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A Study of the Pharmacokinetic and Pharmacodynamic Responses in Healthy and Altered Human Cardiovascular Systems (PRIME)

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ClinicalTrials.gov Identifier: NCT03098680
Recruitment Status : Recruiting
First Posted : April 4, 2017
Last Update Posted : May 17, 2018
Sponsor:
Collaborators:
University of Cambridge
AstraZeneca
Information provided by (Responsible Party):
Joseph Cheriyan, MD, Cambridge University Hospitals NHS Foundation Trust

Brief Summary:
Unwanted effects on the cardiovascular system is one of the most common causes of safety related discontinuation of a drug. This study aims to develop an in silico model of the human cardiovascular system that can be used to predict unwanted cardiovascular effects of drugs. This will be achieved through a drug administration study that will generate comprehensive pharmacokinetic and pharmacodynamic data following the administration of the following drugs, all known to have effects on the cardiovascular system. Half the participants will receive: Placebo, Salbutamol, Nicardipine, Dobutamine and the other half will receive Placebo, Phenylephrine, Verapamil, Phentolamine.

Condition or disease Intervention/treatment Phase
Drug-Related Side Effects and Adverse Reactions Cardiovascular System Disease Drug: Albuterol Sulfate Drug: Nicardipine Hydrochloride Drug: Dobutamine Hydrochloride Drug: Phenylephrine Hydrochloride Drug: Verapamil Hydrochloride Drug: Phentolamine Mesylate Drug: Placebo Phase 1

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Basic Science
Official Title: A Study of the Pharmacokinetic and Pharmacodynamic Responses in Healthy and Altered Human Cardiovascular Systems
Actual Study Start Date : April 24, 2017
Estimated Primary Completion Date : February 29, 2020
Estimated Study Completion Date : February 29, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Group A (Placebo, Salbutamol, Nicardipine, Dobutamine)

Participants will receive each drug, to be given on separate study days. The drugs will be given as a 3 stage infusion with dose increasing at each stage. Each stage will be 30 minutes in duration.

Placebo; Salbutamol(Albuterol) Sulfate (Dose: 2mcg/min, 5mcg/min, 10mcg/min); Nicardipine Hydrochloride (Dose: 1mg/hr, 2.5mg/hr, 5mg/hr); Dobutamine Hydrochloride (Dose: 1mcg/kg/min, 2.5mcg/kg/min, 5mcg/kg/min)

Drug: Albuterol Sulfate
see arm/group descriptions
Other Name: Salbutamol Sulfate

Drug: Nicardipine Hydrochloride
see arm/group descriptions

Drug: Dobutamine Hydrochloride
see arm/group descriptions

Drug: Placebo
see arm/group descriptions
Other Name: 0.9% Sodium Chloride

Experimental: Group B (Placebo, Phenylephrine, Verapamil, Phentolamine)

Participants will receive each drug, to be given on separate study days. The drugs will be given as a 3 stage bolus with dose increasing at each stage. Each stage will be 30 minutes apart.

Placebo; Phenylephrine Hydrochloride (Dose: 100mcg, 200mcg, 300mcg); Verapamil Hydrochloride (Dose: 1mg, 2.5mg, 5mg); Phentolamine Mesylate (Dose: 1mg, 2mg, 3mg)

Drug: Phenylephrine Hydrochloride
see arm/group descriptions

Drug: Verapamil Hydrochloride
see arm/group descriptions
Other Name: Securon IV

Drug: Phentolamine Mesylate
see arm/group descriptions
Other Name: Phentolamine Mesilate

Drug: Placebo
see arm/group descriptions
Other Name: 0.9% Sodium Chloride




Primary Outcome Measures :
  1. Heart rate [ Time Frame: At every study visit (each lasting up to 8 hours) ]
    Change in heart rate from baseline over time after administration of drug

  2. Peripheral blood pressure [ Time Frame: At every study visit (each lasting up to 8 hours) ]
    Change in resting peripheral blood pressure (systolic, diastolic, pulse pressure and mean pressure) over time after administration of drug

  3. Central blood pressure [ Time Frame: At every study visit (each lasting up to 8 hours) ]
    Change in resting central aortic pressure (systolic, diastolic, pulse pressure and mean pressure) from baseline over time after administration of drug

  4. Cardiac output [ Time Frame: At every study visit (each lasting up to 8 hours) ]
    Change in cardiac output from baseline over time after administration of drug

  5. Stroke volume [ Time Frame: At every study visit (each lasting up to 8 hours) ]
    Change in stroke volume from baseline over time after administration of drug

  6. ECG/Cardiac monitor [ Time Frame: At every study visit (each lasting up to 8 hours) ]
    Change in ECG (PR interval/QRS interval/QT interval/QTc interval/RR interval) over time after administration of drug


Secondary Outcome Measures :
  1. Plasma drug concentration (all drugs) [ Time Frame: These will be measured during each part of the study, estimated 6 months per part. Taken at: -(5mins, 10mins,15mins, 30mins, 35mins, 40mins, 45mins, 60mins, 65mins, 70mins, 75mins, 90mins, 120mins, 150mins, 180mins, 240mins, 360mins) ]
    Measure of drug levels (parent compound and active metabolites) at the specified time points

