Dose-Finding Study of Batefenterol (GSK961081) Via Dry Powder Inhaler in Patients With Chronic Obstructive Pulmonary Disease (COPD)

NCT02570165 | Completed Phase 2 Results

• 2 other identifiers: 2010122015-001409-15
• Study Type: interventional
• Target: 325
• Locations: 3 countries
• Sites: 25

Brief Summary

Batefenterol is a novel bifunctional molecule that combines muscarinic antagonism and beta2-agonism in a single molecule. This is a multicenter, randomized, placebo-controlled, double-blind, parallel group study primarily designed to assess the dose response, efficacy and safety of five dose regimens of batefenterol administered via the dry powder inhaler (DPI) once-daily in the morning for 42 days in subjects with COPD. The information obtained from this study will be used to select the minimal, optimally effective and safe dose of batefenterol and also to evaluate the pharmacokinetic profile and established pharmacodynamic (PD) responses of batefenterol. These data will support for future studies with batefenterol in COPD subjects. The study will consist of a pre-screening visit, screening visit; a run-in period (2 weeks), treatment period of 42 days and a follow-up visit 7 days post-treatment. The total duration of the study for each subject will be approximately 9 weeks. Approximately 460 subjects will be screened in order to randomize approximately 320 subjects, assuming that 280 subjects will complete the study. During treatment period, subjects will be randomized to one of the following treatments delivered via DPI once daily in the morning: Batefenterol 37.5 mcg, 75 mcg, 150 mcg, 300 mcg and 600 mcg, umeclidinium/vilanterol (UMEC/VI) 62.5/25 mcg and placebo. All subjects will receive supplemental albuterol/salbutamol to be used on an as-needed basis (rescue medication) throughout the study.

Conditions

Pulmonary Disease, Chronic Obstructive

Keywords

efficacy; dry powder inhaler; vilanterol; batefenterol

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in Weighted Mean FEV1 Over 0 to 6 Hours Post-dose at Day 42

  FEV1 is defined as the volume of air that can be forced out in one second after taking a deep breath. Weighted-mean change from Baseline was the weighted-mean FEV1 on Day 42 minus Baseline where Baseline is defined as the average of Day1 pre-dose FEV1 measured at -30 minutes and 0 minutes. The 0-6 hour (Hr.) serial FEV1 was collected at Day 1 (Visit 2) and Day 42 (Visit 6). The weighted-mean was derived by calculating the area under the curve (AUC) of FEV1 over the 6 hour period, and then dividing it by the 6-hour time interval. Batefenterol dose for each individual was compared with placebo or UMEC/VI. The change from Baseline in FEV1 was statistically analyzed using Bayesian Emax modeling of the dose response curve. Intent-to-Treat (ITT) Population comprised of all participants randomized to treatment and who received at least one dose of study medication. Participants with FEV1 values available at Baseline and Day 42 were analyzed.

  Baseline and Day 42

Secondary Outcomes (1)

• Change From Baseline in Trough FEV1 at Day 42

  Baseline and Day 42

Study Arms (7)

Batefenterol 37.5 mcg

EXPERIMENTAL

Each subject will receive batefenterol 37.5 mcg (1 actuation) once daily via DPI in the morning for 42 days of treatment period.

Drug: Batefenterol

Batefenterol 75 mcg

EXPERIMENTAL

Each subject will receive batefenterol 75 mcg (1 actuation) once daily via DPI in the morning for 42 days of treatment period.

Drug: Batefenterol

Batefenterol 150 mcg

EXPERIMENTAL

Each subject will receive batefenterol 150 mcg (1 actuation) once daily via DPI in the morning for 42 days of treatment period.

Drug: Batefenterol

Batefenterol 300 mcg

EXPERIMENTAL

Each subject will receive batefenterol 300 mcg (1 actuation) once daily via DPI in the morning for 42 days of treatment period.

Drug: Batefenterol

Batefenterol 600 mcg

EXPERIMENTAL

Each subject will receive batefenterol 600 mcg (1 actuation) once daily via DPI in the morning for 42 days of treatment period.

Drug: Batefenterol

UMEC/VI 62.5/25 mcg

EXPERIMENTAL

Each subject will receive UMEC/VI 62.5/25 mcg (1 actuation) once daily via DPI in the morning for 42 days of treatment period.

Drug: Umeclidinium/ Vilanterol

Placebo

EXPERIMENTAL

Each subject will receive placebo (1 actuation) once daily via DPI in the morning for 42 days of treatment period.

