Clinical trial NCT03449251: A Series of Pilot Studies to Evaluate the haemoDynamic and mEtabolic Effects oF apelIn aNd rElaxin
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
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Cardiovascular Diseases
Type 2 Diabetes Mellitus
Keywords: Apelin
Relaxin
Lead sponsor: Cambridge University Hospitals NHS Foundation Trust
Sponsor class: OTHER
Collaborators: name: University of Cambridge
name: AstraZeneca
name: MedImmune LLC
First posted: 2018-02-28
Enrollment: 170
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.

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

Primary outcomes:
measure: Sub-study 1a: Changes in markers of glucose homeostasis in healthy participants after infusion of apelin (Glucose)
timeFrame: Visit 2 to visit 4, over a period of up to 8 weeks
measure: Sub-study 1a: Changes in markers of glucose homeostasis in healthy participants after infusion of apelin (C-Peptide)
timeFrame: Visit 2 to visit 4, over a period of up to 8 weeks
measure: Sub-study 1a: Changes in markers of glucose homeostasis in healthy participants after infusion of apelin (Glucagon)
timeFrame: Visit 2 to visit 4, over a period of up to 8 weeks
measure: Sub-study 1a: Changes in markers of glucose homeostasis in healthy participants after infusion of apelin (Insulin)
timeFrame: Visit 2 to visit 4, over a period of up to 8 weeks
measure: Sub-study 1a: Changes in markers of glucose homeostasis in healthy participants after infusion of apelin (TNF-alpha)
timeFrame: Visit 2 to visit 4, over a period of up to 8 weeks
measure: 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
timeFrame: Visit 2 to visit 5, over a period of up to 14 weeks
measure: 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
timeFrame: Visit 2 to visit 5, over a period of up to 14 weeks
measure: 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
timeFrame: Visit 2 to visit 5, over a period of up to 14 weeks
measure: 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
timeFrame: Visit 2 to visit 5, over a period of up to 14 weeks
measure: 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
timeFrame: Visit 2 to visit 5, over a period of up to 14 weeks
measure: Sub-study 2a: Change in forearm blood flow parameters in healthy participants after infusion of relaxin (Absolute Flow)
timeFrame: Within visit 2, over a period of up to 4 weeks
measure: Sub-study 2a: Change in forearm blood flow parameters in healthy participants after infusion of relaxin (Percentage Change)
timeFrame: Within visit 2, over a period of up to 4 weeks
measure: Sub-study 2a: Change in forearm blood flow parameters in healthy participants after infusion of relaxin (Ratio)
timeFrame: Within visit 2, over a period of up to 4 weeks
measure: 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
timeFrame: Visit 2 to visit 3, over a period of up to 10 weeks
measure: 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)
timeFrame: Visit 2 to visit 3, over a period of up to 10 weeks
measure: 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)
timeFrame: Visit 2 to visit 3, over a period of up to 10 weeks
measure: 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)
timeFrame: Visit 2 to visit 3, over a period of up to 10 weeks
measure: Sub-Study 3a: Change in forearm blood flow parameters in healthy participants after incremental infusions of intra-arterial relaxin in the presence of apelin
timeFrame: Visit 2 to visit 3, over a period of up to 10 weeks
measure: 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)
timeFrame: Visit 2 to visit 3, over a period of up to 10 weeks
measure: 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)
timeFrame: Visit 2 to visit 3, over a period of up to 10 weeks
measure: 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)
timeFrame: Visit 2 to visit 3, over a period of up to 10 weeks
measure: 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)
timeFrame: Visit 2 to visit 3, over a period of up to 10 weeks
measure: 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)
timeFrame: Visit 2 to visit 3, over a period of up to 10 weeks
measure: 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)
timeFrame: Visit 2 to visit 3, over a period of up to 10 weeks
measure: 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)
timeFrame: Visit 2 to Visit 4, over a period of up to 8 weeks
measure: 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)
timeFrame: Visit 2 to Visit 4, over a period of up to 8 weeks
measure: 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)
timeFrame: Visit 2 to Visit 4, over a period of up to 8 weeks
measure: 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)
timeFrame: Visit 2 to Visit 4, over a period of up to 8 weeks
measure: 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)
timeFrame: Visit 2 to Visit 4, over a period of up to 8 weeks
measure: Sub-study 5: Change in hand vein diameter after relaxin infusion in healthy participants
timeFrame: Visit 2
Secondary outcomes:
measure: Sub-study 1a: Changes in parameters of cardiovascular haemodynamics in healthy participants after infusion of apelin (Echocardiography)
