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| ID | Type | Description | Link |
|---|---|---|---|
| 18/EM/0417 | Other Identifier | REC-HRA | |
| 250402 | Other Identifier | IRAS ID |
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The study seeks to explore the cardiovascular effects of co-agonism at two peptide receptors, GLP-1 and glucagon. Glucagon, exenatide and 0.9% saline will be intravenously infused, both in isolation, and combination into healthy male participants. Overall, the aim of the study is to further our understanding on the role these endogenous substances play (both in isolation and combination) in haemodynamic regulation.
Co-agonist peptides (such as at the GLP-1:glucagon receptor) are currently in clinical development for type 2 diabetes with the dual intention of reducing body weight and controlling blood glucose. However, there is a lack of data on the effects that co-agonism has on haemodynamic regulation.
Part A - Healthy male participants, by acting as their own control, will attend for two intravenous infusion visits (combination of 0.9% saline and glucagon). These will occur in a predefined but random order so that participants will be blinded to the infusion they are receiving. Each infusion visit will comprise of 15 minute baseline followed by a 120 minute infusion. Detailed non-invasive cardiovascular measurements (including peripheral/central blood pressure, heart rate, stroke volume, heart rate variability) and bloods (including insulin, glucose, GLP-1, glucagon) will be collected as part of the study. It was previously planned that GLP-1 7-36 amide 0.6pmol/kg/min and 1.2pmol/kg/min would be infused for Part A resulting in 5 infusions (rather than current 2 infusions). However due to supply/technical issues this was not possible and therefore exenatide (GLP-1 receptor agonist) shall be used in Part B.
Part B - Healthy male participants, by acting as their own control, will attend for four intravenous infusion visits (combination of 0.9% saline, glucagon, exenatide). These will occur in a predefined but random order so that participants will be blinded to the infusion they are receiving. Each infusion visit will comprise of 15 minute baseline followed by a 60 minute infusion. Detailed non-invasive cardiovascular measurements (including peripheral/central blood pressure, heart rate, stroke volume, heart rate variability) and bloods (including insulin, glucose, GLP-1, glucagon) will be collected as part of the study.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Part A - Infusion A | Placebo Comparator |
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| Part A - Infusion B | Active Comparator |
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| Part B - Infusion A | Active Comparator | A 60 minute intravenous infusion of 0.9% saline |
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| Part B - Infusion B | Active Comparator | A 60 minute intravenous infusion of exenatide (50ng/min for 30 minutes followed by 25ng/min) and 0.9% saline |
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| Part B - Infusion C | Active Comparator | A 60 minute intravenous infusion of glucagon (25ng/kg/min) and 0.9% saline |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Saline 0.9% | Drug | Intravenous infusion of 0.9% saline |
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| Measure | Description | Time Frame |
|---|---|---|
| Changes in haemodynamic parameters following intravenous infusion of 0.9% saline, glucagon, exenatide and their combination. | Heart rate (bpm) | Comparison between 2 hour infusion visit 1-2 (Part A) / 1 hour infusion visit 1-4 (Part B), over a maximum period of 15 weeks |
| Changes in haemodynamic parameters following intravenous infusion of 0.9% saline, glucagon, exenatide and their combination. | Brachial systolic and diastolic blood pressure (mmHg) | Comparison between 2 hour infusion visit 1-2 (Part A) / 1 hour infusion visit 1-4 (Part B), over a maximum period of 15 weeks |
| Changes in haemodynamic parameters following intravenous infusion of 0.9% saline, glucagon, exenatide and their combination. | Central systolic and diastolic blood pressure and mean arterial pressure (mmHg) measured with SphygmoCor XCEL | Comparison between 2 hour infusion visit 1-2 (Part A) / 1 hour infusion visit 1-4 (Part B), over a maximum period of 15 weeks |
| Changes in haemodynamic parameters following intravenous infusion of 0.9% saline, glucagon, exenatide and their combination. | Stroke volume (ml) measured by bioimpedance | Comparison between 2 hour infusion visit 1-2 (Part A) / 1 hour infusion visit 1-4 (Part B), over a maximum period of 15 weeks |
