A Series of Pilot Studies to Evaluate the haemoDynamic and mEtabolic Effects oF apelIn aNd rElaxin

Study Overview
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Brief Summary
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Type two diabetes mellitus (T2DM) is a common, long term metabolic disorder characterised by hyperglycaemia (high blood glucose) resulting from insulin resistance and relative insulin insufficiency. The risk of developing insulin resistance and subsequently T2DM is increased by being overweight and also through a sedentary lifestyle. As the onset can be gradual, physiological damage may have occurred prior to diagnosis. Diabetes is associated with the development of microvascular complications (diabetic nephropathy, neuropathy, and retinopathy), and macrovascular complications (coronary artery disease, peripheral arterial disease, and stroke). While there are many treatments available for T2DM, these complications may still arise, leading to significant morbidity and mortality. There is therefore an urgent need to identify novel signalling pathways that may contribute to the development of diabetes related complications. The identification of these pathways may ultimately lead to the development of new therapies targeting better blood glucose control and preventing these subsequent complications. Both animal and human studies have indicated that two endogenous peptides, apelin and relaxin both act as vasodilators in the human cardiovascular system and could also have beneficial action in T2DM. Therefore, we aim to carry out experimental medicine studies to test this hypothesis, and explore the signalling pathway in the human vascular system.

Detailed Description
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An extensive body of evidence demonstrates a direct association between T2DM and cardiovascular complications and mortality. Unfortunately, current therapies for diabetes have failed to be translated into improvements in cardiovascular outcomes, highlighting an urgent need to develop novel therapeutic strategies that can ultimately achieve the dual outcome of improving glycaemic control and improving cardiovascular function. While the precise cellular mechanisms involved remain to be elucidated, we hypothesise that the apelin and relaxin pathways meet these two criteria and therefore are potential therapeutic targets in conditions of abnormal glucose metabolism and heart failure. Apelin and relaxin are safe for parenteral use as they are naturally occurring peptide hormones, have a short half-life and will be rapidly cleared. They target endogenous receptors and post-receptor signalling, and have been used in human trials without any significant side effects reported.

Official Title
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A Series of Pilot Studies to Evaluate the Haemodynamic and Metabolic Effects of Apelin and Relaxin in Healthy Humans, Subjects With Increased Weight and Patients With Type 2 Diabetes Mellitus

Conditions
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Cardiovascular Diseases, Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Apelin
* Drug: Relaxin
* Drug: Normal saline
* Diagnostic Test: Verapamil
* Diagnostic Test: LN Monomethyl arginine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy participants Have given written informed consent to participate Aged 18 to 70 years inclusive Male or female Current non-smoker If female, either postmenopausal or on days 2-9 of menstrual cycle and negative pregnancy test performed on the day of the of visit BMI in range for studies 1 and 4: 18.5-24.9 kg/m2 with waist circumference lower than 88 centimetres (35 inches) for women or 102 cm (40 inches) for men, and/or body fat level less than 32 % for women or 25% for men BMI in range for studies 2 and 3: 18.5-30.0 kg/m2 without limitations in waist circumference or body fat level Overweight/obese participants Have given written informed consent to participate Aged 18 to 70 years inclusive Male or female Current non-smoker If female, either postmenopausal or on days 2-9 of menstrual cycle and negative pregnancy