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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03449251
Recruitment Status : Recruiting
First Posted : February 28, 2018
Last Update Posted : March 3, 2022
Sponsor:
Collaborators:
University of Cambridge
AstraZeneca
MedImmune LLC
Information provided by (Responsible Party):
Joseph Cheriyan, MD, Cambridge University Hospitals NHS Foundation Trust

Study Description
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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.


Condition or disease Intervention/treatment Phase
Cardiovascular Diseases Type 2 Diabetes Mellitus Drug: Apelin Drug: Relaxin Drug: Normal saline Diagnostic Test: Verapamil Diagnostic Test: LN Monomethyl arginine Phase 2

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 170 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description: Identical, colourless solution
Primary Purpose: Other
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
Actual Study Start Date : March 28, 2018
Estimated Primary Completion Date : September 2023
Estimated Study Completion Date : September 2023

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Substudy 1A - Apelin
In sub-study 1A Healthy participants will receive systemic infusions of Apelin to establish a dose range
 Drug: 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.
Experimental: 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
 Drug: 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.

Drug: Normal saline
Vehicle
Other Name: Saline
Experimental: Substudy 2A - Relaxin/Normal Saline
In sub-study 2A Healthy participants will receive intra-arterial infusions of Relaxin
 Drug: Relaxin
Relaxin is RLN2 encoded endogenous peptide hormone, which binds to G protein coupled receptor RXFP1.
Other Name: RLX

Drug: Normal saline
Vehicle
Other Name: Saline
Experimental: 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)
 Drug: Relaxin
Relaxin is RLN2 encoded endogenous peptide hormone, which binds to G protein coupled receptor RXFP1.
Other Name: RLX

Diagnostic Test: Verapamil
NO independent challenge agent

Diagnostic Test: LN Monomethyl arginine
Basal NO synthase inhibitor
Other Name: LNMMA
Experimental: Substudy 3A - Relaxin with Apelin/Saline
In sub-study 3A Healthy participants will receive intra-arterial infusions of Relaxin (background infusion apelin/Normal Saline)
 Drug: 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.

Drug: Relaxin
Relaxin is RLN2 encoded endogenous peptide hormone, which binds to G protein coupled receptor RXFP1.
Other Name: RLX

Drug: Normal saline
Vehicle
Other Name: Saline
Experimental: Substudy 3B - Apelin with Relaxin/Saline
In sub-study 3B Healthy participants will receive intra-arterial infusions of Apelin (background infusion Relaxin/Normal Saline)
 Drug: 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.

Drug: Relaxin
Relaxin is RLN2 encoded endogenous peptide hormone, which binds to G protein coupled receptor RXFP1.
Other Name: RLX

Drug: Normal saline
Vehicle
Other Name: Saline
Experimental: 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
 Drug: 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.

Drug: Relaxin
Relaxin is RLN2 encoded endogenous peptide hormone, which binds to G protein coupled receptor RXFP1.
Other Name: RLX
Experimental: 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
 Drug: Relaxin
Relaxin is RLN2 encoded endogenous peptide hormone, which binds to G protein coupled receptor RXFP1.
Other Name: RLX

Drug: Normal saline
Vehicle
Other Name: Saline


Outcome Measures
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Primary Outcome Measures :
  1. Sub-study 1a: Changes in markers of glucose homeostasis in healthy participants after infusion of apelin (Glucose) [ Time Frame: Visit 2 to visit 4, over a period of up to 8 weeks ]
    Glucose, in mmol/l

  2. Sub-study 1a: Changes in markers of glucose homeostasis in healthy participants after infusion of apelin (C-Peptide) [ Time Frame: Visit 2 to visit 4, over a period of up to 8 weeks ]
    C-peptide, in pmol/L

  3. Sub-study 1a: Changes in markers of glucose homeostasis in healthy participants after infusion of apelin (Glucagon) [ Time Frame: Visit 2 to visit 4, over a period of up to 8 weeks ]
    Glucagon, in pg/ml

  4. Sub-study 1a: Changes in markers of glucose homeostasis in healthy participants after infusion of apelin (Insulin) [ Time Frame: Visit 2 to visit 4, over a period of up to 8 weeks ]
    Insulin, in pmol/L

