A 3-period Crossover Study With GSK573719 as Monotherapy in Adult Subjects With Asthma

NCT ID: NCT01641692

Last Updated: 2017-03-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 350 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-05-31
• Study Completion Date: 2013-02-28

Brief Summary

This is a multi-national, randomized, double-blind, 3-period crossover, incomplete block design to evaluate 5 once-daily and 2 twice-daily doses of GSK573719 in combination with placebo. The study will explore the dose range of GSK573719 in asthmatic subjects who are currently using non-ICS controller medications. Subjects will participate in the study for up to a maximum of 14 weeks. At randomization subjects will be stratified by age to ensure adequate exposure to GSK573719 throughout the expected age range. The primary endpoint will be trough FEV1 obtained 24 hours after the last morning dose on Day 14 of each treatment sequence.

A sub-group of subjects at selected sites (approximately 30% of the total population) will have additional serial assessments for spirometry, ECG and Holter, and pharmacokinetic sampling at the start and end of each treatment period. Safety assessments will include monitoring for adverse events, laboratory tests, asthma symptom assessments and twice daily PEF evaluation. Consenting subjects will have a blood sample taken for pharmacogenetic analysis.

Detailed Description

Asthma, a reversible obstructive disease of the airways, is defined as a chronic inflammatory disorder of the airways in which many of the cells and cellular mediators play a role. The chronic inflammation is associated with airway hyper-responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or early in the morning. These episodes are usually associated with widespread, but variable airflow obstruction within the lung that is often reversible either spontaneously or with treatment (NIH 2007, GINA, 2010,). Guidelines recommend a stepwise approach to the management of asthma. For many patients with mild disease, asthma symptoms can be adequately relieved by 'on demand' use of a short acting beta-2 -agonist (SABA) alone. A long-acting, inhaled, muscarinic receptor antagonist (LAMA) exerts its effects via distinct and complementary bronchodilator mechanisms on large and small airways through antagonism of the endogenous agonist acetylcholine at the muscarinic receptors leading to smooth muscle relaxation and bronchodilation. However, most experience with older anti-cholinergics has been with acute use and little is known about their effect in chronic use or as maintenance in asthma.

Newer more selective muscarinic receptor antagonists are being developed for chronic use which appear to have a better adverse event profile compared with older anti-cholinergics in the treatment of asthma [Moulton 2011]. A once daily long-acting, inhaled, muscarinic receptor antagonist (LAMA) bronchodilator, GSK573719, may offer an alternative treatment option to patients with asthma.

The proposed study is a multi-national, randomized, double-blind, 3-period crossover, incomplete block study in outpatient subjects with mild asthma and who are not using inhaled corticosteroids (ICS) for symptom control. The primary objective of this study is to evaluate the dose response, efficacy and safety of five once-daily doses of GSK573719 compared with placebo, over a 14-day treatment period, in patients with asthma. A placebo arm will be included to determine an absolute treatment effect over placebo for each GSK573719 dose regimen.

Each eligible subject will be randomized to receive 3 out of 8 potential treatments in sequence over a total of three 14-day treatment periods. There will be 12 clinic visits including a safety follow-up visit at the end of the study. All subjects will be provided with albuterol (salbutamol) for use on an 'as-needed' basis throughout the run-in, treatment and washout periods. A sub-group (approximately 30%) of the study population will comprise subjects from selected sites. These subjects will have additional assessments at the start and end of each treatment period, including serial spirometry, serial ECGs, 24 hour Holter monitoring, and samples of blood and urine for pharmacokinetic analysis. Other safety parameters include the incidence of adverse events, vital signs, clinical laboratory parameters, ECGs and spirometry, including twice daily peak expiratory flow, asthma exacerbation assessment. and use of salbutamol.