test performed on the day of the of visit BMI in range of 25-34.9 kg/m2 (inclusive) with either waist circumference higher than 88cm (35 inches) for women or 102 cm (40 inches) for men, and/or body fat levels in excess of 32% for women or 25% for men Participants with type 2 diabetes mellitus Have given written informed consent to participate Aged 18 to 70 years inclusive Male or female Current non-smoker If female, either postmenopausal or on days 2-9 of menstrual cycle and negative pregnancy test performed on the day of the of visit BMI in range of 25-34.9 kg/m2 (inclusive) with either waist circumference higher than 88cm (35 inches) for women or 102 cm (40 inches) for men, and/or body fat levels in excess of 32% for women or 25% for men Documented diagnosis of Type 2 Diabetes Mellitus, either diet controlled or treated with oral hypoglycaemic therapy Exclusion Criteria: Hypersensitivity to any of the study drugs or excipients Systemic Hypertension (sustained BP >160/100mmHg) or hypotension (systolic BP below 90 mmHg) Known heart disease Implanted heart pace-maker or implantable cardioverter defibrillator (ICD) Known active malignancy Known renal failure (creatinine >140µmol/L) Known neurological disease History of Scleroderma (Study 4 only) Current pregnancy, breast feeding Use of vasoactive medications or NSAIDS/aspirin within 24 hours of study visits Use of caffeine within 24 hours of study visits Current involvement in the active treatment phase of other research studies, (excluding observations/non-interventional) Second or third-degree AV block, sino-atrial block, sick sinus syndrome or sinus bradycardia Known HIV, hepatitis B or C Needle phobia Participants treated with formal anticoagulant therapy such as, but not limited to, heparin, warfarin or clopidogrel Diagnosis of Type 1 Diabetes Mellitus or current usage of insulin or other injectable drugs for the treatment of diabetes such as but not limited to GLP1 agonists BMI <18.5 Aged <18 or >70 years Any other clinical reason which may preclude entry in the opinion of the investigator

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Substudy 1A - Apelin<br>In sub-study 1A Healthy participants will receive systemic infusions of Apelin to establish a dose range | Drug: Apelin<br>* Apelin is an endogenous peptide that activate a single G-protein couple receptor. Apelin inhibits insulin secretion, decreases glucose levels and increases insulin sensitivity.<br>|
| Experimental: Substudy 1B - Apelin/Normal Saline<br>In sub-study 1B , individuals with Type 2 Diabetes and individuals with increase weight will receive systemic infusions of Apelin or Normal Saline | Drug: Apelin<br>* Apelin is an endogenous peptide that activate a single G-protein couple receptor. Apelin inhibits insulin secretion, decreases glucose levels and increases insulin sensitivity.<br>Drug: Normal saline<br>* Vehicle<br>* Other names: Saline;|
| Experimental: Substudy 2A - Relaxin/Normal Saline<br>In sub-study 2A Healthy participants will receive intra-arterial infusions of Relaxin | Drug: Relaxin<br>* Relaxin is RLN2 encoded endogenous peptide hormone, which binds to G protein coupled receptor RXFP1.<br>* Other names: RLX;Drug: Normal saline<br>* Vehicle<br>* Other names: Saline;|
| Experimental: Substudy 2B - Relaxin<br>In sub-study 2B Healthy participants will receive intra-arterial infusions of Relaxin followed by verapamil (on a background infusion of either LN Monomethyl Arginine or Normal Saline, to test effects on nitric oxide) | Drug: Relaxin<br>* Relaxin is RLN2 encoded endogenous peptide hormone, which binds to G protein coupled receptor RXFP1.<br>* Other names: RLX;Diagnostic Test: Verapamil<br>* NO independent challenge agent<br>Diagnostic Test: LN Monomethyl arginine<br>* Basal NO synthase inhibitor<br>* Other names: LNMMA;|
| Experimental: Substudy 3A - Relaxin with Apelin/Saline<br>In sub-study 3A Healthy participants will receive intra-arterial infusions of Relaxin (background infusion apelin/Normal Saline) | Drug: Apelin<br>* Apelin is an endogenous peptide that activate a single G-protein couple receptor. Apelin inhibits insulin secretion, decreases glucose levels and increases insulin sensitivity.<br>Drug: Relaxin<br>* Relaxin is RLN2 encoded endogenous peptide hormone, which binds to G protein coupled receptor RXFP1.<br>* Other names: RLX;Drug: Normal saline<br>* Vehicle<br>* Other names: Saline;|