  5. Sub-study 1a: Changes in markers of glucose homeostasis in healthy participants after infusion of apelin (TNF-alpha) [ Time Frame: Visit 2 to visit 4, over a period of up to 8 weeks ]
    TNF-alpha, in pg/ml

  6. 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 [ Time Frame: Visit 2 to visit 5, over a period of up to 14 weeks ]
    Glucose, in mmol/l

  7. 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 [ Time Frame: Visit 2 to visit 5, over a period of up to 14 weeks ]
    C-peptide, in pmol/L

  8. 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 [ Time Frame: Visit 2 to visit 5, over a period of up to 14 weeks ]
    Glucagon, in pg/ml

  9. 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 [ Time Frame: Visit 2 to visit 5, over a period of up to 14 weeks ]
    Insulin, in pmol/L

  10. 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 [ Time Frame: Visit 2 to visit 5, over a period of up to 14 weeks ]
    TNF-alpha, in pg/ml

  11. Sub-study 2a: Change in forearm blood flow parameters in healthy participants after infusion of relaxin (Absolute Flow) [ Time Frame: Within visit 2, over a period of up to 4 weeks ]
    Absolute flow in the infused arm, in mg/dL/min

  12. Sub-study 2a: Change in forearm blood flow parameters in healthy participants after infusion of relaxin (Percentage Change) [ Time Frame: Within visit 2, over a period of up to 4 weeks ]
    Percentage change in the infused arm, in %

  13. Sub-study 2a: Change in forearm blood flow parameters in healthy participants after infusion of relaxin (Ratio) [ Time Frame: Within visit 2, over a period of up to 4 weeks ]
    Ratio, expressed as a number (no units as this is a ratio)

  14. 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 [ Time Frame: Visit 2 to visit 3, over a period of up to 10 weeks ]
    Ratio; absolute flow and percentage change in the infused arm

  15. 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) [ Time Frame: Visit 2 to visit 3, over a period of up to 10 weeks ]
    Ratio; expressed as a number (no units as this is a ratio)

  16. 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) [ Time Frame: Visit 2 to visit 3, over a period of up to 10 weeks ]
    Absolute flow in the infused arm, in mg/dL/min

  17. 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) [ Time Frame: Visit 2 to visit 3, over a period of up to 10 weeks ]
    Percentage change in the infused arm, In %

  18. Sub-Study 3a: Change in forearm blood flow parameters in healthy participants after incremental infusions of intra-arterial relaxin in the presence of apelin [ Time Frame: Visit 2 to visit 3, over a period of up to 10 weeks ]
    Ratio; absolute flow and percentage change in the infused arm

  19. 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) [ Time Frame: Visit 2 to visit 3, over a period of up to 10 weeks ]
    Ratio, expressed as a number (no units as this is a ratio)

  20. 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) [ Time Frame: Visit 2 to visit 3, over a period of up to 10 weeks ]
    Absolute flow in the infused arm, in mg/dL/min

  21. 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) [ Time Frame: Visit 2 to visit 3, over a period of up to 10 weeks ]
    Percentage change in the infused arm, In %

  22. 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) [ Time Frame: Visit 2 to visit 3, over a period of up to 10 weeks ]
    Ratio, expressed as a number (no units as this is a ratio)

  23. 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) [ Time Frame: Visit 2 to visit 3, over a period of up to 10 weeks ]
    Absolute flow in the infused arm, in mg/dL/min

  24. 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) [ Time Frame: Visit 2 to visit 3, over a period of up to 10 weeks ]
    Percentage change in the infused arm, In %

  25. 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) [ Time Frame: Visit 2 to Visit 4, over a period of up to 8 weeks ]
    Glucose, in each of the groups, in mmol/L

  26. 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) [ Time Frame: Visit 2 to Visit 4, over a period of up to 8 weeks ]
    C-peptide, in each of the groups, in pmol/L

  27. 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) [ Time Frame: Visit 2 to Visit 4, over a period of up to 8 weeks ]
    glucagon, in each of the groups,in pg/ml

  28. 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) [ Time Frame: Visit 2 to Visit 4, over a period of up to 8 weeks ]
    Insulin, in each of the groups, in pmol/L

  29. 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) [ Time Frame: Visit 2 to Visit 4, over a period of up to 8 weeks ]
    TNF-alpha, in each of the groups, in pg/ml