Conditions

Asthma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

GSK573719 15.6 mcg

GSK573719 (Umeclinidium bromide) 15.6 mcg once-daily

Group Type: EXPERIMENTAL

GSK573719 Active treatment or Placebo

Intervention Type: DRUG

Eligible subjects will be randomised to a sequence of three treatments from 8 possible arms: 7 active drug doses (15.6mcg, 31.25 mc, 62.5mcg 125mcg or 250mcg GSK573719 once daily; 15.6mcg or 31.25 mcg GSK573719 taken twice daily) or matched placebo.

GSK573719 (Sub-group cohort)

Intervention Type: PROCEDURE

Subjects at selected Sub-group sites (approximately 30% of the total population) will have additional serial assessments and procedures (including blood and urine samples for pharmacokinetic analysis) at the start (Day 1) and at the end (Days 14 and 15) of each treatment period. On Day 14 of each treatment period subjects will remain overnight at the clinic for 24-hour assessments, including spirometry, ECGs, and 24-hour Holter monitoring.

Salbutamol/Albuterol

Intervention Type: DRUG

Salbutamol/Albuterol, short-activing beta agonist provided to all subjects to be taken as needed for the relief of asthma symptoms.throughout the study period, including washout periods

GSK573719 31.25 mcg

GSK573719 (Umeclinidium bromide) 31.25 mcg once-daily

Group Type: EXPERIMENTAL

GSK573719 Active treatment or Placebo

Intervention Type: DRUG

Eligible subjects will be randomised to a sequence of three treatments from 8 possible arms: 7 active drug doses (15.6mcg, 31.25 mc, 62.5mcg 125mcg or 250mcg GSK573719 once daily; 15.6mcg or 31.25 mcg GSK573719 taken twice daily) or matched placebo.

GSK573719 (Sub-group cohort)

Intervention Type: PROCEDURE

Subjects at selected Sub-group sites (approximately 30% of the total population) will have additional serial assessments and procedures (including blood and urine samples for pharmacokinetic analysis) at the start (Day 1) and at the end (Days 14 and 15) of each treatment period. On Day 14 of each treatment period subjects will remain overnight at the clinic for 24-hour assessments, including spirometry, ECGs, and 24-hour Holter monitoring.

Salbutamol/Albuterol

Intervention Type: DRUG

Salbutamol/Albuterol, short-activing beta agonist provided to all subjects to be taken as needed for the relief of asthma symptoms.throughout the study period, including washout periods

GSK573719 62.5 mcg

GSK573719 (Umeclinidium bromide) 62.5 mcg once-daily

Group Type: EXPERIMENTAL

GSK573719 Active treatment or Placebo

Intervention Type: DRUG

Eligible subjects will be randomised to a sequence of three treatments from 8 possible arms: 7 active drug doses (15.6mcg, 31.25 mc, 62.5mcg 125mcg or 250mcg GSK573719 once daily; 15.6mcg or 31.25 mcg GSK573719 taken twice daily) or matched placebo.

GSK573719 (Sub-group cohort)

Intervention Type: PROCEDURE

Subjects at selected Sub-group sites (approximately 30% of the total population) will have additional serial assessments and procedures (including blood and urine samples for pharmacokinetic analysis) at the start (Day 1) and at the end (Days 14 and 15) of each treatment period. On Day 14 of each treatment period subjects will remain overnight at the clinic for 24-hour assessments, including spirometry, ECGs, and 24-hour Holter monitoring.

Salbutamol/Albuterol

Intervention Type: DRUG

Salbutamol/Albuterol, short-activing beta agonist provided to all subjects to be taken as needed for the relief of asthma symptoms.throughout the study period, including washout periods

GSK573719 125 mcg

GSK573719 (Umeclinidium bromide) 125 mcg once-daily

Group Type: EXPERIMENTAL

GSK573719 Active treatment or Placebo

Intervention Type: DRUG

Eligible subjects will be randomised to a sequence of three treatments from 8 possible arms: 7 active drug doses (15.6mcg, 31.25 mc, 62.5mcg 125mcg or 250mcg GSK573719 once daily; 15.6mcg or 31.25 mcg GSK573719 taken twice daily) or matched placebo.

