Optimising the Propranolol Block Model

A Study to Optimise the Propranolol Block Model for Assessment of the Pharmacological Activity of Bronchodilators in Healthy Volunteers.

Optimising the propranolol block model

Study Overview

• Status: Completed
• Conditions: Pulmonary Disease, Chronic Obstructive
• Intervention / Treatment: Drug: Propranolol; Drug: Salbutamol; Drug: Placebo; Drug: Ipratropium

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.

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

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom
    • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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: Placebo; Placebo for propranolol tablets; Drug: Ipratropium; Metered dose inhaler (40 μg)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Specific airway conductance (sGAW)	Pre-dose and up to 26 h post-dose

Secondary Outcome Measures

Outcome Measure	Time Frame
Tolerability: adverse events, 12 lead ECG, blood pressure and heart rate	Study duration
Propranolol pharmacokinetics	Pre-dose and up to 28 h post-dose

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

Helpful Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Study record dates

Study Major Dates

• Study Start (Actual): August 15, 2007
• Primary Completion (Actual): October 26, 2007
• Study Completion (Actual): October 26, 2007

Study Registration Dates

• First Submitted: October 23, 2007
• First Submitted That Met QC Criteria: October 23, 2007
• First Posted (Estimate): October 25, 2007

Study Record Updates

• Last Update Posted (Actual): August 4, 2017
• Last Update Submitted That Met QC Criteria: August 2, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: Healthy Subjects; propranolol; muscarinic receptor antagonist; beta-blocker; beta-agonist
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Antagonists; Cholinergic Agents; Adrenergic Agonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Reproductive Control Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Tocolytic Agents; Propranolol; Albuterol; Ipratropium
• Other Study ID Numbers: MAB104954

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Study Data/Documents

1. Annotated Case Report Form
   Information identifier: MAB104954
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Individual Participant Data Set
   Information identifier: MAB104954
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Informed Consent Form
   Information identifier: MAB104954
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Study Protocol
   Information identifier: MAB104954
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Dataset Specification
   Information identifier: MAB104954
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Statistical Analysis Plan
   Information identifier: MAB104954
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Clinical Study Report
   Information identifier: MAB104954
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register