Drug: Placebo

Interventions

Batefenterol DRUG

Batefenterol will be provided as dry white powder for inhalation via a DPI with 30 doses (2 strips with 30 blisters per strip). First strip will contain lactose and the second strip will contain batefenterol blended with lactose with a unit dose strength of 37.5 mcg, 75 mcg, 150 mcg, 300 mcg, or 600 mcg per blister

Batefenterol 150 mcg; Batefenterol 300 mcg; Batefenterol 37.5 mcg; Batefenterol 600 mcg; Batefenterol 75 mcg

Umeclidinium/ Vilanterol DRUG

Umeclidinium/Vilanterol will be provided as dry white powder for inhalation via a DPI with 30 doses (2 strips with 30 blisters per strip). First strip will contain umeclidinium blended with lactose and magnesium stearate with a unit dose strength of 62.5 mcg per blister and the second strip will contain vilanterol blended with lactose and magnesium stearate with a unit dose strength of 25 mcg per blister

UMEC/VI 62.5/25 mcg

Placebo DRUG

Placebo will be provided as dry white powder for inhalation via a DPI with 30 doses (2 strips with 30 blisters per strip) containing lactose

Placebo

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Type of subject: Outpatient
• Informed Consent: A signed and dated written informed consent prior to study participation
• Age: 40 years of age or older at Visit 1.
• Gender: Male and female subjects are eligible to participate in the study. Female subjects are eligible to participate if not pregnant (as confirmed by a negative urine human chorionic gonadotrophin \[hCG\] test), not lactating, and at least one of the following conditions applies:
• Non-reproductive potential defined as:
• Pre-menopausal females with one of the following: Documented tubal ligation Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion Hysterectomy Documented Bilateral Oophorectomy Postmenopausal defined as 12 months of spontaneous amenorrhea. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status prior to study enrolment.
• Reproductive potential and agrees to follow one of the options listed below 30 days prior to the first dose of study medication and until at least five terminal half-lives OR until any continuing pharmacologic effect has ended, whichever is longer after the last dose of study medication and completion of the follow-up visit. This list does not apply to females of reproductive potential with same sex partners, when this is their preferred and usual lifestyle or for subjects who are and will continue to be abstinent from penile-vaginal intercourse on a long term and persistent basis.
• Contraceptive subdermal implant that meets \<1 percent (%) rate of failure per year, as stated in the product label Intrauterine device or intrauterine system that meets \<1% rate of failure per year, as stated in the product label Oral Contraceptive, either combined or progestogen alone Injectable progestogen Contraceptive vaginal ring Percutaneous contraceptive patches Male partner sterilization with documentation of azoospermia prior to the female subjects entry into the study, and this male is the sole partner for that subject These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.
• Diagnosis: An established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society as follows: Chronic obstructive pulmonary disease is a preventable and treatable disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking.
• Smoking History: Current or former cigarette smokers with a history of cigarette smoking of \>=10 pack-years. Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1. Number of pack years = (number of cigarettes per day / 20) x number of years smoked (e.g. 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years both equal 10 pack-years). Note: pipe and cigar cannot be used to calculate pack-year history.
• Severity of Disease: A post-albuterol/salbutamol FEV1/FVC ratio of \<=0.70 and a post-albuterol/salbutamol FEV1 \>=30 and \<=70% of predicted normal at Visit 1.
• Note: Percent predicted will be calculated using the European Respiratory Society Global Lung Function Initiative reference equations.

You may not qualify if:

