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

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.

Study Overview

• Status: Terminated
• Conditions: Drug-Related Side Effects and Adverse Reactions; Cardiovascular System Disease
• Intervention / Treatment: Drug: Albuterol Sulfate; Drug: Nicardipine Hydrochloride; Drug: Dobutamine Hydrochloride; Drug: Placebo; Drug: Phenylephrine Hydrochloride; Drug: Verapamil Hydrochloride; Drug: Phentolamine Mesylate

Detailed Description

Safety is an integral part of developing new medicines. Potential drugs can be withdrawn from development at any stage of the process if there are concerns over safety. In recent years, computer models that recreate physiology have been increasingly adopted in various aspects of drug development, including safety, to predict the effects of new drugs. The accuracy of this predictive model is however, dependent on the ability for animal data (which the model is usually based on) to be 'translated' to human data. As no animal is identical to humans, the difference between species needs to be understood for the model to be accurate.

Unwanted effects on the cardiovascular system is one of the most common causes of safety related discontinuation of a drug. The present study focuses on generating high quality human cardiovascular data that is comparable with existing animal data. This will be achieved through the collection of detailed pharmacokinetic and pharmacodynamic data following administration of drugs that are known to affect the cardiovascular system through a range of mechanisms. This will be first performed in healthy participants before extending it to those with pre-existing (or risk-factors for) cardiovascular disease. The aim is to understand the differences between species and the study populations and using the collected data to help inform how a translational model is to be built.

Study Design: Single centre, single (participant) blind, within subject, drug administration study

Drugs used in study:

1. Salbutamol - a beta-2-adrenergic agonist
2. Nicardipine - a dihydropyridine calcium channel antagonist
3. Dobutamine - a beta-1-adrenergic agonist
4. Phenylephrine - a selective alpha-1-adrenergic agonist
5. Verapamil - a phenylalkylamine calcium channel antagonist
6. Phentolamine - a non-selective alpha adrenergic antagonist

Study Population:

The study will take place in three parts (A, B and C), with each part representing population groups that are of interest.

Part A (16 participants): Healthy individuals with no identifiable cardiovascular risk factors will be recruited for this part of the study. The aim of this part is to enable the collection of physiological data after drug administration in a 'normal' cardiovascular system.

Part B (8 participants): Part B will involve the recruitment of participants who may possess an altered/challenged cardiovascular system. Participants recruited will possess one of the following factors: known diagnosis of diabetes, known diagnosis of hypertension, obesity (BMI>30), age >65. The data collected will provide information on how potential changes to baseline cardiovascular physiology may affect the effect of the drug.

Part C (8 participants): In order to understand the impact of medicines on cardiovascular physiology in the absence of the autonomic nervous system regulation, we will recruit participants with dysfunction of the autonomic system to Part C of the study.

Maximum duration of participation for each participant:

1x screening (1 hour duration), 4x study visits (8 hour duration each) with minimum 72 hours gap in between visits. Maximum duration is 4 months to complete all visits.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Cambridgeshire
    • Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ
      • Addenbrooke's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: Salbutamol Sulfate; Drug: Nicardipine Hydrochloride; see arm/group descriptions; Drug: Dobutamine Hydrochloride; see arm/group descriptions; Drug: Placebo; see arm/group descriptions; Other Names: 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: Placebo; see arm/group descriptions; Other Names: 0.9% Sodium Chloride; Drug: Phenylephrine Hydrochloride; see arm/group descriptions; Drug: Verapamil Hydrochloride; see arm/group descriptions; Other Names: Securon IV; Drug: Phentolamine Mesylate; see arm/group descriptions; Other Names: Phentolamine Mesilate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heart rate	Change in heart rate from baseline over time after administration of drug	At every study visit (each lasting up to 8 hours)
Peripheral blood pressure	Change in resting peripheral blood pressure (systolic, diastolic, pulse pressure and mean pressure) over time after administration of drug	At every study visit (each lasting up to 8 hours)
Central blood pressure	Change in resting central aortic pressure (systolic, diastolic, pulse pressure and mean pressure) from baseline over time after administration of drug	At every study visit (each lasting up to 8 hours)
Cardiac output	Change in cardiac output from baseline over time after administration of drug	At every study visit (each lasting up to 8 hours)
Stroke volume	Change in stroke volume from baseline over time after administration of drug	At every study visit (each lasting up to 8 hours)
ECG/Cardiac monitor	Change in ECG (PR interval/QRS interval/QT interval/QTc interval/RR interval) over time after administration of drug	At every study visit (each lasting up to 8 hours)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma drug concentration (all drugs)	Measure of drug levels (parent compound and active metabolites) at the specified time points	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)
Plasma drug (active) metabolite concentration (varapamil only)	Measure of drug levels (parent compound and active metabolites) at the specified time points	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)
Renal Function	Changes in renal function throughout study	Through study completion, up to 4 months
Liver function	Changes in liver function throughout study	Through study completion, up to 4 months

Collaborators and Investigators

• Sponsor: Cambridge University Hospitals NHS Foundation Trust
• Collaborators: AstraZeneca; University of Cambridge

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 24, 2017
• Primary Completion (ACTUAL): February 29, 2020
• Study Completion (ACTUAL): February 29, 2020

Study Registration Dates

• First Submitted: March 14, 2017
• First Submitted That Met QC Criteria: March 28, 2017
• First Posted (ACTUAL): April 4, 2017

Study Record Updates

• Last Update Posted (ACTUAL): March 22, 2021
• Last Update Submitted That Met QC Criteria: March 18, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Cardiovascular; Pharmacodynamics; Adverse reactions; Translation; Modelling
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Cardiovascular Diseases; Drug-Related Side Effects and Adverse Reactions; Physiological Effects of Drugs; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Protective Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Cardiotonic Agents; Membrane Transport Modulators; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Calcium-Regulating Hormones and Agents; Reproductive Control Agents; Calcium Channel Blockers; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Tocolytic Agents; Sympathomimetics; Adrenergic beta-1 Receptor Agonists; Adrenergic alpha-Antagonists; Vasoconstrictor Agents; Mydriatics; Nasal Decongestants; Adrenergic alpha-1 Receptor Agonists; Albuterol; Verapamil; Dobutamine; Phenylephrine; Oxymetazoline; Nicardipine; Phentolamine
• Other Study ID Numbers: PRIME (A094136)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No