Comparative Study of Umeclidinium/Vilanterol (UMEC/VI) in a Fixed Dose Combination With Indacaterol Plus Tiotropium
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Pulmonary Disease, Chronic Obstructive
Intervention: UMEC/VI; UMEC/VI matching placebo; Tiotropium; Tiotropium matching placebo; Indacaterol; Indacaterol matching placebo; Albuterol/salbutamol Metered Dose Inhaler (MDI)
Intervention description: ELLIPTA DPI will be supplied with 30 doses (2 strips with 30 blisters per strip) where first strip contains Umeclidinium bromide (unit dose strengths 62.5 mcg per blister) blended with lactose monohydrate and magnesium stearate 0.6% weight/weight (w/w) of total drug product and second strip contains Vilanterol (unit dose strengths 25 mcg per blister) blended with lactose monohydrate and magnesium stearate 1.0% w/w of total drug product; ELLIPTA DPI will be supplied with 30 doses (2 strips with 30 blisters per strip) where first strip contains lactose monohydrate and magnesium stearate 0.6% w/w of total drug product and second strip contains lactose monohydrate and magnesium stearate 1.0% w/w of total drug product; Tiotropium (as bromide monohydrate) inhalation capsules 18 mcg per dose will be supplied along with HANDIHALER inhalers manufactured by Boehringer Ingelheim; Tiotropium matching placebo capsules manufactured by GSK, will contain lactose and will be supplied along with HANDIHALER inhalers; Indacaterol inhalation capsules 150 mcg per dose will be supplied by GSK along with BREEZHALER inhalers manufactured by Novartis; Indacaterol matching placebo capsules manufactured by GSK, will contain lactose and will be supplied along with BREEZHALER inhalers manufactured by Novartis; Albuterol/salbutamol MDI or nebules for as needed use will be issued throughout the study. Albuterol/salbutamol will be sourced from local commercial stock. If not available locally, GSK will source centrally
Intervention MeSH terms: Albuterol; Tiotropium Bromide
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 967.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No
Keywords: indacaterol; efficacy; FEV1; ELLIPTA; non inferiority; vilanterol; COPD; safety; tiotropium; umeclidinium bromide; GSK573719

Summary:

      This is a Phase IIIb multicentre, randomised, blinded, triple dummy, parallel group study to
      evaluate the efficacy and safety of UMEC/VI inhalation powder (62.5/25 microgram [mcg] Once
      daily [QD]) when administered via ELLIPTA® Dry Powder Inhaler (DPI) compared to indacaterol
      plus tiotropium (150 mcg/18 mcg respectively QD) administered via individual inhalers over a
      treatment period of 12 weeks in participants with moderate to very severe Chronic Obstructive
      Pulmonary Disease (COPD). The purpose of this study is to demonstrate that UMEC/VI (delivered
      via ELLIPTA DPI), when used in symptomatic moderate to very severe COPD participants, is
      non-inferior to the combination of indacaterol (delivered via BREEZHALER® inhaler) plus
      tiotropium (delivered via HANDIHALER® inhaler) on measures of trough forced expiratory volume
      in one second (FEV1) after 12 weeks of treatment. Participants who met the eligibility
      criteria at screening (Visit 1) will complete a 5 to 7 day run in period prior to
      randomisation at Visit 2. Clinic visits will follow at day 2, week 2, week 4, week 8 and week
      12 of treatment, plus week 12 + 1 day (Visits 3 to 8). The total duration of study
      participation will be approximately 14 weeks. ELLIPTA is a registered trademark of the GSK
      group of companies. HANDIHALER is a registered trademark of Boehringer Ingelheim Pharma GmbH
      & Co. KG. BREEZHALER is a registered trademark of Novartis AG.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Type of subject: Outpatient

          -  Informed Consent: A signed and dated written informed consent prior to study
             participation.

          -  Participants 40 years of age or older at Visit 1.