• Asthma: Subjects with a current diagnosis of asthma. (subjects with a prior history of asthma are eligible if they have a current diagnosis of COPD).
• Other Diseases/Abnormalities: Any significant diseases (including uncontrolled hypertension, diabetes and thyroid disease) that in the opinion of the investigator or the study medical monitor would put the safety of the subject at risk through study participation, or which would affect study analyses if the diseases/condition exacerbated during the study.
• Hepatitis: Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening Visit 1 or within 3 months prior to first dose of study treatment. (subjects with positive hepatitis C antibody due to prior resolved disease can be enrolled only if a confirmatory negative Hepatitis C ribonucleic acid (RNA) polymerase chain reaction (PCR) test is obtained).
• Liver Disease: Current or chronic history of liver disease, known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• Chest X-Ray: A chest X-ray or computed tomography (CT) scan that reveals evidence of clinically significant abnormalities not believed to be due to the presence of COPD. A chest X-ray must be taken at Visit 1 if a chest X-ray or CT scan is not available within 6 months prior to Visit 1. For subjects in Germany, if a chest X-ray (or CT scan) is not available in the 6 months prior to Visit 1 the subject will not be eligible for the study.
• Drug Allergy: A history of hypersensitivity or allergy to any beta adrenergic receptor-agonist, sympathomimetic, anticholinergic/anti-muscarinic receptor antagonist, or lactose/milk protein, which in the opinion of the investigator or GlaxoSmithKline (GSK) medical monitor contraindicates study participation.
• Diseases Preventing Use of Anticholinergic: Medical diagnosis of narrow- angle glaucoma, prostatic hypertrophy or bladder neck obstruction that in the opinion of the study investigator would prevent use of an inhaled anticholinergic.
• Poorly controlled COPD: defined as the occurrence of 'acute worsening of COPD that is managed with corticosteroid and/or antibiotics or that requires treatment prescribed by a physician in the 6 weeks prior to Screening (Visit 1), or 'subjects who are hospitalized due to acute worsening of COPD within 12 weeks of Visit 1.
• History of COPD exacerbation: Subjects who have had more than one exacerbation (moderate or severe) within the 12 months prior to Visit 1.
• Pneumonia and lower respiratory tract infection: Subjects with lower respiratory tract infection that required the use of antibiotics within 6 weeks prior to Visit 1 or subjects hospitalized due to pneumonia within 12 weeks of Visit 1.
• Lung Resection: Lung volume reduction surgery within the 12 months prior to Visit 1.
• lead ECG: An abnormal and clinically significant 12-lead electrocardiogram (ECG). Site investigators will be provided with ECG over-read conducted by a centralized independent cardiologist, to assist in evaluation of subject eligibility. For this study, an abnormal and clinically significant ECG that would preclude a subject from entering the trial is defined as a 12-lead tracing that is interpreted as, but not limited to the criteria mentioned in the protocol.
• Screening Labs: Clinically significant abnormal finding from clinical chemistry or hematology tests at Visit 1.
• Medication Prior to Spirometry: Unable to with hold albuterol/salbutamol for the 4 hour period required prior to spirometry testing at each study visit.
• Excluded Medications: Use of the following medications are not permitted within the defined time intervals prior to Visit 1 and throughout the study: depot corticosteroids (12 weeks), antibiotics (for lower respiratory tract infection) (6 weeks), cytochrome P450 3A4 strong inhibitors and P-glycoprotein inhibitors (4 weeks), systemic, oral or parenteral corticosteroids (2 weeks), inhaled corticosteroids (ICS) or long-acting beta2- agonist (LABA)/ ICS combination products (2 weeks), phosphodiesterase 4 (PDE4) inhibitor (roflumilast) (2 weeks), LABA/ long acting muscarinic receptor antagonist (LAMA) combination (eg vilanterol /umeclidinium bromide) (2 weeks), Once-daily beta2-agonist ( eg Olodaterol and Indacaterol) (10 days), long acting muscarinic antagonists (eg tiotropium, aclidinium, glycopyrronium, umeclidinium) (7 days), theophyllines (48 h), oral leukotriene inhibitors (zafirlukast, montelukast, zileuton) (48 h), oral beta2-agonists long-acting (48 h), short-acting (12 h), inhaled long acting beta2-agonists (LABA, e.g. salmeterol, formoterol, indacaterol) (48 h), inhaled sodium cromoglycate or nedocromil sodium (24 h), inhaled short acting beta2-agonists (4 h), inhaled short-acting anticholinergics (4 h), inhaled short-acting anticholinergic/ short-acting beta2-agonist combination products (4 h), any other investigational medication (30 days or within 5 drug half-lives \[whichever is longer\]).

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (25)

GSK Investigational Site

Hialeah, Florida, 33013, United States

Location

GSK Investigational Site

Baltimore, Maryland, 21225, United States

Location

GSK Investigational Site

St Louis, Missouri, 63141-6361, United States

Location

GSK Investigational Site

Medford, Oregon, 97504, United States

Location

GSK Investigational Site

Anderson, South Carolina, 29621, United States

Location

GSK Investigational Site

Greenville, South Carolina, 29615, United States

Location

GSK Investigational Site

Simpsonville, South Carolina, 29681, United States

Location

GSK Investigational Site

Spartanburg, South Carolina, 29303, United States

Location

GSK Investigational Site

Union, South Carolina, 29379, United States

Location

GSK Investigational Site

Rüdersdorf, Brandenburg, 15562, Germany

Location

GSK Investigational Site

Wiesbaden, Hesse, 65187, Germany

Location

GSK Investigational Site

Großhansdorf, Schleswig-Holstein, 22927, Germany

Location

GSK Investigational Site

Lübeck, Schleswig-Holstein, 23552, Germany

Location

GSK Investigational Site

Berlin, 10119, Germany

Location

GSK Investigational Site

Berlin, 10717, Germany

Location

GSK Investigational Site

Berlin, 10787, Germany

Location

GSK Investigational Site

Hamburg, 22299, Germany

Location

GSK Investigational Site

Port Elizabeth, Eastern Cape, 6001, South Africa

Location

GSK Investigational Site

Middelburg, Mpumalanga, 1050, South Africa

Location

GSK Investigational Site

Bellville, 7530, South Africa

Location

GSK Investigational Site

Bloemfontein, 9301, South Africa

Location

GSK Investigational Site

Meyerspark/ Pretoria, 184, South Africa

Location

GSK Investigational Site

Mowbray, 7700, South Africa

Location

GSK Investigational Site

Somerset West, 7130, South Africa

Location

GSK Investigational Site

Thabazimbi, South Africa

Location

Related Publications (1)

• Crim C, Watkins ML, Bateman ED, Feldman GJ, Schenkenberger I, Kerwin EM, Crawford C, Pudi K, Ho S, Baidoo C, Castro-Santamaria R. Randomized dose-finding study of batefenterol via dry powder inhaler in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2019 Mar 8;14:615-629. doi: 10.2147/COPD.S190603. eCollection 2019.

  PMID: 30880951 BACKGROUND

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Interventions

batefenterol; GSK573719; vilanterol

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 5, 2015
• First Posted: October 7, 2015
• Study Start: November 6, 2015
• Primary Completion: July 6, 2016
• Study Completion: July 6, 2016
• Last Updated: July 16, 2019
• Results First Posted: March 24, 2017

Record last verified: 2019-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

DE (8); ZA (8); US (9)