| Experimental: Substudy 3B - Apelin with Relaxin/Saline<br>In sub-study 3B Healthy participants will receive intra-arterial infusions of Apelin (background infusion Relaxin/Normal Saline) | Drug: Apelin<br>* Apelin is an endogenous peptide that activate a single G-protein couple receptor. Apelin inhibits insulin secretion, decreases glucose levels and increases insulin sensitivity.<br>Drug: Relaxin<br>* Relaxin is RLN2 encoded endogenous peptide hormone, which binds to G protein coupled receptor RXFP1.<br>* Other names: RLX;Drug: Normal saline<br>* Vehicle<br>* Other names: Saline;|
| Experimental: Substudy 4 - Apelin and Relaxin<br>In sub-study 4 Healthy participants, Individuals with Type 2 Diabetes and Individuals with increase weight will receive systemic infusions of Normal saline, Relaxin, Apelin and relaxin | Drug: Apelin<br>* Apelin is an endogenous peptide that activate a single G-protein couple receptor. Apelin inhibits insulin secretion, decreases glucose levels and increases insulin sensitivity.<br>Drug: Relaxin<br>* Relaxin is RLN2 encoded endogenous peptide hormone, which binds to G protein coupled receptor RXFP1.<br>* Other names: RLX;|
| Experimental: Substudy 5 - Relaxin/Saline<br>In sub-study 5 Healthy participants will be allocated to 1 of 4 Relaxin dosing groups and will receive dorsal hand vein infusion of 3 incremental doses of Normal Saline/ D5W and Relaxin | Drug: Relaxin<br>* Relaxin is RLN2 encoded endogenous peptide hormone, which binds to G protein coupled receptor RXFP1.<br>* Other names: RLX;Drug: Normal saline<br>* Vehicle<br>* Other names: Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sub-study 1a: Changes in markers of glucose homeostasis in healthy participants after infusion of apelin (Glucose) | Glucose, in mmol/l | Visit 2 to visit 4, over a period of up to 8 weeks | 
| Sub-study 1a: Changes in markers of glucose homeostasis in healthy participants after infusion of apelin (C-Peptide) | C-peptide, in pmol/L | Visit 2 to visit 4, over a period of up to 8 weeks | 
| Sub-study 1a: Changes in markers of glucose homeostasis in healthy participants after infusion of apelin (Glucagon) | Glucagon, in pg/ml | Visit 2 to visit 4, over a period of up to 8 weeks | 
| Sub-study 1a: Changes in markers of glucose homeostasis in healthy participants after infusion of apelin (Insulin) | Insulin, in pmol/L | Visit 2 to visit 4, over a period of up to 8 weeks | 
| Sub-study 1a: Changes in markers of glucose homeostasis in healthy participants after infusion of apelin (TNF-alpha) | TNF-alpha, in pg/ml | Visit 2 to visit 4, over a period of up to 8 weeks | 
| Sub-study 1b: Changes in markers of glucose homeostasis in participants with increased weight and participants with type 2 diabetes mellitus after infusion of apelin with or without mixed meal tolerance in obese/overweight and T2DM participants | Glucose, in mmol/l | Visit 2 to visit 5, over a period of up to 14 weeks | 
| Sub-study 1b: Changes in markers of glucose homeostasis in participants with increased weight and participants with type 2 diabetes mellitus after infusion of apelin with or without mixed meal tolerance in obese/overweight and T2DM participants | C-peptide, in pmol/L | Visit 2 to visit 5, over a period of up to 14 weeks | 
| Sub-study 1b: Changes in markers of glucose homeostasis in participants with increased weight and participants with type 2 diabetes mellitus after infusion of apelin with or without mixed meal tolerance in obese/overweight and T2DM participants | Glucagon, in pg/ml | Visit 2 to visit 5, over a period of up to 14 weeks | 
| Sub-study 1b: Changes in markers of glucose homeostasis in participants with increased weight and participants with type 2 diabetes mellitus after infusion of apelin with or without mixed meal tolerance in obese/overweight and T2DM participants | Insulin, in pmol/L | Visit 2 to visit 5, over a period of up to 14 weeks | 
