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

Primary Purpose

Cardiovascular Diseases, Type 2 Diabetes Mellitus

Status

Recruiting

Phase

Phase 2

Locations

United Kingdom

Study Type

Interventional

Intervention

Apelin

Relaxin

Normal saline

Verapamil

LN Monomethyl arginine

About this trial

This is an interventional other trial for Cardiovascular Diseases focused on measuring Apelin, Relaxin

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

Addenbrooke's HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm Type

Experimental

Arm Label

Substudy 1A - Apelin

Substudy 1B - Apelin/Normal Saline

Substudy 2A - Relaxin/Normal Saline

Substudy 2B - Relaxin

Substudy 3A - Relaxin with Apelin/Saline

Substudy 3B - Apelin with Relaxin/Saline

Substudy 4 - Apelin and Relaxin

Substudy 5 - Relaxin/Saline

Arm Description

In sub-study 1A Healthy participants will receive systemic infusions of Apelin to establish a dose range

In sub-study 1B , individuals with Type 2 Diabetes and individuals with increase weight will receive systemic infusions of Apelin or Normal Saline

In sub-study 2A Healthy participants will receive intra-arterial infusions of Relaxin

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)

In sub-study 3A Healthy participants will receive intra-arterial infusions of Relaxin (background infusion apelin/Normal Saline)

In sub-study 3B Healthy participants will receive intra-arterial infusions of Apelin (background infusion Relaxin/Normal Saline)

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

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

Outcomes

Primary Outcome Measures

Sub-study 1a: Changes in markers of glucose homeostasis in healthy participants after infusion of apelin (Glucose)

Glucose, in mmol/l

Sub-study 1a: Changes in markers of glucose homeostasis in healthy participants after infusion of apelin (C-Peptide)

C-peptide, in pmol/L

Sub-study 1a: Changes in markers of glucose homeostasis in healthy participants after infusion of apelin (Glucagon)

Glucagon, in pg/ml

Sub-study 1a: Changes in markers of glucose homeostasis in healthy participants after infusion of apelin (Insulin)

Insulin, in pmol/L

Sub-study 1a: Changes in markers of glucose homeostasis in healthy participants after infusion of apelin (TNF-alpha)

TNF-alpha, in pg/ml

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

C-peptide, in pmol/L

Glucagon, in pg/ml

Insulin, in pmol/L

TNF-alpha, in pg/ml

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

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 %

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)

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

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)

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

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 %

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

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)

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

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 %

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)

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

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 %

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

C-peptide, in each of the groups, in pmol/L

glucagon, in each of the groups,in pg/ml

Insulin, in each of the groups, in pmol/L

TNF-alpha, in each of the groups, in pg/ml

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

Secondary Outcome Measures

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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)

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

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 %

Sub-study 4: Change in cardiovascular haemodynamics after infusion of relaxin (Echocardiography)

Cardiac output measured by Echocardiography, in L/min

Sub-study 4: Change in cardiovascular haemodynamics after infusion of relaxin (Bioimpedance)

Cardiac output measured by bioimpedance, in L/min

Sub-study 4: Change in cardiovascular haemodynamics after infusion of relaxin (Innocor)

Cardiac output measured by Innocor, in L/min

Sub-study 4: Change in cardiovascular haemodynamics after combined infusion of relaxin and apelin (Echocardiography)

Cardiac output measured by Echocardiography, in L/min

Sub-study 4: Change in cardiovascular haemodynamics after combined infusion of relaxin and apelin (Bioimpedance)

Cardiac output measured by bioimpedance, in L/min

Sub-study 4: Change in cardiovascular haemodynamics after combined infusion of relaxin and apelin (Innocor)

Cardiac output measured by Innocor, in L/min

Sub-study 4: Change in glucose homeostasis after combined infusion of relaxin and apelin (Glucose)

Glucose, in mmol/L

Substudy 4: Change in glucose homeostasis after combined infusion of relaxin and apelin (C-peptide)

C-peptide, in pmol/L

Sub-study 4: Change in glucose homeostasis after combined infusion of relaxin and apelin (Glucagon)

