Cardiovascular Effects of Apelin In Healthy Volunteers
Condition: Healthy
Study type: Interventional
Phase: Early Phase 1

Summary: 
      Apelin is an endogenous peptide with physiological actions in the cardiovascular system.
      Apelin can modulate vasomotor tone and is a potent endogenous inotrope. In a series of
      clinical studies, we have shown that apelin causes peripheral and coronary vasodilatation and
      increased cardiac contractility. We wish to study and compare the cardiovascular effects of
      subcutaneous versus intravenous apelin. We specifically wish to determine how different
      methods of apelin administration affect cardiac output and peripheral vascular resistance in
      healthy volunteers
    

Detailed description: 
      Study Protocols Groups of 5 subjects will be assigned to receive one of three protocols.

      Protocol 1:

      Five healthy volunteers will be asked to attend the clinical research facility on a total of
      4 occasions as per the protocol below.

      Visits 1 and 2 will occur over two consecutive days. Participants will attend at 07.30 and be
      given a light breakfast. An intravenous sampling cannula will be inserted into the
      antecubital vein of one arm. Blood samples (5 mL) will be taken immediately prior to
      subcutaneous injection (t=0; 08.00) of 1 mg (Pyr1)apelin-13 and at 5, 10, 15, 20, 25, 30, 45,
      60, 90, 120, 180, 240, 300, 360, 480 and 600 min after injection. Subjects will then be
      discharged from the facility and reattend the following day at 08.00 for a single venous
      sample. Approximately 85 mL of blood will be sampled in total over this time.

      Visits 3 and 4 will also occur over two consecutive days, at least one week after visit 2.
      Subjects will attend at 07.30 and be given a light breakfast. An intravenous sampling cannula
      will be inserted into the antecubital vein of one arm. Blood samples (5 mL) will be taken
      immediately prior to an intravenous bolus infusion (t=0; 08.00) of 1 mg (Pyr1)apelin-13 over
      15 min and at 5, 10, 15, 20, 25, 30, 45, 60, 90, 120, 180, 240, 300, 360, 480 and 600 min
      after injection. Subjects will then be discharged from the facility and reattend the
      following day at 08.00 for a single venous sample.

      Protocol 2:

      Five healthy volunteers will be asked to attend the clinical research facility on a total of
      4 occasions as per the protocol below.

      Visits 1 and 2 will occur over two consecutive days. Participants will attend at 07.30 and be
      given a light breakfast. An intravenous sampling cannula will be inserted into the
      antecubital vein of one arm. Blood samples (5 mL) will be taken immediately prior to
      subcutaneous injection (t=0; 08.00) of 5 mg (Pyr1)apelin-13 and at 5, 10, 15, 20, 25, 30, 45,
      60, 90, 120, 180, 240, 300, 360, 480 and 600 min after injection. Subjects will then be
      discharged from the facility and reattend the following day at 08.00 for a single venous
      sample. Approximately 85 mL of blood will be sampled in total over this time.

      Visits 3 and 4 will also occur over two consecutive days, at least one week after visit 2.
      Subjects will attend at 07.30 and be given a light breakfast. An intravenous sampling cannula
      will be inserted into the antecubital vein of one arm. Blood samples (5 mL) will be taken
      immediately prior to an intravenous bolus infusion (t=0; 08.00) of 5 mg (Pyr1)apelin-13 over
      15 min and at 5, 10, 15, 20, 25, 30, 45, 60, 90, 120, 180, 240, 300, 360, 480 and 600 min
      after injection. Subjects will then be discharged from the facility and reattend the
      following day at 08.00 for a single venous sample.

      Protocol 3:

      Five healthy volunteers will be asked to attend the clinical research facility for 2
      consecutive days. Subjects will attend at 07.30 and be given a light breakfast. An
      intravenous sampling cannula will be inserted into the antecubital vein of one arm. Blood
      samples (5 mL) will be taken immediately prior to commencing a 24-h subcutaneous infusion of
      (t=0; 08.00) of 10 mg (Pyr1)apelin-13 dissolved in 10 mL water for injection. Further venous
      sampling will take place at 5, 10, 15, 20, 25, 30, 45, 60, 90, 120, 180, 240, 300, 360, 480
      and 600 min after injection. Subjects will then be discharged from the facility and reattend
      the following day at 08.00 for a single venous sample.

      Measurements

      Thoracic Bioimpedance Cardiography By virtue of changes in transthoracic electrical impedance
      during cardiac ejection, thoracic bioimpedance cardiography allows the non-invasive
      assessment of cardiac stroke volume and the calculation of cardiac output and cardiac index.
      After skin preparation, four pairs of low-contact impedance 'sensing' and 'current injecting'
      electrodes will be attached to the patient and connected to an impedance cardiograph. This
      technique has been applied widely and compares favourably with both invasive and other
      non-invasive (echocardiographic) measures of cardiac output. These variables will therefore
      be recorded at regular intervals throughout the study in all 3 protocols. Heart rate and
      blood pressure will also be monitored at regular intervals throughout each study using a
      semi-automated oscillometric sphygmomanometer (Omron HEM-705CP, Omron, Matsusaka, Japan).
      Mean arterial pressure (MAP) will be calculated as diastolic blood pressure plus a third of
      the pulse pressure.

      Assays Blood samples (5 mL) will be collected before and at the end of each drug infusion
      into ethylene diamine tetraacetic acid (EDTA), centrifuged and plasma frozen in three 1-mL
      aliquots to be stored at -80 °C until assay. Plasma concentrations of apelin will be measured
      by collaborators at Bristol Myers Squibb, Princeton, USA.

      Methods of Statistical Analysis

      Outcome data will be analysed where appropriate, by analysis of variance (ANOVA) with
      repeated measures, regression analysis, and paired and unpaired Student's t-test. Statistical
      significance will be taken at the 5% level.
    

Intervention name(s): Apelin 1mg subcutaneous; Apelin 1mg intravenous; Apelin 5mg subcutaneous; Apelin 5mg intravenous; Apelin 10 mg subcutaneous
Intervention type(s): Drug; Drug; Drug; Drug; Drug
Intervention description(s): single subcutaneous injection of Apelin 1mg subcutaneous; 15 minute intravenous bolus of Apelin 1mg intravenous; single subcutaneous injection of Apelin 5mg subcutaneous; 15 minute intravenous infusion of Apelin 5mg intravenous; 24 hour continuous subcutaneous infusion of Apelin 10 mg subcutaneous
Other intervention name(s): 1mg Sc; 1mg iv; 5mg Sc; 5mg iv; 10mg sc
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Keywords: Apelin; volunteers