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

NCT03098680 | Terminated Phase 1

• 1 other identifier: PRIME (A094136)
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

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.

Conditions

Drug-Related Side Effects and Adverse Reactions; Cardiovascular System Disease

Keywords

Adverse reactions; Cardiovascular; Translation; Modelling; Pharmacokinetics; Pharmacodynamics

Outcome Measures

Primary Outcomes (6)

• 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 Outcomes (4)

• Plasma drug concentration (all drugs)

  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)

  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

  Through study completion, up to 4 months

• Liver function

  Through study completion, up to 4 months

Study Arms (2)

Group A (Placebo, Salbutamol, Nicardipine, Dobutamine)

EXPERIMENTAL

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; Drug: Nicardipine Hydrochloride; Drug: Dobutamine Hydrochloride; Drug: Placebo

Group B (Placebo, Phenylephrine, Verapamil, Phentolamine)

EXPERIMENTAL

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; Drug: Verapamil Hydrochloride; Drug: Phentolamine Mesylate; Drug: Placebo

Interventions

Albuterol Sulfate DRUG

see arm/group descriptions

Also known as: Salbutamol Sulfate

Group A (Placebo, Salbutamol, Nicardipine, Dobutamine)

Nicardipine Hydrochloride DRUG

see arm/group descriptions

Group A (Placebo, Salbutamol, Nicardipine, Dobutamine)

Dobutamine Hydrochloride DRUG

see arm/group descriptions

Group A (Placebo, Salbutamol, Nicardipine, Dobutamine)

Phenylephrine Hydrochloride DRUG

see arm/group descriptions

Group B (Placebo, Phenylephrine, Verapamil, Phentolamine)

Verapamil Hydrochloride DRUG

see arm/group descriptions

Also known as: Securon IV

Group B (Placebo, Phenylephrine, Verapamil, Phentolamine)

Phentolamine Mesylate DRUG

see arm/group descriptions

Also known as: Phentolamine Mesilate

Group B (Placebo, Phenylephrine, Verapamil, Phentolamine)

Placebo DRUG

see arm/group descriptions

Also known as: 0.9% Sodium Chloride

Group A (Placebo, Salbutamol, Nicardipine, Dobutamine); Group B (Placebo, Phenylephrine, Verapamil, Phentolamine)

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• To be included in the study the patient must:
• Have given written informed consent to participate
• Male

Sponsors & Collaborators

• Cambridge University Hospitals NHS Foundation Trust: lead
• University of Cambridge: collaborator
• AstraZeneca: collaborator

Study Sites (1)

Addenbrooke's Hospital

Cambridge, Cambridgeshire, CB2 0QQ, United Kingdom

Location

MeSH Terms

Conditions

Drug-Related Side Effects and Adverse Reactions; Cardiovascular Diseases

Interventions

Albuterol; Nicardipine; Dobutamine; Phenylephrine; Verapamil; Phentolamine; Sodium Chloride

Condition Hierarchy (Ancestors)

Chemically-Induced Disorders

Intervention Hierarchy (Ancestors)

Ethanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Amines; Phenethylamines; Ethylamines; Dihydropyridines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Catecholamines; Catechols; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Imidazoles; Azoles; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Joseph Cheriyan, MBCHB, MA, FRCP

  Cambridge University Hospitals NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Dr

Study Record Dates

• First Submitted: March 14, 2017
• First Posted: April 4, 2017
• Study Start: April 24, 2017
• Primary Completion: February 29, 2020
• Study Completion: February 29, 2020
• Last Updated: March 22, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)