Glucagon, in pg/ml

Sub-study 4: Change in glucose homeostasis after combined infusion of relaxin and apelin (Insulin)

Insulin, in pmol/L

Sub-study 4: Change in glucose homeostasis after combined infusion of relaxin and apelin (TNF alpha)

TNF alpha, glucose homeostasis

Full Information

NCT ID

NCT03449251

First Posted

February 6, 2018

Last Updated

February 15, 2022

Sponsor

Cambridge University Hospitals NHS Foundation Trust

Collaborators

University of Cambridge, AstraZeneca, MedImmune LLC

1. Study Identification

Unique Protocol Identification Number

NCT03449251

Brief Title

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

Acronym

DEFINE

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

February 2022

Overall Recruitment Status

Recruiting

Study Start Date

March 28, 2018 (Actual)

Primary Completion Date

September 2023 (Anticipated)

Study Completion Date

September 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Cambridge University Hospitals NHS Foundation Trust

Collaborators

University of Cambridge, AstraZeneca, MedImmune LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Cardiovascular Diseases, Type 2 Diabetes Mellitus

Keywords

Apelin, Relaxin

7. Study Design

Primary Purpose

Other

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigatorOutcomes Assessor

Masking Description

Identical, colourless solution

Allocation

Randomized

Enrollment

170 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Substudy 1A - Apelin

Arm Type

Experimental

Arm Description

In sub-study 1A Healthy participants will receive systemic infusions of Apelin to establish a dose range

Arm Title

Substudy 1B - Apelin/Normal Saline

Arm Type

Experimental

Arm Description

In sub-study 1B , individuals with Type 2 Diabetes and individuals with increase weight will receive systemic infusions of Apelin or Normal Saline

Arm Title

Substudy 2A - Relaxin/Normal Saline

Arm Type

Experimental

Arm Description

In sub-study 2A Healthy participants will receive intra-arterial infusions of Relaxin

Arm Title

Substudy 2B - Relaxin

Arm Type

Experimental

Arm Description

Arm Title

Substudy 3A - Relaxin with Apelin/Saline

Arm Type

Experimental

Arm Description

In sub-study 3A Healthy participants will receive intra-arterial infusions of Relaxin (background infusion apelin/Normal Saline)

Arm Title

Substudy 3B - Apelin with Relaxin/Saline

Arm Type

Experimental

Arm Description

In sub-study 3B Healthy participants will receive intra-arterial infusions of Apelin (background infusion Relaxin/Normal Saline)

Arm Title

Substudy 4 - Apelin and Relaxin

Arm Type

Experimental

Arm Description

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

Arm Title

Substudy 5 - Relaxin/Saline

Arm Type

Experimental

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Apelin

Intervention Description

Apelin is an endogenous peptide that activate a single G-protein couple receptor. Apelin inhibits insulin secretion, decreases glucose levels and increases insulin sensitivity.

Intervention Type

Drug

Intervention Name(s)

Relaxin

Other Intervention Name(s)

RLX

Intervention Description

Relaxin is RLN2 encoded endogenous peptide hormone, which binds to G protein coupled receptor RXFP1.

Intervention Type

Drug

Intervention Name(s)

Normal saline

Other Intervention Name(s)

Saline

Intervention Description

Vehicle

Intervention Type

Diagnostic Test

Intervention Name(s)

Verapamil

Intervention Description

NO independent challenge agent

Intervention Type

Diagnostic Test

Intervention Name(s)

LN Monomethyl arginine

Other Intervention Name(s)

LNMMA

Intervention Description

Basal NO synthase inhibitor

Primary Outcome Measure Information:

Title

Sub-study 1a: Changes in markers of glucose homeostasis in healthy participants after infusion of apelin (Glucose)

Description

Glucose, in mmol/l

Time Frame

Visit 2 to visit 4, over a period of up to 8 weeks

Title

Sub-study 1a: Changes in markers of glucose homeostasis in healthy participants after infusion of apelin (C-Peptide)

Description

C-peptide, in pmol/L

Time Frame

Visit 2 to visit 4, over a period of up to 8 weeks

Title

Sub-study 1a: Changes in markers of glucose homeostasis in healthy participants after infusion of apelin (Glucagon)