GSK573719 (Sub-group cohort)

Intervention Type: PROCEDURE

Subjects at selected Sub-group sites (approximately 30% of the total population) will have additional serial assessments and procedures (including blood and urine samples for pharmacokinetic analysis) at the start (Day 1) and at the end (Days 14 and 15) of each treatment period. On Day 14 of each treatment period subjects will remain overnight at the clinic for 24-hour assessments, including spirometry, ECGs, and 24-hour Holter monitoring.

Salbutamol/Albuterol

Intervention Type: DRUG

Salbutamol/Albuterol, short-activing beta agonist provided to all subjects to be taken as needed for the relief of asthma symptoms.throughout the study period, including washout periods

GSK573719 250 mcg

GSK573719 (Umeclinidium bromide) 250 mcg once-daily

Group Type: EXPERIMENTAL

GSK573719 Active treatment or Placebo

Intervention Type: DRUG

Eligible subjects will be randomised to a sequence of three treatments from 8 possible arms: 7 active drug doses (15.6mcg, 31.25 mc, 62.5mcg 125mcg or 250mcg GSK573719 once daily; 15.6mcg or 31.25 mcg GSK573719 taken twice daily) or matched placebo.

GSK573719 (Sub-group cohort)

Intervention Type: PROCEDURE

Subjects at selected Sub-group sites (approximately 30% of the total population) will have additional serial assessments and procedures (including blood and urine samples for pharmacokinetic analysis) at the start (Day 1) and at the end (Days 14 and 15) of each treatment period. On Day 14 of each treatment period subjects will remain overnight at the clinic for 24-hour assessments, including spirometry, ECGs, and 24-hour Holter monitoring.

Salbutamol/Albuterol

Intervention Type: DRUG

Salbutamol/Albuterol, short-activing beta agonist provided to all subjects to be taken as needed for the relief of asthma symptoms.throughout the study period, including washout periods

GSK573719 15.6 mcg twice-daily

GSK573719 (Umeclinidium bromide) 15.6 mcg twice-daily

Group Type: EXPERIMENTAL

GSK573719 Active treatment or Placebo

Intervention Type: DRUG

Eligible subjects will be randomised to a sequence of three treatments from 8 possible arms: 7 active drug doses (15.6mcg, 31.25 mc, 62.5mcg 125mcg or 250mcg GSK573719 once daily; 15.6mcg or 31.25 mcg GSK573719 taken twice daily) or matched placebo.

GSK573719 (Sub-group cohort)

Intervention Type: PROCEDURE

Subjects at selected Sub-group sites (approximately 30% of the total population) will have additional serial assessments and procedures (including blood and urine samples for pharmacokinetic analysis) at the start (Day 1) and at the end (Days 14 and 15) of each treatment period. On Day 14 of each treatment period subjects will remain overnight at the clinic for 24-hour assessments, including spirometry, ECGs, and 24-hour Holter monitoring.

Salbutamol/Albuterol

Intervention Type: DRUG

Salbutamol/Albuterol, short-activing beta agonist provided to all subjects to be taken as needed for the relief of asthma symptoms.throughout the study period, including washout periods

GSK573719 31.25 mcg twice daily

Gsk573719 (Umeclinidium bromide) 31.25 mcg twice-daily

Group Type: EXPERIMENTAL

GSK573719 Active treatment or Placebo

Intervention Type: DRUG

Eligible subjects will be randomised to a sequence of three treatments from 8 possible arms: 7 active drug doses (15.6mcg, 31.25 mc, 62.5mcg 125mcg or 250mcg GSK573719 once daily; 15.6mcg or 31.25 mcg GSK573719 taken twice daily) or matched placebo.

GSK573719 (Sub-group cohort)

Intervention Type: PROCEDURE

Subjects at selected Sub-group sites (approximately 30% of the total population) will have additional serial assessments and procedures (including blood and urine samples for pharmacokinetic analysis) at the start (Day 1) and at the end (Days 14 and 15) of each treatment period. On Day 14 of each treatment period subjects will remain overnight at the clinic for 24-hour assessments, including spirometry, ECGs, and 24-hour Holter monitoring.

