Optimising the Propranolol Block Model

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00549120
First received: October 23, 2007
Last updated: July 26, 2012
Last verified: July 2012
  Purpose

Optimising the propranolol block model


Condition Intervention Phase
Pulmonary Disease, Chronic Obstructive
Drug: Propranolol
Drug: Salbutamol
Drug: Ipratropium
Drug: Placebo
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Basic Science
Official Title: A Study to Optimise the Propranolol Block Model for Assessment of the Pharmacological Activity of Bronchodilators in Healthy Volunteers.

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Specific airway conductance (sGAW) [ Time Frame: Pre-dose and up to 26 h post-dose ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Tolerability: adverse events, 12 lead ECG, blood pressure and heart rate [ Time Frame: Study duration ] [ Designated as safety issue: Yes ]
  • Propranolol pharmacokinetics [ Time Frame: Pre-dose and up to 28 h post-dose ] [ Designated as safety issue: No ]

Enrollment: 18
Study Start Date: August 2007
Study Completion Date: October 2007
Primary Completion Date: October 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Propranolol alone
Propranolol 80 mg (5 doses at 6 hourly intervals)
Drug: Propranolol
40 mg tablets
Experimental: Propranolol + salbutamol
Propranolol 80 mg (5 doses at 6 hourly intervals) + salbutamol 600 μg (4 doses at 6 hourly intervals)
Drug: Propranolol
40 mg tablets
Drug: Salbutamol
Metered dose inhaler (600 μg)
Experimental: Salbutamol alone
Salbutamol 600 μg (4 doses at 6 hourly) + placebo (5 doses at 6 hourly intervals)
Drug: Salbutamol
Metered dose inhaler (600 μg)
Drug: Placebo
Placebo for propranolol tablets
Placebo Comparator: Placebo
Placebo (5 doses at 6 hourly)
Drug: Placebo
Placebo for propranolol tablets
Experimental: Propranolol + ipratropium + salbutamol
Propranolol 80 mg (2 doses at 6 hourly intervals) + ipratropium bromide 40 μg (2 doses at 6 hourly interval) + salbutamol 600 μg (1 dose)
Drug: Propranolol
40 mg tablets
Drug: Salbutamol
Metered dose inhaler (600 μg)
Drug: Ipratropium
Metered dose inhaler (40 μg)
Experimental: Placebo + ipratropium + salbutamol
Placebo (2 doses at 6 hourly intervals) + ipratropium bromide 40 μg (2 doses at 6 hourly interval) + salbutamol 600 μg (1 dose)
Drug: Salbutamol
Metered dose inhaler (600 μg)
Drug: Ipratropium
Metered dose inhaler (40 μg)
Drug: Placebo
Placebo for propranolol tablets

Detailed Description:

The bronchodilatory effects of inhaled beta2 agonists and anti-muscarinic drugs are the mainstay of symptomatic treatment of asthma and Chronic Obstructive Pulmonary Disease (COPD). A new approach is to combine both pharmacological approaches in a single molecule - ie a dual pharmacophore. It will be necessary to explore the relative contribution of the beta2 agonist versus anti-muscarinic bronchodilator properties of such a molecule. One way to do that is to block one of the components. Inhibition of beta2 agonist-mediated bronchodilatation by the non-selective beta-blocker propranolol is an established experimental method. Therefore this method may be useful in exploring the pharmacology of a dual pharmacophore.

Published studies have generally looked at the effect of a single dose of propranolol on a beta2 agonist over a relatively short period of time (a few hours). There is a desire to develop long acting bronchodilators that require once daily dosing only. Thus any dual pharmacophore developed is likely to have 24 hour duration of action after a single dose. Therefore to use this method of beta blockade to inhibit beta2 agonist mediated bronchodilation, it is necessary to confirm a dosing regimen of propranolol that has acceptable tolerability and is effective in blocking the effects of a beta2 agonist over 24 hours. That is the main purpose of this study.

It is also important to confirm that the bronchodilator effect of an antimuscarinic is unaffected by beta blockade. In addition, it is of interest to examine the bronchodilator effect of a combination of an antimuscarinic and beta2 agonist in healthy volunteers and the effect of propranolol on the combination.

  Eligibility

Ages Eligible for Study:   18 Years to 50 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy adult male or female aged between 18 and 50 years.
  • Body mass index within the range 19-29.9 kilograms/metre2
  • Forced Expiratory Volume in 1 second (FEV1) >80% predicted and a FEV1/ Forced Vital Capacity (FVC) ratio > 0.7
  • The subject has an increase in sGAW of >% over pre-dose baseline within 2 h of administration of 400 ug salbutamol by MDI inhaler at screening or in the 3 months before screening.
  • Subject has an increase in sGaw of 25% over pre-dose baseline within 2 h following 40 ug ipratropium bromide at screening or in the 3 months before screening
  • Subjects are current non-smokers who have not used any tobacco products in the 6-month period preceding the screening visit and have a pack history of < 10 pack years.

Exclusion criteria:

  • A past or present disease, which as judged by the Investigator and medical monitor may affect the outcome of the study or the safety of the subject
  • History of respiratory disease
  • Significant abnormal 12 lead ECG, QTc(B) and QTc(F) value at screening >450msec on an individual ECG or a PR interval outside the range 120-210 msec
  • Supine mean heart rate outside the range 45-90 beats per minute (bpm) at screening
  • Subject has donated a unit of blood within the 56 days or intends to donate within 56 days after completing the study
  • Subject is currently taking regular (or course of) medication whether prescribed or not (with the exception of contraceptives, including vitamins and herbal remedies such as St John's Wort)
  • Subject has participated in a clinical study with a New Chemical Entity (NCE) within the past 1 month
  • Infected with the Hepatitis B, Hepatitis C, or HIV virus
  • Subject has a history of drug or other allergy, which, in the opinion of the Investigator, contraindicates their participation
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00549120

Locations
United Kingdom
GSK Investigational Site
London, United Kingdom
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00549120     History of Changes
Other Study ID Numbers: MAB104954
Study First Received: October 23, 2007
Last Updated: July 26, 2012
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by GlaxoSmithKline:
Healthy Subjects
muscarinic receptor antagonist
propranolol
beta-blocker
beta-agonist

Additional relevant MeSH terms:
Chronic Disease
Lung Diseases
Pulmonary Disease, Chronic Obstructive
Disease Attributes
Lung Diseases, Obstructive
Pathologic Processes
Respiratory Tract Diseases
Albuterol
Ipratropium
Propranolol
Adrenergic Agents
Adrenergic Agonists
Adrenergic Antagonists
Adrenergic beta-2 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic beta-Antagonists
Anti-Arrhythmia Agents
Anti-Asthmatic Agents
Antihypertensive Agents
Autonomic Agents
Bronchodilator Agents
Cardiovascular Agents
Cholinergic Agents
Cholinergic Antagonists
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Reproductive Control Agents

ClinicalTrials.gov processed this record on October 20, 2014