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

NHS Foundation Trust

Status and phase: Active, not recruiting; Phase 2

Conditions: Type 2 Diabetes Mellitus; Cardiovascular Diseases

Treatments: Drug: Relaxin; Drug: Normal saline; Diagnostic Test: LN Monomethyl arginine; Diagnostic Test: Verapamil; Drug: Apelin

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT03449251

DEFINE (A094666)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 170 estimated patients

Sex: All

Ages: 18 to 75 years old

Volunteers: Accepts 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

Trial design

Primary purpose: Other

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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170 participants in 8 patient groups

Substudy 1A - Apelin

Experimental group

Description:

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

Treatment:

Drug: Apelin

Substudy 1B - Apelin/Normal Saline

Experimental group

Description:

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

Treatment:

Drug: Apelin

Drug: Normal saline

Substudy 2A - Relaxin/Normal Saline

Experimental group

Description:

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

Treatment:

Drug: Normal saline

Drug: Relaxin

Substudy 2B - Relaxin

Experimental group

Description:

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)

Treatment:

Diagnostic Test: LN Monomethyl arginine

Diagnostic Test: Verapamil

Drug: Relaxin

Substudy 3A - Relaxin with Apelin/Saline

Experimental group

Description:

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

Treatment:

Drug: Apelin

Drug: Normal saline

Drug: Relaxin

Substudy 3B - Apelin with Relaxin/Saline

Experimental group

Description:

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

Treatment:

Drug: Apelin

Drug: Normal saline

Drug: Relaxin

Substudy 4 - Apelin and Relaxin

Experimental group

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

Treatment:

Drug: Apelin

Drug: Relaxin

Substudy 5 - Relaxin/Saline

Experimental group

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

Treatment:

Drug: Normal saline

Drug: Relaxin