Clinical trial NCT01641692: A 3-period Crossover Study With GSK573719 as Monotherapy in Adult Subjects With Asthma
Official title: A Multi-national, Randomized, Double-blind, Placebo-controlled, 3-period Crossover Study With GSK 573719 as Monotherapy in Adult Subjects With Asthma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Asthma
Keywords: Asthma
Pharmacokinetics
GSK573719
Adults
Pharmacogenetics
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2012-07-17
Enrollment: 350
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Final Dose-response Model for Trough Forced Expiratory Volume in One Second (FEV1)
timeFrame: Day 15 of each treatment period (up to Study Day 71)
measure: Change From Baseline in Trough FEV1 on Day 15 of Each Treatment Period
timeFrame: Day 15 of each treatment period (up to Study Day 71)
measure: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)
timeFrame: From Baseline until the end of Treatment Period 3 (up to Study Day 70)
measure: Number of Participants With Asthma Exacerbations During the Treatment Period
timeFrame: From Baseline until the end of Treatment Period 3 (up to Study Day 70)
measure: Change From Baseline in Systolic Blood Pressure on Day 14 of Each Treatment Period
timeFrame: Baseline and Day 14 of each treatment period (up to Study Day 70)
measure: Change From Baseline in Diastolic Blood Pressure on Day 14 of Each Treatment Period
timeFrame: Baseline and Day 14 of each treatment period (up to Study Day 70)
measure: Change From Baseline in Pulse Rate on Day 14 of Each Treatment Period
timeFrame: Baseline and Day 14 of each treatment period (up to Study Day 70)
measure: Change From Baseline in Albumin, Total Protein, and Hemoglobin on Day 14 of Each Treatment Period
timeFrame: Baseline and Day 14 of each treatment period (up to Study Day 70))
measure: Change From Baseline in Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Kinase (CK), Gamma Glutamyl Transferase (GGT) and Lactate Dehydrogenase (LDH) on Day 14 of Each Treatment Period
timeFrame: Baseline and Day 14 of each treatment period (up to Study Day 70)
measure: Change From Baseline in Direct Bilirubin, Indirect Bilirubin, Total Bilirubin, and Creatinine on Day 14 of Each Treatment Period
timeFrame: Baseline and Day 14 of each treatment period (up to Study Day 70)
measure: Change From Baseline in Calcium, Chloride, Carbon Dioxide, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) on Day 14 of Each Treatment Period
timeFrame: Baseline and Day 14 of each treatment period (up to Study Day 70)
measure: Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (ANC - Absolute Neutrophil Count), Platelet, and Leukocytes Count on Day 14 of Each Treatment Period
timeFrame: Baseline and Day 14 of each treatment period (up to Study Day 70)
measure: Change From Baseline in the Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes, and Segmented Neutrophils in Blood on Day 14 of Each Treatment Period
timeFrame: Baseline and Day 14 of each treatment period (up to Study Day 70)
measure: Change From Baseline in Hematocrit on Day 14 of Each Treatment Period
timeFrame: Baseline and Day 14 of each treatment period (up to Study Day 70)
measure: Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick on Day 14 of Each Treatment Period
timeFrame: Baseline and Day 14 of each treatment period (up to Study Day 70))
measure: Urine pH on Day 14 of Each Treatment Period
timeFrame: Day 14 of each treatment period (up to Study Day 70)
measure: Urine Specific Gravity on Day 14 of Each Treatment Period
timeFrame: Day 14 of each treatment period (up to Study Day 70)
measure: Number of Participants With the Indicated Abnormal Electrocardiogram Findings
timeFrame: Day 14 of each treatment period (up to Study Day 70)
measure: Number of Participants With the Indicated 24 Hour Holter Findings
timeFrame: Day 14 of each treatment period (up to Study Day 70)
Secondary outcomes:
measure: Change From Baseline (BL) in the Weighted Mean (WM) 0-24 Hour FEV1 Obtained Post-AM Dose on Day 14 of Each Treatment Period
timeFrame: Baseline and Day 14 of each treatment period (up to Study Day 70)
measure: Change in Baseline in Serial FEV1 Over 0-24 Hours After the Morning Dose on Day 14 of Each Treatment Period
timeFrame: Baseline and Day 14 of each treatment period (up to Study Day 70)
measure: Change From Baseline in Mean Morning (AM) and Evening (PM) Pre-treatment Peak Expiratory Flow (PEF) Over Day 7 to Day 14 of Each Treatment Period
timeFrame: Baseline (Day 7 prior to each treatment period) and the last 7 days of each treatment period (up to Study Day 70)
measure: Change From Baseline in the Mean Number of Puffs Per Day of Rescue Albuterol/Salbutamol Over Day 7 to Day 14 of Each Treatment Period
timeFrame: Baseline (Day 7 prior to each treatment period) and the last 7 days of each treatment period (up to Study Day 70)
Other outcomes:
Locations:
city: Newport Beach
country: United States
facility: GSK Investigational Site
state: California
city: Sunset
country: United States
facility: GSK Investigational Site
state: Louisiana
city: Bethesda
country: United States
facility: GSK Investigational Site
state: Maryland
city: Columbia
country: United States
facility: GSK Investigational Site
state: Missouri
city: Rolla
country: United States
facility: GSK Investigational Site
state: Missouri
city: St. Louis
country: United States
facility: GSK Investigational Site
state: Missouri
city: Bellevue
country: United States
facility: GSK Investigational Site
state: Nebraska
city: Medford
country: United States
facility: GSK Investigational Site
state: Oregon
city: Orangeburg
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Spartanburg
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Austin
country: United States
facility: GSK Investigational Site
state: Texas
city: San Antonio
country: United States
facility: GSK Investigational Site
state: Texas
city: Lovech
country: Bulgaria
facility: GSK Investigational Site
city: Pleven
country: Bulgaria
facility: GSK Investigational Site
city: Plovdiv
country: Bulgaria
facility: GSK Investigational Site
city: Ruse
country: Bulgaria
facility: GSK Investigational Site
city: Sofia
country: Bulgaria
facility: GSK Investigational Site
city: Stara Zagora
country: Bulgaria
facility: GSK Investigational Site
city: Varna
country: Bulgaria
facility: GSK Investigational Site
city: Weinheim
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Frankfurt
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Neu isenburg
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Geesthacht
country: Germany
facility: GSK Investigational Site
state: Schleswig-Holstein
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Guadalajara
country: Mexico
facility: GSK Investigational Site
state: Jalisco
city: Zapopan
country: Mexico
facility: GSK Investigational Site
state: Jalisco
city: Lima 27
country: Peru
facility: GSK Investigational Site
state: Lima
city: San Borja
country: Peru
facility: GSK Investigational Site
state: Lima
city: San Miguel
country: Peru
facility: GSK Investigational Site
state: Lima
city: Santiago de Surco
country: Peru
facility: GSK Investigational Site
state: Lima
city: Lima
country: Peru
facility: GSK Investigational Site
city: Lima
country: Peru
facility: GSK Investigational Site
city: Bialystok
country: Poland
facility: GSK Investigational Site
city: Krakow
country: Poland
facility: GSK Investigational Site
city: Krakow
country: Poland
facility: GSK Investigational Site
city: Ruda Slaska
country: Poland
facility: GSK Investigational Site
city: Zawadzkie
country: Poland
facility: GSK Investigational Site
city: Zgierz
country: Poland
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.