Salbutamol/Albuterol

Intervention Type: DRUG

Salbutamol/Albuterol, short-activing beta agonist provided to all subjects to be taken as needed for the relief of asthma symptoms.throughout the study period, including washout periods

Matched Placebo

Matched Placebo arm

Group Type: PLACEBO_COMPARATOR

GSK573719 Active treatment or Placebo

Intervention Type: DRUG

Eligible subjects will be randomised to a sequence of three treatments from 8 possible arms: 7 active drug doses (15.6mcg, 31.25 mc, 62.5mcg 125mcg or 250mcg GSK573719 once daily; 15.6mcg or 31.25 mcg GSK573719 taken twice daily) or matched placebo.

GSK573719 (Sub-group cohort)

Intervention Type: PROCEDURE

Subjects at selected Sub-group sites (approximately 30% of the total population) will have additional serial assessments and procedures (including blood and urine samples for pharmacokinetic analysis) at the start (Day 1) and at the end (Days 14 and 15) of each treatment period. On Day 14 of each treatment period subjects will remain overnight at the clinic for 24-hour assessments, including spirometry, ECGs, and 24-hour Holter monitoring.

Salbutamol/Albuterol

Intervention Type: DRUG

Salbutamol/Albuterol, short-activing beta agonist provided to all subjects to be taken as needed for the relief of asthma symptoms.throughout the study period, including washout periods

Interventions

GSK573719 Active treatment or Placebo

Eligible subjects will be randomised to a sequence of three treatments from 8 possible arms: 7 active drug doses (15.6mcg, 31.25 mc, 62.5mcg 125mcg or 250mcg GSK573719 once daily; 15.6mcg or 31.25 mcg GSK573719 taken twice daily) or matched placebo.

Intervention Type: DRUG

GSK573719 (Sub-group cohort)

Subjects at selected Sub-group sites (approximately 30% of the total population) will have additional serial assessments and procedures (including blood and urine samples for pharmacokinetic analysis) at the start (Day 1) and at the end (Days 14 and 15) of each treatment period. On Day 14 of each treatment period subjects will remain overnight at the clinic for 24-hour assessments, including spirometry, ECGs, and 24-hour Holter monitoring.

Intervention Type: PROCEDURE

Salbutamol/Albuterol

Salbutamol/Albuterol, short-activing beta agonist provided to all subjects to be taken as needed for the relief of asthma symptoms.throughout the study period, including washout periods

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Written informed consent
• Outpatient (sub-group will have 3 overnight stays at clinic)
• Diagnosis of asthma (NIH 2007) for at least 6 months
• Male or Eligible female (females of child-bearing potential must use acceptable method of birth control)
• A best AM pre-bronchodilator FEV1 of 60% to 85% of predicted normal value at Screening
• Reversibility of disease demonstrated by at least 12% and 200mL increase in FEV1 .
• Subjects must have been prescribed a non-corticosteroid controller at least 3 months preceding Visit 1, and/or a short-acting beta 2 agonist, without the use of inhaled corticosteroids in the 4 weeks prior to Visit 1
• Subjects must be able to replace their current short-acting Beta-2-agonist with albuterol/salbutamol aerosol inhaler for the duration of the study
• Subjects must be judged capable of withholding albuterol/salbutamol for at least 4 hours prior to study visits

