Drug OverdosePhase 4GLUCAGONNCT03533179
Glucagon's Cardiovascular Effects With and Without Beta-blocker-induced Cardioinhibition
A Phase 4 study testing Glucagon, Esmolol and Physiologic saline - glucagon dummy in people with Drug Overdose and Overdose of Beta-adrenergic Blocking Drug, run by University Hospital Bispebjerg and Frederiksberg at 1 site in Denmark.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 40 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Drug Overdose, Overdose of Beta-adrenergic Blocking Drug
- What is being tested?
- Glucagon, Esmolol and Physiologic saline - glucagon dummy
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 1 siteDenmark
- Study dates
- 1 Jun 2018to 1 Oct 2019
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 40 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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.
Who cannot join
- 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
Show all 14Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
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.
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.
Read the 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.
- Being tested
- Glucagon, Esmolol, Physiologic saline - glucagon dummy, Physiologic saline - esmolol dummy
- Keywords
- Glucagon, Beta-adrenergic antagonist, poisoning
- Medical subject headings
- Drug Overdose, Poisoning
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
GlucagonDrug
Also called GlucaGen, ATC H04AA01
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.
EsmololDrug
Also called Brevibloc, ATC C07AB09
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.
Physiologic saline - glucagon dummyDrug
Also called normal saline
Isotonic 0.9 % sodium chloride solution is administered as matching placebo to glucagon, and injected in identical rates on corresponding days.
Physiologic saline - esmolol dummyDrug
Also called normal saline
Isotonic 0.9 % sodium chloride solution is administered as matching placebo to esmolol, and injected in identical rates on corresponding days.
| Study group | Role | What they receive |
|---|---|---|
| Esmolol-placebo+glucagon 1 placebo (A) | Experimental | 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. Receives: Drug: Physiologic saline - glucagon dummy; Drug: Physiologic saline - esmolol dummy |
| Esmolol+glucagon 1 placebo (B) | Experimental | 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. Receives: Drug: Esmolol; Drug: Physiologic saline - glucagon dummy |
| Esmolol+glucagon 1 (C) | Experimental | 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) Receives: Drug: Glucagon; Drug: Esmolol |
| Esmolol-placebo+glucagon 2 (D) | Experimental | 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) Receives: Drug: Glucagon; Drug: Physiologic saline - esmolol dummy |
| Esmolol-placebo+glucagon 1 (E) | Experimental | 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) Receives: Drug: Glucagon; Drug: Physiologic saline - esmolol dummy |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: Glucagon bolus + 5±1 minute
Secondary outcomes (6)
Change in heart rate from baseline compared between study days.
Arterial catheter connected to a pressure transducer records heart rate (beats per minute).
Measured: -20, -10, 0, glucagon+3, +5, +10, +15, +20, +30, +40, +50, +60 minutes
Change in stroke volume (ml) from baseline compared between study days.
Stroke volume (ml) derived from arterial pulse contour analysis.
Measured: -20, -10, 0, glucagon+3, +5, +10, +15, +20, +30, +40, +50, +60 minutes
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.
Measured: -20, -10, 0, glucagon+3, +5, +10, +15, +20, +30, +40, +50, +60 minutes
Glucagon pharmacokinetics
Blood samples drawn for measurements of plasma glucagon
Measured: Baseline and glucagon +2, +4, +6, +10, +15, +20, +30, +40, +50, +60 minutes
Effects of glucagon on blood glucose compared to placebo
Full blood glucose measured with a blood glucose meter
Measured: Baseline and glucagon +2, +4, +6, +10, +15, +20, +30, +40, +50, +60 minutes
Adverse effects of glucagon
Nausea rated by a 4-point, verbal description scale (VDS) (no nausea=0, mild=1, moderate=2, severe=3).
Measured: Baseline and glucagon +6,+10, +30, +60 minutes
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 May 2018
- Study start1 Jun 2018
- Primary completion1 Oct 2019
- Study completion1 Oct 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (11)Papers the sponsor has linked to this study.
- Other trials for Drug OverdoseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- 5-arm, participant and outcome-assessor blinded, randomized, placebo-controlled study.
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Hospital Bispebjerg and Frederiksberg
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Kasper Meidahl Petersen, University Hospital Bispebjerg and Frederiksberg
- Investigators
- Kasper M Petersen, MD, Principal investigator, University Hospital Bispebjerg and Frederiksberg
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03533179
- Sponsor's protocol ID
- Glucagon+Beta-blocker
- Acronym
- GLUCAGON
- Status last verified
- Oct 2019
- First submitted
- 9 Mar 2018
- Last updated
- 17 Oct 2019
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Brubacher JR. 62. β-adrenergic antagonists. In: Hoffman RS, Howland MA, Lewin NA, et al., eds. Goldfrank's toxicologic emergencies. New York: : McGraw-Hill Education 2015. 856-69.
Graudins A, Lee HM, Druda D. Calcium channel antagonist and beta-blocker overdose: antidotes and adjunct therapies. Br J Clin Pharmacol. 2016 Mar;81(3):453-61. doi: 10.1111/bcp.12763. Epub 2015 Oct 30.