| Sub-study 1b: Changes in markers of glucose homeostasis in participants with increased weight and participants with type 2 diabetes mellitus after infusion of apelin with or without mixed meal tolerance in obese/overweight and T2DM participants | TNF-alpha, in pg/ml | Visit 2 to visit 5, over a period of up to 14 weeks | 
| Sub-study 2a: Change in forearm blood flow parameters in healthy participants after infusion of relaxin (Absolute Flow) | Absolute flow in the infused arm, in mg/dL/min | Within visit 2, over a period of up to 4 weeks | 
| Sub-study 2a: Change in forearm blood flow parameters in healthy participants after infusion of relaxin (Percentage Change) | Percentage change in the infused arm, in % | Within visit 2, over a period of up to 4 weeks | 
| Sub-study 2a: Change in forearm blood flow parameters in healthy participants after infusion of relaxin (Ratio) | Ratio, expressed as a number (no units as this is a ratio) | Within visit 2, over a period of up to 4 weeks | 
| Sub-study 2b: Change in forearm blood flow parameters in healthy participants after infusion of relaxin in the presence of L-NMMA or normal saline | Ratio; absolute flow and percentage change in the infused arm | Visit 2 to visit 3, over a period of up to 10 weeks | 
| Sub-study 2b: Change in forearm blood flow parameters in health participants after infusion of verapamil in the presence of L-NMMA or normal saline (Ratio) | Ratio; expressed as a number (no units as this is a ratio) | Visit 2 to visit 3, over a period of up to 10 weeks | 
| Sub-study 2b: Change in forearm blood flow parameters in health participants after infusion of verapamil in the presence of L-NMMA or normal saline (Absolute Flow) | Absolute flow in the infused arm, in mg/dL/min | Visit 2 to visit 3, over a period of up to 10 weeks | 
| Sub-study 2b: Change in forearm blood flow parameters in health participants after infusion of verapamil in the presence of L-NMMA or normal saline (Percentage Change) | Percentage change in the infused arm, In % | Visit 2 to visit 3, over a period of up to 10 weeks | 
| Sub-Study 3a: Change in forearm blood flow parameters in healthy participants after incremental infusions of intra-arterial relaxin in the presence of apelin | Ratio; absolute flow and percentage change in the infused arm | Visit 2 to visit 3, over a period of up to 10 weeks | 
| Sub-Study 3a: Change in forearm blood flow parameters in healthy participants after incremental infusions of intra-arterial relaxin in the presence of apelin (Ratio) | Ratio, expressed as a number (no units as this is a ratio) | Visit 2 to visit 3, over a period of up to 10 weeks | 
| Sub-Study 3a: Change in forearm blood flow parameters in healthy participants after incremental infusions of intra-arterial relaxin in the presence of apelin (Absolute Flow) | Absolute flow in the infused arm, in mg/dL/min | Visit 2 to visit 3, over a period of up to 10 weeks | 
| Sub-Study 3a: Change in forearm blood flow parameters in healthy participants after incremental infusions of intra-arterial relaxin in the presence of apelin (Percentage Change) | Percentage change in the infused arm, In % | Visit 2 to visit 3, over a period of up to 10 weeks | 
| Sub-Study 3b: Change in forearm blood flow parameters in healthy participants after incremental infusions of intra-arterial apelin in the presence of relaxin (Ratio) | Ratio, expressed as a number (no units as this is a ratio) | Visit 2 to visit 3, over a period of up to 10 weeks | 
| Sub-Study 3b: Change in forearm blood flow parameters in healthy participants after incremental infusions of intra-arterial apelin in the presence of relaxin (Absolute Flow) | Absolute flow in the infused arm, in mg/dL/min | Visit 2 to visit 3, over a period of up to 10 weeks | 
| Sub-Study 3b: Change in forearm blood flow parameters in healthy participants after incremental infusions of intra-arterial apelin in the presence of relaxin (Percentage Change) | Percentage change in the infused arm, In % | Visit 2 to visit 3, over a period of up to 10 weeks | 