  2. Plasma drug (active) metabolite concentration (varapamil only) [ Time Frame: Throughout the study, estimated 6 months per part. Taken at specified timepoints (5mins, 10min, 15mins, 30mins, 35mins, 40mins, 45mins, 60mins, 65mins, 70mins, 75mins, 90mins, 120mins, 150mins, 180mins, 240mins, 360mins) ]
    Measure of drug levels (parent compound and active metabolites) at the specified time points

  3. Renal Function [ Time Frame: Through study completion, up to 4 months ]
    Changes in renal function throughout study

  4. Liver function [ Time Frame: Through study completion, up to 4 months ]
    Changes in liver function throughout study



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Part A Inclusion Criteria

To be included in the study the patient must:

  • Have given written informed consent to participate
  • Male
  • Be aged between 18 and 30 years at the time of first study appointment
  • BMI <30
  • Deemed healthy to partake in the study at the discretion of the investigator

Exclusion Criteria

The presence of any of the following will preclude patient inclusion:

  • Less than 18 years old, >30 years old
  • BMI >30
  • On regular medications
  • Known allergy to medications
  • History of psychiatric, chronic cardiac / respiratory / renal disease
  • Known diagnosis of diabetes
  • Habitual smoker
  • Screening heart rate of less than 60 beats per minute
  • Screening heart rate of greater than 100 beats per minute
  • Screening blood pressure of less than 100mmHg systolic and/or 55mmHg diastolic
  • Any concomitant condition or circumstance that, at the discretion of the investigator, may affect the participant's ability to complete the study
  • Current participation in another interventional research study

Part B Inclusion Criteria

To be included in the study the patient must:

  • Have given written informed consent to participate
  • Male
  • Be aged over 18 years at the time of first study appointment
  • Possess one of the following - known diagnosis of diabetes, known diagnosis of hypertension, obesity (BMI>30), aged >65
  • Deemed healthy to partake in the study at the discretion of the investigator

Exclusion Criteria

The presence of any of the following will preclude patient inclusion:

  • Less than 18 years old
  • On regular medications that are contraindicated for co-use with the study drugs
  • Known allergy to medications
  • Screening heart rate of less than 60 beats per minute
  • Screening heart rate of greater than 100 beats per minute
  • Screening blood pressure of less than 100mmHg systolic and/or 55mmHg diastolic
  • Any concomitant condition or circumstance that, at the discretion of the investigator, may affect the participant's ability to complete the study
  • Current participation in another interventional research study

Part C Inclusion Criteria

To be included in the study the patient must:

  • Have given written informed consent to participate
  • Male
  • Be aged over 18 years at the time of first study appointment
  • Clinical diagnosis of autonomic dysfunction
  • BMI<30
  • Deemed healthy to partake in the study at the discretion of the investigator

Exclusion Criteria

The presence of any of the following will preclude patient inclusion:

  • Less than 18 years old
  • BMI >30
  • On regular medication
  • Known allergy to medications
  • History of psychiatric, chronic cardiac / respiratory / renal disease
  • Habitual smoker
  • Screening heart rate of less than 60 beats per minute
  • Screening heart rate of greater than 100 beats per minute
  • Screening blood pressure of less than 100mmHg systolic and/or 55mmHg diastolic
  • Any concomitant condition or circumstance that, at the discretion of the investigator, may affect the participant's ability to complete the study
  • Current participation in another interventional research study

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): NCT03098680


Contacts
Contact: Charmaine Griffiths 01223 348963 charmaine.griffiths@addenbrookes.nhs.uk

Locations
United Kingdom
Addenbrooke's Hospital Recruiting
Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ
Contact: Joseph Cheriyan, MBChB, MA, FRCP       jc403@medschl.cam.ac.uk   
Sponsors and Collaborators
Cambridge University Hospitals NHS Foundation Trust
University of Cambridge
AstraZeneca
Investigators
Principal Investigator: Joseph Cheriyan, MBCHB, MA, FRCP Cambridge University Hospitals NHS Foundation Trust

Responsible Party: Joseph Cheriyan, MD, Dr, Cambridge University Hospitals NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT03098680     History of Changes
Other Study ID Numbers: PRIME (A094136)
First Posted: April 4, 2017    Key Record Dates
Last Update Posted: May 17, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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:
Adverse reactions
Cardiovascular
Translation
Modelling
Pharmacokinetics
Pharmacodynamics

Additional relevant MeSH terms:
Drug-Related Side Effects and Adverse Reactions
Cardiovascular Diseases
Chemically-Induced Disorders
Albuterol
Phenylephrine
Oxymetazoline
Dobutamine
Phentolamine
Verapamil
Nicardipine
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Tocolytic Agents
Reproductive Control Agents
Adrenergic beta-2 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Cardiotonic Agents
Mydriatics
Sympathomimetics
Vasoconstrictor Agents
Nasal Decongestants
Adrenergic alpha-1 Receptor Agonists