PubMed 26344579Bailey B. Glucagon in beta-blocker and calcium channel blocker overdoses: a systematic review. J Toxicol Clin Toxicol. 2003;41(5):595-602. doi: 10.1081/clt-120023761.
PubMed 14514004Beta blocker poisoning - UpToDate. https://www.uptodate.com/contents/beta-blocker-poisoning? search=beta%20blocker%20overdose&source=search_result&selectedTitle=1~14&usage_type=default&display_rank=1 (accessed 14 Feb 2018).
Parmley WW, Glick G, Sonnenblick EH. Cardiovascular effects of glucagon in man. N Engl J Med. 1968 Jul 4;279(1):12-7. doi: 10.1056/NEJM196807042790103. No abstract available.
PubMed 4872564Yagami T. Differential coupling of glucagon and beta-adrenergic receptors with the small and large forms of the stimulatory G protein. Mol Pharmacol. 1995 Nov;48(5):849-54.
PubMed 7476915Rodgers RL. Glucagon and cyclic AMP: time to turn the page? Curr Diabetes Rev. 2012 Sep;8(5):362-81. doi: 10.2174/157339912802083540.
PubMed 22587514St-Onge M, Dube PA, Gosselin S, Guimont C, Godwin J, Archambault PM, Chauny JM, Frenette AJ, Darveau M, Le Sage N, Poitras J, Provencher J, Juurlink DN, Blais R. Treatment for calcium channel blocker poisoning: a systematic review. Clin Toxicol (Phila). 2014 Nov;52(9):926-44. doi: 10.3109/15563650.2014.965827. Epub 2014 Oct 6.
PubMed 25283255Reilly CS, Wood M, Koshakji RP, Wood AJ. Ultra-short-acting beta-blockade: a comparison with conventional beta-blockade. Clin Pharmacol Ther. 1985 Nov;38(5):579-85. doi: 10.1038/clpt.1985.227.
PubMed 2865029Medhus AW, Lofthus CM, Bredesen J, Husebye E. Gastric emptying: the validity of the paracetamol absorption test adjusted for individual pharmacokinetics. Neurogastroenterol Motil. 2001 Jun;13(3):179-85. doi: 10.1046/j.1365-2982.2001.00249.x.
PubMed 11437980Petersen KM, Bogevig S, Riis T, Andersson NW, Dalhoff KP, Holst JJ, Knop FK, Faber J, Petersen TS, Christensen MB. High-Dose Glucagon Has Hemodynamic Effects Regardless of Cardiac Beta-Adrenoceptor Blockade: A Randomized Clinical Trial. J Am Heart Assoc. 2020 Nov 3;9(21):e016828. doi: 10.1161/JAHA.120.016828. Epub 2020 Oct 26.
PubMed 33103603
Study at a glance
From the registry record, last updated by the sponsor on 17 Oct 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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.
- ClinicalTrials.gov ID
- NCT03533179
- Acronym / sponsor ID
- GLUCAGON / Glucagon+Beta-blocker
- Keywords
- Glucagon, Beta-adrenergic antagonist, poisoning
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 10 participants (actual)
- Lead sponsor
- University Hospital Bispebjerg and FrederiksbergUniversity, hospital or other
- Study start
- 1 Jun 2018 (actual)
- Primary completion
- 1 Oct 2019 (actual)
- Study completion
- 1 Oct 2019 (actual)
- First posted
- 23 May 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 5
- Model description
- 5-arm, participant and outcome-assessor blinded, randomized, placebo-controlled study.
| Arm | Type | Receives |
|---|---|---|
| Esmolol-placebo+glucagon 1 placebo (A) | Experimental | Drug: Physiologic saline - glucagon dummy, Drug: Physiologic saline - esmolol dummyPhysiologic 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+glucagon 1 placebo (B) | Experimental | Drug: Esmolol, Drug: Physiologic saline - glucagon dummyEsmolol 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+glucagon 1 (C) | Experimental | Drug: Glucagon, Drug: EsmololEsmolol 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) |
| Esmolol-placebo+glucagon 2 (D) | Experimental | Drug: Glucagon, Drug: Physiologic saline - esmolol dummyPhysiologic 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) |
| Esmolol-placebo+glucagon 1 (E) | Experimental | Drug: Glucagon, Drug: Physiologic saline - esmolol dummyPhysiologic 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) |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (2 listed)
- 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.