| Sub-study 4: Changes in markers of glucose homeostasis healthy participants, participants with increased weight and participants with type 2 diabetes mellitus after infusion of relaxin with and without apelin (Glucose) | Glucose, in each of the groups, in mmol/L | Visit 2 to Visit 4, over a period of up to 8 weeks | 
| Sub-study 4: Changes in markers of glucose homeostasis healthy participants, participants with increased weight and participants with type 2 diabetes mellitus after infusion of relaxin with and without apelin (C-peptide) | C-peptide, in each of the groups, in pmol/L | Visit 2 to Visit 4, over a period of up to 8 weeks | 
| Sub-study 4: Changes in markers of glucose homeostasis healthy participants, participants with increased weight and participants with type 2 diabetes mellitus after infusion of relaxin with and without apelin (Glucagon) | glucagon, in each of the groups,in pg/ml | Visit 2 to Visit 4, over a period of up to 8 weeks | 
| Sub-study 4: Changes in markers of glucose homeostasis healthy participants, participants with increased weight and participants with type 2 diabetes mellitus after infusion of relaxin with and without apelin (Insulin) | Insulin, in each of the groups, in pmol/L | Visit 2 to Visit 4, over a period of up to 8 weeks | 
| Sub-study 4: Changes in markers of glucose homeostasis healthy participants, participants with increased weight and participants with type 2 diabetes mellitus after infusion of relaxin with and without apelin (TNF-alpha) | TNF-alpha, in each of the groups, in pg/ml | Visit 2 to Visit 4, over a period of up to 8 weeks | 
| Sub-study 5: Change in hand vein diameter after relaxin infusion in healthy participants | Hand vein Demeter is measured using Aellig dorsal hand vein technique | Visit 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sub-study 1a: Changes in parameters of cardiovascular haemodynamics in healthy participants after infusion of apelin (Echocardiography) | Cardiac output measured by Echocardiography, in L/min | Visit 2 to visit 4, over a period of up to 8 weeks | 
| Sub-study 1a: Changes in parameters of cardiovascular haemodynamics in healthy participants after infusion of apelin (Innocor) | Cardiac output measured by Innocor, in L/min | Visit 2 to visit 4, over a period of up to 8 weeks | 
| Sub-study 1a: Changes in parameters of cardiovascular haemodynamics in healthy participants after infusion of apelin (Bioimpedance) | Cardiac output measured by bioimpedance, in L/min | Visit 2 to visit 4, over a period of up to 8 weeks | 
| Sub-study 1b: Changes in parameters of cardiovascular haemodynamics in obese/overweight and T2DM participants after infusion of apelin (Echocardiography) | Cardiac output measured by Echocardiography, in L/min | VIsit 2 to visit 4, over a period of up to 8 weeks | 
| Sub-study 1b: Changes in parameters of cardiovascular haemodynamics in obese/overweight and T2DM participants after infusion of apelin (Innocor) | Cardiac output measured by Innocor, in L/min | Visit 2 to visit 4, over a period of up to 8 weeks | 
| Sub-study 1b: Changes in parameters of cardiovascular haemodynamics in obese/overweight and T2DM participants after infusion of apelin (Bioimpedance) | Cardiac output measured by bioimpedance, in L/min | Visit 2 to visit 4, over a period of up to 8 weeks | 
| Sub-study 1b: Changes in parameters of cardiovascular haemodynamics in obese/overweight and T2DM participants after infusion of apelin,after a mixed meal challenge (Echocardiography) | Cardiac output measured by Echocardiography, in L/min | Visit 2 to visit 4, over a period of up to 8 weeks | 
| Sub-study 1b: Changes in parameters of cardiovascular haemodynamics in obese/overweight and T2DM participants after infusion of apelin, after a mixed meal challenge (Innocor) | Cardiac output measured by Innocor, in L/min | Visit 2 to visit 4, over a period of up to 8 weeks | 
| Sub-study 1b: Changes in parameters of cardiovascular haemodynamics in obese/overweight and T2DM participants after infusion of apelin,after a mixed meal challenge (Bioimpedance) | Cardiac output measured by bioimpedance, in L/min | VIsit 2 to visit 4, over a period of up to 8 weeks | 
