Effects of Urocortins on Forearm Arterial Blood Flow in Healthy Volunteers - Protocol 4

Effects of Urocortins on Forearm Arterial Blood Flow in Healthy Volunteers

Impairment of the heart's pumping capacity (heart failure) remains a major clinical problem with a poor prognosis and the search for novel treatments remains an important area of research.

Urocortins are proteins that appear to increase blood flow and heart pumping activity. There has been particular interest in the role of Urocortins 2 & 3 (subtypes of Urocortins) in heart failure.

In this study, we will examine the pharmacokinetics and pharmacodynamics (in particular the onset-offset of action and reproducibility of vasodilator effects) of Urocortins 2 & 3 on forearm arterial blood flow healthy volunteers.

Utilising the well-established technique of 'forearm venous occlusion plethysmography', we will be able to focus on the local effects of urocortins on arterial blood flow in forearm vessels, without affecting this system in the body as a whole.

Study Overview

• Status: Completed
• Conditions: Heart Failure; Cardiovascular Disease
• Intervention / Treatment: Drug: Urocortin 2; Drug: Urocortin 3

• Study Type: Interventional
• Enrollment (Anticipated): 12
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • Mid Lothian
    • Edinburgh, Mid Lothian, United Kingdom, EH16 4SA
      • Wellcome Trust Clinical Research Facility, Royal Infirmary of Edinburgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Healthy male volunteers between 18 - 65 years (inclusive)

Exclusion Criteria:

• Lack of informed consent- Age <18 years > 65 years
• Current involvement in a clinical trial
• Severe or significant co-morbidity including bleeding diathesis, renal or hepatic failure
• Smoker
• History of anaemia
• Recent infective/inflammatory condition
• Recent blood donation (prior 3 months)
• Positive baseline urine test for drugs of abuse (including cannabinoids, benzodiazepines, opiates, cocaine and amphetamines)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Urocortin 2; This arm studies the onset/ offset of action and the reproducibility of effect on forearm blood flow of of intra-arterial Urocortin 2 in the presence and absence of a saline washout between incremental doses.	Drug: Urocortin 2; Protocol 4a: Onset/Offset protocol: (Visits 1 or 3) Following a 20-minute period of saline infusion for equilibration of the set-up, subjects will receive incremental doses of Urocortin 2 in the presence of a saline washout between each dose. Urocortin 2 will be infused at 3.6, 12, 36 and 120 pmol/min (15, 50, 150 and 498 nanograms/min) to achieve estimated end-organ concentrations of 0.6, 2, 6 and 20 micrograms/L respectively. Protocol 4b: Reproducibility protocol (Visit 2 or 4) Following a 20-minute period of saline infusion for equilibration of the set-up, subjects will receive ascending doses of urocortin 2 in the absence of saline washout between each dose. This protocol aims to assess the reproducibility of the vasodilatory effect of urocortin 2 on repeated dosing. The doses used for this protocol will be identical to Protocol a.
Other: Urocortin 3; This arm studies the onset/ offset of action and the reproducibility of effect on forearm blood flow of of intra-arterial Urocortin 3 in the presence and absence of a saline washout between incremental doses.	Drug: Urocortin 3; Protocol 4a: Onset/ Offset protocol: (Visit 1 or 3) Following a 20-minute period of saline infusion for equilibration of the set-up, subjects will receive incremental doses of Urocortin 2 or Urocortin 3 in the presence of a saline washout between each dose. Urocortin 3 will be infused at 1200, 3600, 12000 and 36000 pmol/min (5, 15, 50 and 150 micrograms/min) to achieve estimated end organ concentrations of 199, 600, 2000 and 6000 micrograms/L respectively. Protocol 4b: Reproducibility protocol (Visit 2 or 4) Following a 20-minute period of saline infusion for equilibration of the set-up, subjects will receive ascending doses of urocortin 3 in the absence of saline washout between each dose. This protocol aims to assess the reproducibility of the vasodilatory effect of 3 on repeated dosing. The doses used for this protocol will be identical to Protocol a.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Forearm blood flow	Difference in forearm blood flow in response to increasing doses of Urocortin 2 and Urocortin 3 in the presence and absence of saline washout between doses	3.5 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Urocortin 2 and 3 levels	Change in plasma levels of Urocortin 2 and 3 in response to intra-arterial infusion of Urocortin 2 and 3 respectively.	3.5 hours

Collaborators and Investigators

• Sponsor: University of Edinburgh
• Collaborators: NHS Lothian
• Investigators: Principal Investigator: David E Newby, PhD, FRCP, University of Edinburgh

Publications and helpful links

General Publications

• Venkatasubramanian S, Griffiths ME, McLean SG, Miller MR, Luo R, Lang NN, Newby DE. Vascular effects of urocortins 2 and 3 in healthy volunteers. J Am Heart Assoc. 2013 Jan 31;2(1):e004267. doi: 10.1161/JAHA.112.004267.

Study record dates

Study Major Dates

• Study Start: February 1, 2011
• Primary Completion (Actual): June 1, 2011
• Study Completion (Actual): July 1, 2011

Study Registration Dates

• First Submitted: February 14, 2011
• First Submitted That Met QC Criteria: February 14, 2011
• First Posted (Estimate): February 15, 2011

Study Record Updates

• Last Update Posted (Estimate): September 2, 2011
• Last Update Submitted That Met QC Criteria: August 31, 2011
• Last Verified: August 1, 2011

More Information

Terms related to this study

• Keywords: Heart Failure; Pharmacokinetics; Pharmacodynamics; Reproducibility; Urocortin 2; Urocortin 3; Plethysmography; Forearm blood flow; Onset/ Offset
• Additional Relevant MeSH Terms: Heart Diseases; Heart Failure; Cardiovascular Diseases
• Other Study ID Numbers: SV.Protocol 4