Description

Glucagon, in pg/ml

Time Frame

Visit 2 to visit 4, over a period of up to 8 weeks

Title

Sub-study 1a: Changes in markers of glucose homeostasis in healthy participants after infusion of apelin (Insulin)

Description

Insulin, in pmol/L

Time Frame

Visit 2 to visit 4, over a period of up to 8 weeks

Title

Sub-study 1a: Changes in markers of glucose homeostasis in healthy participants after infusion of apelin (TNF-alpha)

Description

TNF-alpha, in pg/ml

Time Frame

Visit 2 to visit 4, over a period of up to 8 weeks

Title

Description

Glucose, in mmol/l

Time Frame

Visit 2 to visit 5, over a period of up to 14 weeks

Title

Description

C-peptide, in pmol/L

Time Frame

Visit 2 to visit 5, over a period of up to 14 weeks

Title

Description

Glucagon, in pg/ml

Time Frame

Visit 2 to visit 5, over a period of up to 14 weeks

Title

Description

Insulin, in pmol/L

Time Frame

Visit 2 to visit 5, over a period of up to 14 weeks

Title

Description

TNF-alpha, in pg/ml

Time Frame

Visit 2 to visit 5, over a period of up to 14 weeks

Title

Sub-study 2a: Change in forearm blood flow parameters in healthy participants after infusion of relaxin (Absolute Flow)

Description

Absolute flow in the infused arm, in mg/dL/min

Time Frame

Within visit 2, over a period of up to 4 weeks

Title

Sub-study 2a: Change in forearm blood flow parameters in healthy participants after infusion of relaxin (Percentage Change)

Description

Percentage change in the infused arm, in %

Time Frame

Within visit 2, over a period of up to 4 weeks

Title

Sub-study 2a: Change in forearm blood flow parameters in healthy participants after infusion of relaxin (Ratio)

Description

Ratio, expressed as a number (no units as this is a ratio)

Time Frame

Within visit 2, over a period of up to 4 weeks

Title

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

Description

Ratio; absolute flow and percentage change in the infused arm

Time Frame

Visit 2 to visit 3, over a period of up to 10 weeks

Title

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)

Description

Ratio; expressed as a number (no units as this is a ratio)

Time Frame

Visit 2 to visit 3, over a period of up to 10 weeks

Title

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)

Description

Absolute flow in the infused arm, in mg/dL/min

Time Frame

Visit 2 to visit 3, over a period of up to 10 weeks

Title

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)

Description

Percentage change in the infused arm, In %

Time Frame

Visit 2 to visit 3, over a period of up to 10 weeks

Title

Sub-Study 3a: Change in forearm blood flow parameters in healthy participants after incremental infusions of intra-arterial relaxin in the presence of apelin

Description

Ratio; absolute flow and percentage change in the infused arm

Time Frame

Visit 2 to visit 3, over a period of up to 10 weeks

Title

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)

Description

Ratio, expressed as a number (no units as this is a ratio)

Time Frame

Visit 2 to visit 3, over a period of up to 10 weeks

Title

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)

Description

Absolute flow in the infused arm, in mg/dL/min

Time Frame

Visit 2 to visit 3, over a period of up to 10 weeks

Title

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)

Description

Percentage change in the infused arm, In %

Time Frame

Visit 2 to visit 3, over a period of up to 10 weeks

Title

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)

Description

Ratio, expressed as a number (no units as this is a ratio)

Time Frame

Visit 2 to visit 3, over a period of up to 10 weeks

Title

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)

Description

Absolute flow in the infused arm, in mg/dL/min

Time Frame

Visit 2 to visit 3, over a period of up to 10 weeks

Title

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)