  30. Sub-study 5: Change in hand vein diameter after relaxin infusion in healthy participants [ Time Frame: Visit 2 ]
    Hand vein Demeter is measured using Aellig dorsal hand vein technique


Secondary Outcome Measures :
  1. Sub-study 1a: Changes in parameters of cardiovascular haemodynamics in healthy participants after infusion of apelin (Echocardiography) [ Time Frame: Visit 2 to visit 4, over a period of up to 8 weeks ]
    Cardiac output measured by Echocardiography, in L/min

  2. Sub-study 1a: Changes in parameters of cardiovascular haemodynamics in healthy participants after infusion of apelin (Innocor) [ Time Frame: Visit 2 to visit 4, over a period of up to 8 weeks ]
    Cardiac output measured by Innocor, in L/min

  3. Sub-study 1a: Changes in parameters of cardiovascular haemodynamics in healthy participants after infusion of apelin (Bioimpedance) [ Time Frame: Visit 2 to visit 4, over a period of up to 8 weeks ]
    Cardiac output measured by bioimpedance, in L/min

  4. Sub-study 1b: Changes in parameters of cardiovascular haemodynamics in obese/overweight and T2DM participants after infusion of apelin (Echocardiography) [ Time Frame: VIsit 2 to visit 4, over a period of up to 8 weeks ]
    Cardiac output measured by Echocardiography, in L/min

  5. Sub-study 1b: Changes in parameters of cardiovascular haemodynamics in obese/overweight and T2DM participants after infusion of apelin (Innocor) [ Time Frame: Visit 2 to visit 4, over a period of up to 8 weeks ]
    Cardiac output measured by Innocor, in L/min

  6. Sub-study 1b: Changes in parameters of cardiovascular haemodynamics in obese/overweight and T2DM participants after infusion of apelin (Bioimpedance) [ Time Frame: Visit 2 to visit 4, over a period of up to 8 weeks ]
    Cardiac output measured by bioimpedance, in L/min

  7. 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) [ Time Frame: Visit 2 to visit 4, over a period of up to 8 weeks ]
    Cardiac output measured by Echocardiography, in L/min

  8. 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) [ Time Frame: Visit 2 to visit 4, over a period of up to 8 weeks ]
    Cardiac output measured by Innocor, in L/min

  9. 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) [ Time Frame: VIsit 2 to visit 4, over a period of up to 8 weeks ]
    Cardiac output measured by bioimpedance, in L/min

  10. Sub-study 1b: Changes in markers of glucose homeostasis after infusion of apelin in obese/overweight and T2DM, after a mixed meal challenge (Clugose) [ Time Frame: Visit 2 to visit 5, over a period of up to 14 weeks ]
    Glucose, in mmol/L

  11. 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) [ Time Frame: Visit 2 to visit 5, over a period of up to 14 weeks ]
    C-peptide, in pmol/L

  12. Sub-study 1b: Changes in markers of glucose homeostasis after infusion of apelin in obese/overweight and T2DM, after a mixed meal challenge (Glucagon) [ Time Frame: Visit 2 to visit 5, over a period of up to 14 weeks ]
    Glucagon, in pg/ml

  13. Sub-study 1b: Changes in markers of glucose homeostasis after infusion of apelin in obese/overweight and T2DM, after a mixed meal challenge (Insulin) [ Time Frame: Visit 2 to visit 5, over a period of up to 14 weeks ]
    Insulin, in pmol/L

  14. 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) [ Time Frame: Visit 2 to visit 5, over a period of up to 14 weeks ]
    TNF alpha, in pg/ml

  15. Sub-study 2b: Change in forearm blood flow parameters after infusion of verapamil in the presence of L-NMMA or saline (Ratio) [ Time Frame: Visit 2 to visit 3, over a period of up to 10 weeks ]
    Ratio,expressed as a number (no units as this is a ratio)

  16. Sub-study 2b: Change in forearm blood flow parameters after infusion of verapamil in the presence of L-NMMA or saline (Absolute Flow) [ Time Frame: Visit 2 to visit 3, over a period of up to 10 weeks ]
    Absolute flow in the infused arm, in mg/dL/min

  17. Sub-study 2b: Change in forearm blood flow parameters after infusion of verapamil in the presence of L-NMMA or saline (Percentage Change) [ Time Frame: Visit 2 to visit 3, over a period of up to 10 weeks ]
    Percentage change in the infused arm, In %

