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

NCT03449251 | Active Not Recruiting Phase 2

• 1 other identifier: DEFINE (A094666)
• Study Type: interventional
• Target: 170
• Locations: 1 country
• Sites: 1

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.

Conditions

Cardiovascular Diseases; Type 2 Diabetes Mellitus

Keywords

Apelin; Relaxin

Outcome Measures

Primary Outcomes (30)

• 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 Outcomes (28)

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

  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)

  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)

  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)

  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)

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

Study Arms (8)

Substudy 1A - Apelin

EXPERIMENTAL

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

Drug: Apelin

Substudy 1B - Apelin/Normal Saline

EXPERIMENTAL

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; Drug: Normal saline

Substudy 2A - Relaxin/Normal Saline

EXPERIMENTAL

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

Drug: Relaxin; Drug: Normal saline

Substudy 2B - Relaxin

EXPERIMENTAL

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; Diagnostic Test: Verapamil; Diagnostic Test: LN Monomethyl arginine

Substudy 3A - Relaxin with Apelin/Saline

EXPERIMENTAL

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

Drug: Apelin; Drug: Relaxin; Drug: Normal saline

Substudy 3B - Apelin with Relaxin/Saline

EXPERIMENTAL

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

Drug: Apelin; Drug: Relaxin; Drug: Normal saline

Substudy 4 - Apelin and Relaxin

EXPERIMENTAL

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; Drug: Relaxin

Substudy 5 - Relaxin/Saline

EXPERIMENTAL

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; Drug: Normal saline

Interventions

Apelin 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 1A - Apelin; Substudy 1B - Apelin/Normal Saline; Substudy 3A - Relaxin with Apelin/Saline; Substudy 3B - Apelin with Relaxin/Saline; Substudy 4 - Apelin and Relaxin

Relaxin DRUG

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

Also known as: RLX

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

Normal saline DRUG

Vehicle

Also known as: Saline

Substudy 1B - Apelin/Normal Saline; Substudy 2A - Relaxin/Normal Saline; Substudy 3A - Relaxin with Apelin/Saline; Substudy 3B - Apelin with Relaxin/Saline; Substudy 5 - Relaxin/Saline

Verapamil DIAGNOSTIC_TEST

NO independent challenge agent

Substudy 2B - Relaxin

LN Monomethyl arginine DIAGNOSTIC_TEST

Basal NO synthase inhibitor

Also known as: LNMMA

Substudy 2B - Relaxin

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Cambridge University Hospitals NHS Foundation Trust: lead
• University of Cambridge: collaborator
• AstraZeneca: collaborator
• MedImmune LLC: collaborator

Study Sites (1)

Addenbrooke's Hospital

Cambridge, Cambridgeshire, CB20QQ, United Kingdom

Location

MeSH Terms

Conditions

Cardiovascular Diseases; Diabetes Mellitus, Type 2

Interventions

Apelin; Relaxin; Saline Solution; Sodium Chloride

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Biological Factors; Corpus Luteum Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptide Hormones; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Joseph Cheriyan, MBCHB, FRCP

  Cambridge University Hospitals NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Identical, colourless solution
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Consultant Physician & Clinical Pharmacologist/Assoc Lecturer

Study Record Dates

• First Submitted: February 6, 2018
• First Posted: February 28, 2018
• Study Start: March 28, 2018
• Primary Completion: September 1, 2025
• Study Completion: September 1, 2025
• Last Updated: February 7, 2024

Record last verified: 2024-02

Locations

GB (1)