Description

Percentage change in the infused arm, In %

Time Frame

Visit 2 to visit 3, over a period of up to 10 weeks

Title

Description

Glucose, in each of the groups, in mmol/L

Time Frame

Visit 2 to Visit 4, over a period of up to 8 weeks

Title

Description

C-peptide, in each of the groups, in pmol/L

Time Frame

Visit 2 to Visit 4, over a period of up to 8 weeks

Title

Description

glucagon, in each of the groups,in pg/ml

Time Frame

Visit 2 to Visit 4, over a period of up to 8 weeks

Title

Description

Insulin, in each of the groups, in pmol/L

Time Frame

Visit 2 to Visit 4, over a period of up to 8 weeks

Title

Description

TNF-alpha, in each of the groups, in pg/ml

Time Frame

Visit 2 to Visit 4, over a period of up to 8 weeks

Title

Sub-study 5: Change in hand vein diameter after relaxin infusion in healthy participants

Description

Hand vein Demeter is measured using Aellig dorsal hand vein technique

Time Frame

Visit 2

Secondary Outcome Measure Information:

Title

Sub-study 1a: Changes in parameters of cardiovascular haemodynamics in healthy participants after infusion of apelin (Echocardiography)

Description

Cardiac output measured by Echocardiography, in L/min

Time Frame

Visit 2 to visit 4, over a period of up to 8 weeks

Title

Sub-study 1a: Changes in parameters of cardiovascular haemodynamics in healthy participants after infusion of apelin (Innocor)

Description

Cardiac output measured by Innocor, in L/min

Time Frame

Visit 2 to visit 4, over a period of up to 8 weeks

Title

Sub-study 1a: Changes in parameters of cardiovascular haemodynamics in healthy participants after infusion of apelin (Bioimpedance)

Description

Cardiac output measured by bioimpedance, in L/min

Time Frame

Visit 2 to visit 4, over a period of up to 8 weeks

Title

Sub-study 1b: Changes in parameters of cardiovascular haemodynamics in obese/overweight and T2DM participants after infusion of apelin (Echocardiography)

Description

Cardiac output measured by Echocardiography, in L/min

Time Frame

VIsit 2 to visit 4, over a period of up to 8 weeks

Title

Sub-study 1b: Changes in parameters of cardiovascular haemodynamics in obese/overweight and T2DM participants after infusion of apelin (Innocor)

Description

Cardiac output measured by Innocor, in L/min

Time Frame

Visit 2 to visit 4, over a period of up to 8 weeks

Title

Sub-study 1b: Changes in parameters of cardiovascular haemodynamics in obese/overweight and T2DM participants after infusion of apelin (Bioimpedance)

Description

Cardiac output measured by bioimpedance, in L/min

Time Frame

Visit 2 to visit 4, over a period of up to 8 weeks

Title

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)

Description

Cardiac output measured by Echocardiography, in L/min

Time Frame

Visit 2 to visit 4, over a period of up to 8 weeks

Title

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)

Description

Cardiac output measured by Innocor, in L/min

Time Frame

Visit 2 to visit 4, over a period of up to 8 weeks

Title

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)

Description

Cardiac output measured by bioimpedance, in L/min

Time Frame

VIsit 2 to visit 4, over a period of up to 8 weeks

Title

Sub-study 1b: Changes in markers of glucose homeostasis after infusion of apelin in obese/overweight and T2DM, after a mixed meal challenge (Clugose)

Description

Glucose, in mmol/L

Time Frame

Visit 2 to visit 5, over a period of up to 14 weeks

Title

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)

Description

C-peptide, in pmol/L

Time Frame

Visit 2 to visit 5, over a period of up to 14 weeks

Title

Sub-study 1b: Changes in markers of glucose homeostasis after infusion of apelin in obese/overweight and T2DM, after a mixed meal challenge (Glucagon)

Description

Glucagon, in pg/ml

Time Frame

Visit 2 to visit 5, over a period of up to 14 weeks

Title

Sub-study 1b: Changes in markers of glucose homeostasis after infusion of apelin in obese/overweight and T2DM, after a mixed meal challenge (Insulin)

Description

Insulin, in pmol/L

Time Frame

Visit 2 to visit 5, over a period of up to 14 weeks

Title

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)

Description

TNF alpha, in pg/ml

Time Frame

Visit 2 to visit 5, over a period of up to 14 weeks

Title

Sub-study 2b: Change in forearm blood flow parameters after infusion of verapamil in the presence of L-NMMA or saline (Ratio)