timeFrame: Visit 2 to visit 4, over a period of up to 8 weeks
measure: Sub-study 1a: Changes in parameters of cardiovascular haemodynamics in healthy participants after infusion of apelin (Innocor)
timeFrame: Visit 2 to visit 4, over a period of up to 8 weeks
measure: Sub-study 1a: Changes in parameters of cardiovascular haemodynamics in healthy participants after infusion of apelin (Bioimpedance)
timeFrame: Visit 2 to visit 4, over a period of up to 8 weeks
measure: Sub-study 1b: Changes in parameters of cardiovascular haemodynamics in obese/overweight and T2DM participants after infusion of apelin (Echocardiography)
timeFrame: VIsit 2 to visit 4, over a period of up to 8 weeks
measure: Sub-study 1b: Changes in parameters of cardiovascular haemodynamics in obese/overweight and T2DM participants after infusion of apelin (Innocor)
timeFrame: Visit 2 to visit 4, over a period of up to 8 weeks
measure: Sub-study 1b: Changes in parameters of cardiovascular haemodynamics in obese/overweight and T2DM participants after infusion of apelin (Bioimpedance)
timeFrame: Visit 2 to visit 4, over a period of up to 8 weeks
measure: 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)
timeFrame: Visit 2 to visit 4, over a period of up to 8 weeks
measure: 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)
timeFrame: Visit 2 to visit 4, over a period of up to 8 weeks
measure: 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)
timeFrame: VIsit 2 to visit 4, over a period of up to 8 weeks
measure: Sub-study 1b: Changes in markers of glucose homeostasis after infusion of apelin in obese/overweight and T2DM, after a mixed meal challenge (Clugose)
timeFrame: Visit 2 to visit 5, over a period of up to 14 weeks
measure: 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)
timeFrame: Visit 2 to visit 5, over a period of up to 14 weeks
measure: Sub-study 1b: Changes in markers of glucose homeostasis after infusion of apelin in obese/overweight and T2DM, after a mixed meal challenge (Glucagon)
timeFrame: Visit 2 to visit 5, over a period of up to 14 weeks
measure: Sub-study 1b: Changes in markers of glucose homeostasis after infusion of apelin in obese/overweight and T2DM, after a mixed meal challenge (Insulin)
timeFrame: Visit 2 to visit 5, over a period of up to 14 weeks
measure: 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)
timeFrame: Visit 2 to visit 5, over a period of up to 14 weeks
measure: Sub-study 2b: Change in forearm blood flow parameters after infusion of verapamil in the presence of L-NMMA or saline (Ratio)
timeFrame: Visit 2 to visit 3, over a period of up to 10 weeks
measure: Sub-study 2b: Change in forearm blood flow parameters after infusion of verapamil in the presence of L-NMMA or saline (Absolute Flow)
timeFrame: Visit 2 to visit 3, over a period of up to 10 weeks
measure: Sub-study 2b: Change in forearm blood flow parameters after infusion of verapamil in the presence of L-NMMA or saline (Percentage Change)
timeFrame: Visit 2 to visit 3, over a period of up to 10 weeks
measure: Sub-study 4: Change in cardiovascular haemodynamics after infusion of relaxin (Echocardiography)
timeFrame: Visit 2 to visit 4, over a period of up to 8 weeks
measure: Sub-study 4: Change in cardiovascular haemodynamics after infusion of relaxin (Bioimpedance)
timeFrame: Visit 2 to visit 4, over a period of up to 8 weeks
measure: Sub-study 4: Change in cardiovascular haemodynamics after infusion of relaxin (Innocor)
timeFrame: Visit 2 to visit 4, over a period of up to 8 weeks
measure: Sub-study 4: Change in cardiovascular haemodynamics after combined infusion of relaxin and apelin (Echocardiography)
timeFrame: Visit 2 to visit 4, over a period of up to 8 weeks
measure: Sub-study 4: Change in cardiovascular haemodynamics after combined infusion of relaxin and apelin (Bioimpedance)
timeFrame: Visit 2 to visit 4, over a period of up to 8 weeks
measure: Sub-study 4: Change in cardiovascular haemodynamics after combined infusion of relaxin and apelin (Innocor)
timeFrame: Visit 2 to visit 4, over a period of up to 8 weeks
measure: Sub-study 4: Change in glucose homeostasis after combined infusion of relaxin and apelin (Glucose)
timeFrame: Visit 2 to visit 4, over a period of up to 8 weeks
measure: Substudy 4: Change in glucose homeostasis after combined infusion of relaxin and apelin (C-peptide)
timeFrame: Visit 2 to visit 4, over a period of up to 8 weeks
measure: Sub-study 4: Change in glucose homeostasis after combined infusion of relaxin and apelin (Glucagon)
timeFrame: Visit 2 to visit 4, over a period of up to 8 weeks
measure: Sub-study 4: Change in glucose homeostasis after combined infusion of relaxin and apelin (Insulin)
timeFrame: Visit 2 to visit 4, over a period of up to 8 weeks
measure: Sub-study 4: Change in glucose homeostasis after combined infusion of relaxin and apelin (TNF alpha)
timeFrame: Visit 2 to visit 4, over a period of up to 8 weeks
Other outcomes:
Locations:
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
state: Cambridgeshire
Study officials:
affiliation: Cambridge University Hospitals NHS Foundation Trust
name: Joseph Cheriyan, MBCHB, FRCP
role: PRINCIPAL_INVESTIGATOR
References: