Clinical trial NCT03012061: Phase IIb Study of Umeclidinium (UMEC) Bromide Versus Placebo in Subjects With Asthma
Official title: A Phase IIb, 24 Week, Randomized, Double-blind, 3 Arm Parallel Group Study, Comparing the Efficacy, Safety and Tolerability of Two Doses of Umeclidinium Bromide Administered Once-daily Via a Dry Powder Inhaler, Versus Placebo, in Participants With Asthma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Asthma
Keywords: Respiratory
Efficacy
Umeclidinium bromide
Parallel
Asthma
Dry powder inhaler
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2017-01-06
Enrollment: 425
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is conducted to evaluate the effects of UMEC 62.5 microgram (mcg) and UMEC 31.25 mcg on lung function versus placebo after 24 weeks of treatment. This study will provide important information regarding the efficacy and safety of UMEC when administered in a separate inhaler to subjects on a background of fluticasone furoate (FF). This is a Phase IIb, randomized, double-blind, placebo controlled study that will compare the efficacy, safety and tolerability of UMEC (62.5 mcg and 31.25 mcg) administered once-daily in subjects with asthma that is not well controlled. Eligible subjects will be requested to participate in the study for a maximum of approximately 31 weeks with 4 phases (pre screening, screening/run-in, randomization/treatment and safety follow-up). The total number of randomized subjects required is approximately 384, with 128 subjects randomized 1:1:1 to each of the 3 double-blind treatment arms.


Eligibility criteria: Inclusion Criteria:

* 18 years of age or older at the time of signing the informed consent.
* Subjects with a diagnosis of asthma as defined by the National Institutes of Health at least 6 months prior to Visit 0.
* Asthma Control Questionnaire (ACQ)-6 total score of \>0.75 at Visit 1.
* Subjects are eligible if they have required daily Inhaled Corticosteroids (ICS) therapy \>=100 milligram per day (mg/day) fluticasone propionate (FP) or equivalent with or without Long-Acting Beta-2-Agonists (LABA) or Long-Acting Muscarinic Antagonist (LAMA) for at least 12 weeks prior to Visit 0 and there have been no changes in maintenance asthma medications during the 4 weeks immediately prior to Visit 0. Dosing regimen (once or twice daily to equal the total daily dose) should be restricted to the current local product labels.
* A best pre-bronchodilator morning FEV1 \<=85% of the predicted normal value. Predicted values will be based upon the European Respiratory Society (ERS) Global Lung Function Initiative. A best post-bronchodilator FEV1/ forced vital capacity (FVC) \>=0.7 at Visit 1.
* Airway reversibility is defined as \>=12% and \>=200 mL increase in FEV1 between 20 and 60 minutes following 4 inhalations of albuterol/salbutamol aerosol at Visit 1. Note: If the subject does not meet the above reversibility criteria at Visit 1 then the reversibility assessment may be repeated once within 7 days of Visit 1 if either criteria are met: The \>=9% increase in FEV1 between 20 and 60 minutes following 4 inhalations of albuterol/salbutamol aerosol at Visit 1; Documented evidence of a reversibility assessment within 1 year prior to Visit 1 which demonstrated a post-bronchodilator increase in FEV1 of \>=12% and \>=200 milliliter (mL). Should the subject successfully demonstrate airway reversibility (defined as \>=12% and \>=200 mL increase in FEV1 between 20 and 60 minutes following 4 inhalations of albuterol/salbutamol aerosol) at the second attempt then, provided that all other eligibility criteria assessed at Visit 1 are met, the subject may enter the 2-week run-in period.
* All subjects must be able to replace their current Short-Acting Beta-2-Agonists (SABA) inhaler with albuterol/salbutamol aerosol inhaler at Visit 1 as needed for the duration of the study. Subjects must be judged capable of withholding albuterol/salbutamol for at least 6 hours prior to study visits.
* Both male and female subjects are eligible to participate in the study. A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) or a WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 5 days after the last dose of study treatment.
* Able to give written informed consent prior to participation in the study, which will include the ability to comply with the requirements and restrictions listed in the consent form and in this protocol. Subjects must be able to read, comprehend, and write at a level sufficient to complete study related materials.

Inclusion Criteria (for randomization)

* ACQ-6 total score of \>0.75 at Visit 2.
* Spirometry: A best pre-bronchodilator morning FEV1 \<=85% of the predicted normal value at Visit 2. Predicted values will be based upon the ERS Global Lung Function Initiative.
* Alanine aminotransferase (ALT) \<=2 x upper limit of normal (ULN). Alkaline phosphatase \<=1.5 x ULN. Bilirubin \<=1.5 x ULN (isolated bilirubin \>1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
* Compliance with completion of the Daily electronic diary (eDiary) reporting defined as completion of all questions/assessments on \>=4 of the last 7 days during the run-in period.

Exclusion Criteria:

* Chest X-ray documented pneumonia in the 12 weeks prior to Visit 1.
* Any severe asthma exacerbation, defined as deterioration of asthma requiring the use of systemic corticosteroids (oral, parenteral or depot) within 12 weeks of Visit 1, or an inpatient hospitalization or emergency department visit due to asthma that required systemic corticosteroids within 12 weeks of Visit 1.
* Current evidence of pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic obstructive pulmonary disease, lung cancer, or other respiratory abnormalities other than asthma.
* Women who are pregnant or lactating or are planning to become pregnant during the study.
* Immune suppression (e.g., Human Immunodeficiency Virus \[HIV\], Lupus) or other risk factors for pneumonia (e.g., neurological disorders affecting control of the upper airway, such as Parkinson's disease, Myasthenia Gravis). Subjects at potentially high risk (e.g., very low Body Mass Index \[BMI\], severely malnourished, or very low FEV1) will only be included at the discretion of the Investigator
* Subjects with historical or current evidence of clinically significant cardiovascular, neurological, psychiatric, renal, hepatic, immunological, gastrointestinal, urogenital, nervous system, musculoskeletal, skin, sensory, endocrine (including uncontrolled diabetes or thyroid disease) or hematological abnormalities that are uncontrolled. Significant is defined as any disease that, in the opinion of the Investigator, would put the safety of the subject at risk through participation, or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study.
* Unstable liver disease as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices or persistent jaundice, cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). Note: Chronic stable hepatitis B and C is acceptable if the subject otherwise meets entry criteria.
* Evidence of a clinically significant abnormality in the 12-lead ECG performed during screening or run-in. The Principal Investigator will determine the clinical significance of each abnormal ECG finding in relation to the subject's medical history and exclude subjects who would be at undue risk by participating in the trial. An abnormal and clinically significant finding is defined as a 12-lead tracing that is interpreted as, but not limited to, any of the following: Atrial fibrillation (AF) with rapid ventricular rate \>120 beats per minute (BPM); Sustained or nonsustained ventricular tachycardia (VT); Second degree heart block Mobitz type II and third degree heart block (unless pacemaker or defibrillator had been inserted); QT interval corrected for heart rate by Fridericia's formula (QTcF) \>=500 millisecond (msec) in subjects with QRS \<120 msec and QTcF \>=530 msec in subjects with QRS \>=120 msec.
* Subjects with any of the following at Screening (Visit 1) would be excluded: Myocardial infarction or unstable angina in the last 6 months; Unstable or life threatening cardiac arrhythmia requiring intervention in the last 3 months; New York Heart Association (NYHA) Class IV Heart failure.
* Subjects with a medical condition such as narrow-angle glaucoma, urinary retention, prostatic hypertrophy or bladder neck obstruction should only be included if in the opinion of the Investigator the benefit outweighs the risk and that the condition would not contraindicate study participation.
* Subjects with carcinoma that has not been in complete remission for at least 5 years. Subjects who have had carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma of the skin would not be excluded based on the 5 year waiting period if the subject has been considered cured by treatment.
* Subjects with a history of psychiatric disease, intellectual deficiency, poor motivation or other conditions that will limit the validity of informed consent to participate in the study.
* Subjects who are medically unable to withhold their albuterol/salbutamol for the 6-hour period required prior to spirometry testing at each study visit.
* Current smoker or a smoking history of \>=10 pack years (e.g., 20 cigarettes/day for 10 years). A subject may not have used inhaled tobacco products within the past 12 months (i.e., cigarettes, e-cigarettes/vaping, cigars or pipe tobacco).
* Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years. This includes marijuana, which is considered an abused drug.
* A history of allergy or hypersensitivity to any corticosteroid, anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or magnesium stearate.
* Subjects at risk of non-compliance, or unable to comply with the study procedures. Any infirmity, disability, or geographic location that would limit compliance for scheduled visits.
* Study investigators, sub-investigators, study coordinators, employees of a participating investigator or study site, or immediate family members of the aforementioned that is involved with this study.
* In the opinion of the Investigator, any subject who is unable to read and/or would not be able to complete study related materials.

Exclusion Criteria (for randomization)

* Occurrence of a culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear during the run-in period that led to a change in asthma management or, in the opinion of the Investigator, is expected to affect the subject's asthma status or the subject's ability to participate in the study.
* Evidence of a moderate asthma exacerbation leading to a change in therapy or severe exacerbation during screening or the run-in period, defined as deterioration of asthma requiring the use of systemic corticosteroids (tablets, suspension, or injection) or an in-patient hospitalization or emergency department visit due to asthma that required systemic corticosteroids.
* Changes in asthma medication (excluding changes after Visit 0 or run-in medication and albuterol/salbutamol inhalation aerosol provided at Visit 1).
* Evidence of clinically significant abnormal laboratory tests during screening or run-in, which are still abnormal upon repeat analysis and are not believed to be due to disease(s) present. Each Investigator will use his/her own discretion in determining the clinical significance of the abnormality.