Description

Ratio,expressed as a number (no units as this is a ratio)

Time Frame

Visit 2 to visit 3, over a period of up to 10 weeks

Title

Sub-study 2b: Change in forearm blood flow parameters after infusion of verapamil in the presence of L-NMMA or saline (Absolute Flow)

Description

Absolute flow in the infused arm, in mg/dL/min

Time Frame

Visit 2 to visit 3, over a period of up to 10 weeks

Title

Sub-study 2b: Change in forearm blood flow parameters after infusion of verapamil in the presence of L-NMMA or saline (Percentage Change)

Description

Percentage change in the infused arm, In %

Time Frame

Visit 2 to visit 3, over a period of up to 10 weeks

Title

Sub-study 4: Change in cardiovascular haemodynamics after infusion of relaxin (Echocardiography)

Description

Cardiac output measured by Echocardiography, in L/min

Time Frame

Visit 2 to visit 4, over a period of up to 8 weeks

Title

Sub-study 4: Change in cardiovascular haemodynamics after infusion of relaxin (Bioimpedance)

Description

Cardiac output measured by bioimpedance, in L/min

Time Frame

Visit 2 to visit 4, over a period of up to 8 weeks

Title

Sub-study 4: Change in cardiovascular haemodynamics after infusion of relaxin (Innocor)

Description

Cardiac output measured by Innocor, in L/min

Time Frame

Visit 2 to visit 4, over a period of up to 8 weeks

Title

Sub-study 4: Change in cardiovascular haemodynamics after combined infusion of relaxin and apelin (Echocardiography)

Description

Cardiac output measured by Echocardiography, in L/min

Time Frame

Visit 2 to visit 4, over a period of up to 8 weeks

Title

Sub-study 4: Change in cardiovascular haemodynamics after combined infusion of relaxin and apelin (Bioimpedance)

Description

Cardiac output measured by bioimpedance, in L/min

Time Frame

Visit 2 to visit 4, over a period of up to 8 weeks

Title

Sub-study 4: Change in cardiovascular haemodynamics after combined infusion of relaxin and apelin (Innocor)

Description

Cardiac output measured by Innocor, in L/min

Time Frame

Visit 2 to visit 4, over a period of up to 8 weeks

Title

Sub-study 4: Change in glucose homeostasis after combined infusion of relaxin and apelin (Glucose)

Description

Glucose, in mmol/L

Time Frame

Visit 2 to visit 4, over a period of up to 8 weeks

Title

Substudy 4: Change in glucose homeostasis after combined infusion of relaxin and apelin (C-peptide)

Description

C-peptide, in pmol/L

Time Frame

Visit 2 to visit 4, over a period of up to 8 weeks

Title

Sub-study 4: Change in glucose homeostasis after combined infusion of relaxin and apelin (Glucagon)

Description

Glucagon, in pg/ml

Time Frame

Visit 2 to visit 4, over a period of up to 8 weeks

Title

Sub-study 4: Change in glucose homeostasis after combined infusion of relaxin and apelin (Insulin)

Description

Insulin, in pmol/L

Time Frame

Visit 2 to visit 4, over a period of up to 8 weeks

Title

Sub-study 4: Change in glucose homeostasis after combined infusion of relaxin and apelin (TNF alpha)

Description

TNF alpha, glucose homeostasis

Time Frame

Visit 2 to visit 4, over a period of up to 8 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Joseph Cheriyan, MBCHB, FRCP

Organizational Affiliation

Cambridge University Hospitals NHS Foundation Trust

Official's Role

Principal Investigator

Facility Information:

Facility Name

Addenbrooke's Hospital

City

Cambridge

State/Province

Cambridgeshire

ZIP/Postal Code

CB20QQ

Country

United Kingdom

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Joseph Cheriyan, MBChB, FRCP

Phone

01223 926590

jc403@medschl.cam.ac.uk

First Name & Middle Initial & Last Name & Degree

Joseph Cheriyan, MBChB, FRCP

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Learn more about this trial

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

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