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

NCT ID: NCT03449251

Last Updated: 2024-02-07

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 170 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-03-28
• Study Completion Date: 2025-09-30

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.

Conditions

Cardiovascular Diseases; Type 2 Diabetes Mellitus

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: TRIPLE

Study Groups

Substudy 1A - Apelin

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

Group Type: EXPERIMENTAL

Apelin

Intervention Type: DRUG

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

Substudy 1B - Apelin/Normal Saline

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

Group Type: EXPERIMENTAL

Apelin

Intervention Type: DRUG

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

Normal saline

Intervention Type: DRUG

Vehicle

Substudy 2A - Relaxin/Normal Saline

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

Group Type: EXPERIMENTAL

Relaxin

Intervention Type: DRUG

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

Normal saline

Intervention Type: DRUG

Vehicle

Substudy 2B - 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)

Group Type: EXPERIMENTAL

Relaxin

Intervention Type: DRUG

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

Verapamil

Intervention Type: DIAGNOSTIC_TEST

NO independent challenge agent

LN Monomethyl arginine

Intervention Type: DIAGNOSTIC_TEST

Basal NO synthase inhibitor

Substudy 3A - Relaxin with Apelin/Saline

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

Group Type: EXPERIMENTAL

Apelin

Intervention Type: DRUG

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

Relaxin

Intervention Type: DRUG

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

Normal saline

Intervention Type: DRUG

Vehicle

Substudy 3B - Apelin with Relaxin/Saline

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

Group Type: EXPERIMENTAL

Apelin

Intervention Type: DRUG

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

Relaxin

Intervention Type: DRUG

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

Normal saline

Intervention Type: DRUG

Vehicle

Substudy 4 - Apelin and Relaxin

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

Group Type: EXPERIMENTAL

Apelin

Intervention Type: DRUG

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

Relaxin

Intervention Type: DRUG

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

Substudy 5 - Relaxin/Saline

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

Group Type: EXPERIMENTAL

Relaxin

Intervention Type: DRUG

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

Normal saline

Intervention Type: DRUG

Vehicle

Interventions

Apelin

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

Relaxin

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

Intervention Type: DRUG

Normal saline

Vehicle

Intervention Type: DRUG

Verapamil

NO independent challenge agent

Intervention Type: DIAGNOSTIC_TEST

LN Monomethyl arginine

Basal NO synthase inhibitor

Intervention Type: DIAGNOSTIC_TEST

Other Intervention Names

RLX; Saline; LNMMA

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Cambridge

OTHER

Sponsor Role: collaborator

AstraZeneca

INDUSTRY

Sponsor Role: collaborator

MedImmune LLC

INDUSTRY

Sponsor Role: collaborator

Cambridge University Hospitals NHS Foundation Trust

OTHER

Sponsor Role: lead

Responsible Party

Joseph Cheriyan, MD

Consultant Physician & Clinical Pharmacologist/Assoc Lecturer

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Joseph Cheriyan, MBCHB, FRCP

Role: PRINCIPAL_INVESTIGATOR

Cambridge University Hospitals NHS Foundation Trust

Locations

Addenbrooke's Hospital

Cambridge, Cambridgeshire, United Kingdom

Countries

United Kingdom

Other Identifiers

DEFINE (A094666)

Identifier Type: -

Identifier Source: org_study_id