Primary outcomes:
measure: Mean Change From Baseline in Clinic Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 24
timeFrame: Baseline (Day 1 pre-dose) and Week 24
Secondary outcomes:
measure: Mean Change From Baseline in Clinic FEV1 at 3 Hours Post Dose at Week 24
timeFrame: Baseline (Day 1 pre-dose) and Week 24
measure: Number of Participants With On-treatment Adverse Events (AE), Non-serious Adverse Events (Non-SAE)
timeFrame: Up to Week 24
measure: Number of Participants With On-treatment Abnormal Electrocardiograms (ECG) Findings
timeFrame: Week 4 and Week 24
measure: Mean Change From Baseline in On-treatment Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline (Day 1 pre-dose), Weeks 4, 12 and 24
measure: Mean Change From Baseline in On-treatment Pulse Rate
timeFrame: Baseline (Day 1 pre-dose), Weeks 4, 12 and 24
Other outcomes:
Locations:
city: Tempe
country: United States
facility: GSK Investigational Site
state: Arizona
city: Rolling Hills Estates
country: United States
facility: GSK Investigational Site
state: California
city: Colorado Springs
country: United States
facility: GSK Investigational Site
state: Colorado
city: Topeka
country: United States
facility: GSK Investigational Site
state: Kansas
city: Natchitoches
country: United States
facility: GSK Investigational Site
state: Louisiana
city: Sunset
country: United States
facility: GSK Investigational Site
state: Louisiana
city: North Dartmouth
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Minneapolis
country: United States
facility: GSK Investigational Site
state: Minnesota
city: Monroe
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Raleigh
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Shelby
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Cincinnati
country: United States
facility: GSK Investigational Site
state: Ohio
city: Cincinnati
country: United States
facility: GSK Investigational Site
state: Ohio
city: Medford
country: United States
facility: GSK Investigational Site
state: Oregon
city: Indian Land
country: United States
facility: GSK Investigational Site
state: South Carolina
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: Union
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Calgary
country: Canada
facility: GSK Investigational Site
state: Alberta
city: Vancouver
country: Canada
facility: GSK Investigational Site
state: British Columbia
city: Brampton
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Burlington
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Corunna
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Mississauga
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Windsor
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Quebec
country: Canada
facility: GSK Investigational Site
city: Bialystok
country: Poland
facility: GSK Investigational Site
city: Elblag
country: Poland
facility: GSK Investigational Site
city: Kielce
country: Poland
facility: GSK Investigational Site
city: Krakow
country: Poland
facility: GSK Investigational Site
city: Krakow
country: Poland
facility: GSK Investigational Site
city: Lodz
country: Poland
facility: GSK Investigational Site
city: Lublin
country: Poland
facility: GSK Investigational Site
city: Poznan
country: Poland
facility: GSK Investigational Site
city: Rzeszow
country: Poland
facility: GSK Investigational Site
city: Sopot
country: Poland
facility: GSK Investigational Site
city: Tarnow
country: Poland
facility: GSK Investigational Site
city: Warszawa
country: Poland
facility: GSK Investigational Site
city: Wroclaw
country: Poland
facility: GSK Investigational Site
city: Zgierz
country: Poland
facility: GSK Investigational Site
city: Brasov
country: Romania
facility: GSK Investigational Site
city: Bucharest
country: Romania
facility: GSK Investigational Site
city: Cluj Napoca
country: Romania
facility: GSK Investigational Site
city: Codlea
country: Romania
facility: GSK Investigational Site
city: Deva
country: Romania
facility: GSK Investigational Site
city: Iasi
country: Romania
facility: GSK Investigational Site
city: Pitesti
country: Romania
facility: GSK Investigational Site
city: Ramnicu Valcea
country: Romania
facility: GSK Investigational Site
city: Sibiu
country: Romania
facility: GSK Investigational Site
city: Timisoara
country: Romania
facility: GSK Investigational Site
city: Arkhangelsk
country: Russian Federation
facility: GSK Investigational Site
city: Barnaul
country: Russian Federation
facility: GSK Investigational Site
city: Ekaterinburg
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Odintsovo
country: Russian Federation
facility: GSK Investigational Site
city: Pyatigorsk
country: Russian Federation
facility: GSK Investigational Site
city: Saint-Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Samara
country: Russian Federation
facility: GSK Investigational Site
city: Smolensk
country: Russian Federation
facility: GSK Investigational Site
city: St'Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Tomsk
country: Russian Federation
facility: GSK Investigational Site
city: Volgodonsk
country: Russian Federation
facility: GSK Investigational Site
city: Voronezh
country: Russian Federation
facility: GSK Investigational Site
city: Yaroslavl
country: Russian Federation
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Kerwin E, Pascoe S, Bailes Z, Nathan R, Bernstein D, Dahl R, von Maltzahn R, Robbins K, Fowler A, Lee L. A phase IIb, randomised, parallel-group study: the efficacy, safety and tolerability of once-daily umeclidinium in patients with asthma receiving inhaled corticosteroids. Respir Res. 2020 Jun 12;21(1):148. doi: 10.1186/s12931-020-01400-5.