| Changes in haemodynamic parameters following intravenous infusion of 0.9% saline, glucagon, exenatide and their combination. | Cardiac output (L/min) measured by bioimpedance | Comparison between 2 hour infusion visit 1-2 (Part A) / 1 hour infusion visit 1-4 (Part B), over a maximum period of 15 weeks |
| Changes in haemodynamic parameters following intravenous infusion of 0.9% saline, glucagon, exenatide and their combination. |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in glucose homeostasis following intravenous infusion of 0.9% saline, glucagon, exenatide and their combination. | Glucose, in mmol/L | Comparison between 2 hour infusion visit 1-5 (Part A) / 1 hour infusion visit 1-4 (Part B), over a maximum period of 15 weeks |
| Changes in glucose homeostasis following intravenous infusion of 0.9% saline, glucagon, exenatide and their combination. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Ian Wilkinson, MA DM FRCP | University of Cambridge | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Addenbrooke's Hospital | Cambridge | Cambridgeshire | CB2 0QQ | United Kingdom |
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| ID | Term |
|---|---|
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D012965 | Sodium Chloride |
| D005934 | Glucagon |
| D000077270 | Exenatide |
| ID | Term |
|---|---|
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
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Part A - 2 infusions Part B - 4 infusions
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| Part B - Infusion D | Active Comparator | A 60 minute intravenous infusion of exenatide (50ng/min for 30 minutes then 25ng/min) and glucagon (25ng/kg/min) |
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| Glucagon (25ng/kg/min) | Drug | Intravenous infusion of glucagon 25ng/kg/min |
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| Glucagon (50ng/kg/min) | Drug | Intravenous infusion of glucagon 50ng/kg/min |
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| Exenatide | Drug | Intravenous infusion of Exenatide (loading 50ng/min for 30 minutes followed by 25ng/min for 30 minutes |
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peripheral vascular resistance (dynes/sec/cm) |
| Comparison between 2 hour infusion visit 1-2 (Part A) / 1 hour infusion visit 1-4 (Part B), over a maximum period of 15 weeks |
| Changes in haemodynamic parameters following intravenous infusion of 0.9% saline, glucagon, exenatide and their combination. | Heart rate variability (normalised low frequency, LF, high frequency, HF and LF/HF ratio) | Comparison between 2 hour infusion visit 1-2 (Part A) / 1 hour infusion visit 1-4 (Part B), over a maximum period of 15 weeks |
C-peptide, in pmol/L |
| Comparison between 2 hour infusion visit 1-2 (Part A) / 1 hour infusion visit 1-4 (Part B), over a maximum period of 15 weeks |
| Changes in glucose homeostasis following intravenous infusion of 0.9% saline, glucagon, exenatide and their combination. | Glucagon, in pg/ml | Comparison between 2 hour infusion visit 1-2 (Part A) / 1 hour infusion visit 1-4 (Part B), over a maximum period of 15 weeks |
| Changes in glucose homeostasis following intravenous infusion of 0.9% saline, glucagon, exenatide and their combination. | Insulin, in pmol/L | Comparison between 2 hour infusion visit 1-2 (Part A) / 1 hour infusion visit 1-4 (Part B), over a maximum period of 15 weeks |
| Changes in glucose homeostasis following intravenous infusion of 0.9% saline, glucagon, exenatide and their combination. | Free fatty acids, in μmol/L | Comparison between 2 hour infusion visit 1-2 (Part A) / 1 hour infusion visit 1-4 (Part B), over a maximum period of 15 weeks |
| Changes in glucose homeostasis following intravenous infusion of 0.9% saline, glucagon, exenatide and their combination. | Total GLP-1 and total active GLP-1, in pg/ml | Comparison between 2 hour infusion visit 1-2 (Part A) / 1 hour infusion visit 1-4 (Part B), over a maximum period of 15 weeks |
| Changes in glucose homeostasis following intravenous infusion of 0.9% saline, glucagon, exenatide and their combination. | Gastric inhibitory polypeptide, in pg/ml | Comparison between 2 hour infusion visit 1-2 (Part A) / 1 hour infusion visit 1-4 (Part B), over a maximum period of 15 weeks |
| D017670 |
| Sodium Compounds |
| D052336 | Proglucagon |
| D010187 | Pancreatic Hormones |
| D036361 | Peptide Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D014688 | Venoms |
| D045424 | Complex Mixtures |
| D014118 | Toxins, Biological |
| D001685 | Biological Factors |