Key exclusion criteria (14 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| GlucagonAlso: GlucaGen, ATC H04AA01Glucagon 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. | Drug | Esmolol+glucagon 1 (C), Esmolol-placebo+glucagon 1 (E), Esmolol-placebo+glucagon 2 (D) |
| EsmololAlso: Brevibloc, ATC C07AB09Esmolol 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. | Drug | Esmolol+glucagon 1 (C), Esmolol+glucagon 1 placebo (B) |
| Physiologic saline - glucagon dummyAlso: normal salineIsotonic 0.9 % sodium chloride solution is administered as matching placebo to glucagon, and injected in identical rates on corresponding days. | Drug | Esmolol+glucagon 1 placebo (B), Esmolol-placebo+glucagon 1 placebo (A) |
| Physiologic saline - esmolol dummyAlso: normal salineIsotonic 0.9 % sodium chloride solution is administered as matching placebo to esmolol, and injected in identical rates on corresponding days. | Drug | Esmolol-placebo+glucagon 1 (E), Esmolol-placebo+glucagon 1 placebo (A), Esmolol-placebo+glucagon 2 (D) |
Primary outcome
Heart rates on the esmolol+glucagon-day compared to the esmolol+placebo-day (2 minute average)
Time frame: Glucagon bolus + 5±1 minute
Arterial catheter connected to a pressure transducer records heart rate (beats per minute).
6 secondary outcomes
Change in heart rate from baseline compared between study days.
Time frame: -20, -10, 0, glucagon+3, +5, +10, +15, +20, +30, +40, +50, +60 minutes
Change in stroke volume (ml) from baseline compared between study days.
Time frame: -20, -10, 0, glucagon+3, +5, +10, +15, +20, +30, +40, +50, +60 minutes
Change in systolic, diastolic and mean arterial pressure (mmHg) from baseline compared between study days.
Time frame: -20, -10, 0, glucagon+3, +5, +10, +15, +20, +30, +40, +50, +60 minutes
Glucagon pharmacokinetics
Time frame: Baseline and glucagon +2, +4, +6, +10, +15, +20, +30, +40, +50, +60 minutes
Effects of glucagon on blood glucose compared to placebo
Time frame: Baseline and glucagon +2, +4, +6, +10, +15, +20, +30, +40, +50, +60 minutes
Adverse effects of glucagon
Time frame: Baseline and glucagon +6,+10, +30, +60 minutes
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Oct 2019.
- BackgroundBrubacher JR. 62. β-adrenergic antagonists. In: Hoffman RS, Howland MA, Lewin NA, et al., eds. Goldfrank's toxicologic emergencies. New York: : McGraw-Hill Education 2015. 856-69.
- Background: PubMed 26344579Graudins A, Lee HM, Druda D. Calcium channel antagonist and beta-blocker overdose: antidotes and adjunct therapies. Br J Clin Pharmacol. 2016 Mar;81(3):453-61. doi: 10.1111/bcp.12763. Epub 2015 Oct 30.
- Background: PubMed 14514004Bailey B. Glucagon in beta-blocker and calcium channel blocker overdoses: a systematic review. J Toxicol Clin Toxicol. 2003;41(5):595-602. doi: 10.1081/clt-120023761.
- BackgroundBeta blocker poisoning - UpToDate. https://www.uptodate.com/contents/beta-blocker-poisoning? search=beta%20blocker%20overdose&source=search_result&selectedTitle=1~14&usage_type=default&display_rank=1 (accessed 14 Feb 2018).
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- Background: PubMed 7476915Yagami T. Differential coupling of glucagon and beta-adrenergic receptors with the small and large forms of the stimulatory G protein. Mol Pharmacol. 1995 Nov;48(5):849-54.
- Background: PubMed 22587514Rodgers RL. Glucagon and cyclic AMP: time to turn the page? Curr Diabetes Rev. 2012 Sep;8(5):362-81. doi: 10.2174/157339912802083540.
- Background: PubMed 25283255St-Onge M, Dube PA, Gosselin S, Guimont C, Godwin J, Archambault PM, Chauny JM, Frenette AJ, Darveau M, Le Sage N, Poitras J, Provencher J, Juurlink DN, Blais R. Treatment for calcium channel blocker poisoning: a systematic review. Clin Toxicol (Phila). 2014 Nov;52(9):926-44. doi: 10.3109/15563650.2014.965827. Epub 2014 Oct 6.
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- Derived from this study: PubMed 33103603Petersen KM, Bogevig S, Riis T, Andersson NW, Dalhoff KP, Holst JJ, Knop FK, Faber J, Petersen TS, Christensen MB. High-Dose Glucagon Has Hemodynamic Effects Regardless of Cardiac Beta-Adrenoceptor Blockade: A Randomized Clinical Trial. J Am Heart Assoc. 2020 Nov 3;9(21):e016828. doi: 10.1161/JAHA.120.016828. Epub 2020 Oct 26.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Kasper M Petersen, MD principal investigator
University Hospital Bispebjerg and Frederiksberg
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Glucagon, Esmolol and Physiologic saline - glucagon dummy in people with Drug Overdose and Overdose of Beta-adrenergic Blocking Drug, run by University Hospital Bispebjerg and Frederiksberg at 1 site in Denmark.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 Oct 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Heart rates on the esmolol+glucagon-day compared to the esmolol+placebo-day (2 minute average) (time frame: Glucagon bolus + 5±1 minute). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03533179, which also lists 11 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Oct 2019.