Exclusion Criteria

• History of life threatening asthma
• Severe asthma exacerbation
• Respiratory infection within expected to affect subject's ability to participate
• Concurrent respiratory disease
• Current smoker or smoking history of 10 pack years or more
• Diseases preventing use of anticholinergics
• Other clinically significant, uncontrolled condition or disease which would pose a safety risk to the patient, or confound interpretation of study results
• Drug allergy to any Beta-2-agonist, sympathomimetic drug, intranasal, inhaled or systemic corticosteroid therapy
• Known or suspected sensitivity to the constituents of the Novel DPI (ie lactose)
• History of severe milk protein allergy
• Administration of prescription or over-the-counter medication that would significantly affect the course of asthma, or interact with the study drug
• Any infirmity, disability or disease of a child or family member likely to impair compliance
• Alcohol or substance abuse history
• Viral hepatitis B surface antigen or Hepatitis C antibody
• Known HIV-positive history.
• Affiliation with investigator or site staff

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Newport Beach, California, United States

GSK Investigational Site

Sunset, Louisiana, United States

GSK Investigational Site

Bethesda, Maryland, United States

GSK Investigational Site

Columbia, Missouri, United States

GSK Investigational Site

Rolla, Missouri, United States

GSK Investigational Site

St Louis, Missouri, United States

GSK Investigational Site

Bellevue, Nebraska, United States

GSK Investigational Site

Medford, Oregon, United States

GSK Investigational Site

Orangeburg, South Carolina, United States

GSK Investigational Site

Spartanburg, South Carolina, United States

GSK Investigational Site

Austin, Texas, United States

GSK Investigational Site

San Antonio, Texas, United States

GSK Investigational Site

Lovech, , Bulgaria

GSK Investigational Site

Pleven, , Bulgaria

GSK Investigational Site

Plovdiv, , Bulgaria

GSK Investigational Site

Rousse, , Bulgaria

GSK Investigational Site

Sofia, , Bulgaria

GSK Investigational Site

Stara Zagora, , Bulgaria

GSK Investigational Site

Varna, , Bulgaria

GSK Investigational Site

Weinheim, Baden-Wurttemberg, Germany

GSK Investigational Site

Hamburg, City state of Hamburg, Germany

GSK Investigational Site

Hamburg, City state of Hamburg, Germany

GSK Investigational Site

Frankfurt am Main, Hesse, Germany

GSK Investigational Site

Neu-Isenburg, Hesse, Germany

GSK Investigational Site

Geesthacht, Schleswig-Holstein, Germany

GSK Investigational Site

Berlin, State of Berlin, Germany

GSK Investigational Site

Berlin, State of Berlin, Germany

GSK Investigational Site

Berlin, State of Berlin, Germany

GSK Investigational Site

Berlin, State of Berlin, Germany

GSK Investigational Site

Guadalajara, Jalisco, Mexico

GSK Investigational Site

Zapopan, Jalisco, Mexico

GSK Investigational Site

Lima, Lima Province, Peru

GSK Investigational Site

Lima, Lima Province, Peru

GSK Investigational Site

Lima, Lima Province, Peru

GSK Investigational Site

San Borja, Lima region, Peru

GSK Investigational Site

San Miguel, Lima region, Peru

GSK Investigational Site

Santiago de Surco, Lima region, Peru

GSK Investigational Site

Bialystok, , Poland

GSK Investigational Site

Krakow, , Poland

GSK Investigational Site

Krakow, , Poland

GSK Investigational Site

Ruda Śląska, , Poland

GSK Investigational Site

Zawadzkie, , Poland

GSK Investigational Site

Zgierz, , Poland

Countries

United States; Bulgaria; Germany; Mexico; Peru; Poland

References

Lee LA, Briggs A, Edwards LD, Yang S, Pascoe S. A randomized, three-period crossover study of umeclidinium as monotherapy in adult patients with asthma. Respir Med. 2015 Jan;109(1):63-73. doi: 10.1016/j.rmed.2014.10.009. Epub 2014 Oct 28.

Reference Type: DERIVED

PMID: 25464907 (View on PubMed)

Study Documents

Document Type: Informed Consent Form

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Study Protocol

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Statistical Analysis Plan

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Dataset Specification

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Individual Participant Data Set

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Annotated Case Report Form

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Clinical Study Report

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Related Links

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Other Identifiers

116402

Identifier Type: -

Identifier Source: org_study_id