| Sub-study 1b: Changes in markers of glucose homeostasis after infusion of apelin in obese/overweight and T2DM, after a mixed meal challenge (Clugose) | Glucose, in mmol/L | Visit 2 to visit 5, over a period of up to 14 weeks | 
| Sub-study 1b: Changes in markers of glucose homeostasis after infusion of apelin in obese/overweight and T2DM, after a mixed meal challenge (C-peptide) | C-peptide, in pmol/L | Visit 2 to visit 5, over a period of up to 14 weeks | 
| Sub-study 1b: Changes in markers of glucose homeostasis after infusion of apelin in obese/overweight and T2DM, after a mixed meal challenge (Glucagon) | Glucagon, in pg/ml | Visit 2 to visit 5, over a period of up to 14 weeks | 
| Sub-study 1b: Changes in markers of glucose homeostasis after infusion of apelin in obese/overweight and T2DM, after a mixed meal challenge (Insulin) | Insulin, in pmol/L | Visit 2 to visit 5, over a period of up to 14 weeks | 
| Sub-study 1b: Changes in markers of glucose homeostasis after infusion of apelin in obese/overweight and T2DM, after a mixed meal challenge (TNF alpha) | TNF alpha, in pg/ml | Visit 2 to visit 5, over a period of up to 14 weeks | 
| Sub-study 2b: Change in forearm blood flow parameters after infusion of verapamil in the presence of L-NMMA or saline (Ratio) | Ratio,expressed as a number (no units as this is a ratio) | Visit 2 to visit 3, over a period of up to 10 weeks | 
| Sub-study 2b: Change in forearm blood flow parameters after infusion of verapamil in the presence of L-NMMA or saline (Absolute Flow) | Absolute flow in the infused arm, in mg/dL/min | Visit 2 to visit 3, over a period of up to 10 weeks | 
| Sub-study 2b: Change in forearm blood flow parameters after infusion of verapamil in the presence of L-NMMA or saline (Percentage Change) | Percentage change in the infused arm, In % | Visit 2 to visit 3, over a period of up to 10 weeks | 
| Sub-study 4: Change in cardiovascular haemodynamics after infusion of relaxin (Echocardiography) | Cardiac output measured by Echocardiography, in L/min | Visit 2 to visit 4, over a period of up to 8 weeks | 
| Sub-study 4: Change in cardiovascular haemodynamics after infusion of relaxin (Bioimpedance) | Cardiac output measured by bioimpedance, in L/min | Visit 2 to visit 4, over a period of up to 8 weeks | 
| Sub-study 4: Change in cardiovascular haemodynamics after infusion of relaxin (Innocor) | Cardiac output measured by Innocor, in L/min | Visit 2 to visit 4, over a period of up to 8 weeks | 
| Sub-study 4: Change in cardiovascular haemodynamics after combined infusion of relaxin and apelin (Echocardiography) | Cardiac output measured by Echocardiography, in L/min | Visit 2 to visit 4, over a period of up to 8 weeks | 
| Sub-study 4: Change in cardiovascular haemodynamics after combined infusion of relaxin and apelin (Bioimpedance) | Cardiac output measured by bioimpedance, in L/min | Visit 2 to visit 4, over a period of up to 8 weeks | 
| Sub-study 4: Change in cardiovascular haemodynamics after combined infusion of relaxin and apelin (Innocor) | Cardiac output measured by Innocor, in L/min | Visit 2 to visit 4, over a period of up to 8 weeks | 
| Sub-study 4: Change in glucose homeostasis after combined infusion of relaxin and apelin (Glucose) | Glucose, in mmol/L | Visit 2 to visit 4, over a period of up to 8 weeks | 
| Substudy 4: Change in glucose homeostasis after combined infusion of relaxin and apelin (C-peptide) | C-peptide, in pmol/L | Visit 2 to visit 4, over a period of up to 8 weeks | 
| Sub-study 4: Change in glucose homeostasis after combined infusion of relaxin and apelin (Glucagon) | Glucagon, in pg/ml | Visit 2 to visit 4, over a period of up to 8 weeks | 
| Sub-study 4: Change in glucose homeostasis after combined infusion of relaxin and apelin (Insulin) | Insulin, in pmol/L | Visit 2 to visit 4, over a period of up to 8 weeks | 
| Sub-study 4: Change in glucose homeostasis after combined infusion of relaxin and apelin (TNF alpha) | TNF alpha, glucose homeostasis | Visit 2 to visit 4, over a period of up to 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Apelin, Relaxin