  18. Sub-study 4: Change in cardiovascular haemodynamics after infusion of relaxin (Echocardiography) [ Time Frame: Visit 2 to visit 4, over a period of up to 8 weeks ]
    Cardiac output measured by Echocardiography, in L/min

  19. Sub-study 4: Change in cardiovascular haemodynamics after infusion of relaxin (Bioimpedance) [ Time Frame: Visit 2 to visit 4, over a period of up to 8 weeks ]
    Cardiac output measured by bioimpedance, in L/min

  20. Sub-study 4: Change in cardiovascular haemodynamics after infusion of relaxin (Innocor) [ Time Frame: Visit 2 to visit 4, over a period of up to 8 weeks ]
    Cardiac output measured by Innocor, in L/min

  21. Sub-study 4: Change in cardiovascular haemodynamics after combined infusion of relaxin and apelin (Echocardiography) [ Time Frame: Visit 2 to visit 4, over a period of up to 8 weeks ]
    Cardiac output measured by Echocardiography, in L/min

  22. Sub-study 4: Change in cardiovascular haemodynamics after combined infusion of relaxin and apelin (Bioimpedance) [ Time Frame: Visit 2 to visit 4, over a period of up to 8 weeks ]
    Cardiac output measured by bioimpedance, in L/min

  23. Sub-study 4: Change in cardiovascular haemodynamics after combined infusion of relaxin and apelin (Innocor) [ Time Frame: Visit 2 to visit 4, over a period of up to 8 weeks ]
    Cardiac output measured by Innocor, in L/min

  24. Sub-study 4: Change in glucose homeostasis after combined infusion of relaxin and apelin (Glucose) [ Time Frame: Visit 2 to visit 4, over a period of up to 8 weeks ]
    Glucose, in mmol/L

  25. Substudy 4: Change in glucose homeostasis after combined infusion of relaxin and apelin (C-peptide) [ Time Frame: Visit 2 to visit 4, over a period of up to 8 weeks ]
    C-peptide, in pmol/L

  26. Sub-study 4: Change in glucose homeostasis after combined infusion of relaxin and apelin (Glucagon) [ Time Frame: Visit 2 to visit 4, over a period of up to 8 weeks ]
    Glucagon, in pg/ml

  27. Sub-study 4: Change in glucose homeostasis after combined infusion of relaxin and apelin (Insulin) [ Time Frame: Visit 2 to visit 4, over a period of up to 8 weeks ]
    Insulin, in pmol/L

  28. Sub-study 4: Change in glucose homeostasis after combined infusion of relaxin and apelin (TNF alpha) [ Time Frame: Visit 2 to visit 4, over a period of up to 8 weeks ]
    TNF alpha, glucose homeostasis


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03449251


Locations
Layout table for location information
United Kingdom
Addenbrooke's Hospital Recruiting
Cambridge, Cambridgeshire, United Kingdom, CB20QQ
Contact: Joseph Cheriyan, MBChB, FRCP    01223 926590    jc403@medschl.cam.ac.uk   
Principal Investigator: Joseph Cheriyan, MBChB, FRCP         
Sponsors and Collaborators
Cambridge University Hospitals NHS Foundation Trust
University of Cambridge
AstraZeneca
MedImmune LLC
Investigators
Layout table for investigator information
Principal Investigator: Joseph Cheriyan, MBCHB, FRCP Cambridge University Hospitals NHS Foundation Trust
More Information
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Layout table for additonal information
Responsible Party: Joseph Cheriyan, MD, Consultant Physician & Clinical Pharmacologist/Assoc Lecturer, Cambridge University Hospitals NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT03449251    
Other Study ID Numbers: DEFINE (A094666)
First Posted: February 28, 2018    Key Record Dates
Last Update Posted: March 3, 2022
Last Verified: February 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Joseph Cheriyan, MD, Cambridge University Hospitals NHS Foundation Trust:
Apelin
Relaxin
Additional relevant MeSH terms:
Layout table for MeSH terms
Cardiovascular Diseases
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Verapamil
omega-N-Methylarginine
 Anti-Arrhythmia Agents
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Calcium-Regulating Hormones and Agents
Physiological Effects of Drugs
Vasodilator Agents
Enzyme Inhibitors