml) is administered as a loading dose at baseline (time= -15 minutes) (corresponding to 0.125 ml/kg/min of saline). Continuous infusion (0.05-0.075 ml/kg/min) of saline is then administered until T=30 minutes. + Glukagon 1 (50 μg/kg bolus - over 1-3 min from time=0 min in 50 ml isotonic fluid)
Intervention Type
Drug
Intervention Name(s)
Glucagon
Other Intervention Name(s)
GlucaGen, ATC H04AA01
Intervention Description
Glucagon 1 mg/ml solution is dissolved in 50 ml isotonic fluid and injected as bolus corresponding to 50 micrograms/kg over 1-3 minutes from time=0 on day C+E. on day D ("glucagon 2"), 50 micrograms/kg of glucagon is infused over 30 minutes from time=0 to time =30.
Intervention Type
Drug
Intervention Name(s)
Esmolol
Other Intervention Name(s)
Brevibloc, ATC C07AB09
Intervention Description
Esmolol hydrochloride 10 mg/ml is infused from time -15 min to time + 30 minutes as an initial bolus followed by an infusion. infusion rate is tapered if heart rate declines below 30 beats per minute (bpm) or >25 % from baseline, systolic blood pressure decreases below 80 mmHg or the participant experiences side effects.
Intervention Type
Drug
Intervention Name(s)
Physiologic saline - glucagon dummy
Other Intervention Name(s)
normal saline
Intervention Description
Isotonic 0.9 % sodium chloride solution is administered as matching placebo to glucagon, and injected in identical rates on corresponding days.
Intervention Type
Drug
Intervention Name(s)
Physiologic saline - esmolol dummy
Other Intervention Name(s)
normal saline
Intervention Description
Isotonic 0.9 % sodium chloride solution is administered as matching placebo to esmolol, and injected in identical rates on corresponding days.
Primary Outcome Measure Information:
Title
Heart rates on the esmolol+glucagon-day compared to the esmolol+placebo-day (2 minute average)
Description
Arterial catheter connected to a pressure transducer records heart rate (beats per minute).
Time Frame
Glucagon bolus + 5±1 minute
Secondary Outcome Measure Information:
Title
Change in heart rate from baseline compared between study days.
Description
Arterial catheter connected to a pressure transducer records heart rate (beats per minute).
Time Frame
-20, -10, 0, glucagon+3, +5, +10, +15, +20, +30, +40, +50, +60 minutes
Title
Change in stroke volume (ml) from baseline compared between study days.
Description
Stroke volume (ml) derived from arterial pulse contour analysis.
Time Frame
-20, -10, 0, glucagon+3, +5, +10, +15, +20, +30, +40, +50, +60 minutes
Title
Change in systolic, diastolic and mean arterial pressure (mmHg) from baseline compared between study days.
Description
Arterial catheter connected to a pressure transducer records blood pressure in mm Hg.
Time Frame
-20, -10, 0, glucagon+3, +5, +10, +15, +20, +30, +40, +50, +60 minutes
Title
Glucagon pharmacokinetics
Description
Blood samples drawn for measurements of plasma glucagon
Time Frame
Baseline and glucagon +2, +4, +6, +10, +15, +20, +30, +40, +50, +60 minutes
Title
Effects of glucagon on blood glucose compared to placebo
Description
Full blood glucose measured with a blood glucose meter
Time Frame
Baseline and glucagon +2, +4, +6, +10, +15, +20, +30, +40, +50, +60 minutes
Title
Adverse effects of glucagon
Description
Nausea rated by a 4-point, verbal description scale (VDS) (no nausea=0, mild=1, moderate=2, severe=3).
Time Frame
Baseline and glucagon +6,+10, +30, +60 minutes
Other Pre-specified Outcome Measures:
Title
Effects of glucagon compared to placebo on gastric emptying time
Description
Blood samples drawn for measurements of plasma paracetamol. Paracetamol is used as a tool for measuring gastric emptying time
Time Frame
Baseline and glucagon +10, +20, +30, +40, +50, +60 minutes
Title
Effects of glucagon compared to placebo on norepinephrine levels
Description
Blood samples drawn for measurements of norepinephrine.
Time Frame
T-20, T0, glucagon+5, +30, +60 minutes
Title
Cardiac conductivity compared between days with glucagon1 and corresponding placebo days.
Description
5-lead ECG
Time Frame
Baseline and glucagon +5, +10, +20, +30, +40, +50, +60 minutes

10. Eligibility

Sex
Male
Gender Based
Yes
Gender Eligibility Description
Male volunteers, determined healthy by medical history, physical examination including laboratory results
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Healthy male determined by investigator, based upon physical examination, medical history, ECG, vital signs and laboratory results Body mass index (BMI) ≥ 18.5 and ≤ 29.9 kg/m2 and body weight between 50 and 100 kg, inclusive, at screening visit. Exclusion Criteria: Abnormal blood levels of sodium, potassium, creatinine, alanine transaminase (ALT), alkaline phosphatase, albumin, bilirubin, hemoglobin, HbA1c, cholesterol fractions. Bradycardia (<45 beats per minute) Hypotension (systolic blood pressure < 100 mmHg) Second or third degree atrioventricular conduction delay Sick sinus syndrome Any heart disease or hypertension Pheochromocytoma Allergy to any active or inactive ingredient contained in investigatory medicines or tools. Raynaud's syndrome Prinzmetal's angina Diabetes Pulmonary disease Pheochromocytoma Any contraindication against investigatory medicines or tools.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kasper M Petersen, MD
Organizational Affiliation
University Hospital Bispebjerg and Frederiksberg
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospital Bispebjerg
City
Copenhagen
Country
Denmark

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
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Glucagon's Cardiovascular Effects With and Without Beta-blocker-induced Cardioinhibition

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