          -  Gender: Male or female participants. A female is eligible to enter and participate in
             the study if she is of: Non-child bearing potential (i.e., physiologically incapable
             of becoming pregnant, including any female who is post-menopausal or surgically
             sterile). Surgically sterile females are defined as those with a documented
             hysterectomy and/or bilateral oophorectomy or tubal ligation. Post-menopausal females
             are defined as being amenorrhoeic for greater than 1 year with an appropriate clinical
             profile, e.g., age appropriate, > 45 years, in the absence of hormone replacement
             therapy.OR Child bearing potential, has a negative pregnancy test at screening, and
             agrees to one of the following acceptable contraceptive methods used consistently and
             correctly (i.e., in accordance with the approved product label and the instructions of
             the physician for the duration of the study screening to follow-up contact):
             Abstinence, Oral Contraceptive, either combined or progestogen alone, Injectable
             progestogen, Implants of levonorgestrel, Estrogenic vaginal ring, Percutaneous
             contraceptive patches, Intrauterine device (IUD) or intrauterine system (IUS) that
             meets the Standard Operating Procedure (SOP) effectiveness criteria as stated in the
             product label, Male partner sterilization (vasectomy with documentation of
             azoospermia) prior to the female subject's entry into the study, and this male is the
             sole partner for that subject. For this definition, "documented" refers to the outcome
             of the investigator's/designee's medical examination of the subject or review of the
             subject's medical history for study eligibility, as obtained via a verbal interview
             with the subject or from the subject' s medical records. Double barrier method: condom
             and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal
             agent (foam/gel/film/cream/suppository)

          -  Diagnosis: An established clinical history of COPD in accordance with the definition
             by the American Thoracic Society/European Respiratory Society.

          -  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.

          -  Severity of Disease: A pre and post-albuterol/salbutamol Forced Expiratory Volume in
             One Second/ Forced Vital Capacity (FEV1/ FVC) ratio of <0.70 and a pre and
             post-albuterol/salbutamol FEV1 of <=70% predicted normal value at Visit 1, calculated
             using Quanjer reference equations.

          -  Dyspnoea: A score of >= 2 on the Modified Medical Research Council Dyspnoea Scale
             (mMRC) at Visit 1.

          -  QT interval corrected (QTc) Criteria: QTc <450 milliseconds (msec) or QTc <480 msec
             for patients with bundle branch block The QTc is the QT interval corrected for heart
             rate according to either Bazett's formula (QTcB), Fridericia's formula (QTcF), or
             another method, machine or manual overread. For subject eligibility and withdrawal,
             QTcF will be used. For purposes of data analysis, QTcF will be used as primary. The
             QTc should be based on single or averaged QTc values of triplicate Electrocardiogram
             (ECGs) obtained over a brief recording period.

          -  French participants: In France, a subject will be eligible for inclusion in this study
             only if either affiliated to or a beneficiary of a social security category.

        Exclusion Criteria:

          -  Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant
             during the study.

          -  Asthma: A current diagnosis of asthma.

          -  Other Respiratory Disorders: Known alpha-1 antitrypsin deficiency, active lung
             infections (such as tuberculosis), and lung cancer are absolute exclusionary
             conditions. A subject who, in the opinion of the investigator, has any other
             significant respiratory conditions in addition to COPD should be excluded. Examples
             may include clinically significant bronchiectasis, pulmonary hypertension,
             sarcoidosis, or interstitial lung disease. Allergy rhinitis is not exclusionary.

          -  Other Diseases/Abnormalities: Participants with historical or current evidence of
             clinically significant cardiovascular, neurological, psychiatric, renal, hepatic,
             immunological, endocrine (including uncontrolled diabetes or thyroid disease) or
             hematological abnormalities that are uncontrolled and/or a previous history of cancer
             in remission for <5 years prior to Visit 1 (localized carcinoma of the skin that has
             been resected for cure is not exclusionary). 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.

          -  Contraindications: A history of allergy or hypersensitivity to any
             anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or
             magnesium stearate or a medical condition such as narrow-angle glaucoma, prostatic
             hypertrophy or bladder neck obstruction that, in the opinion of the study physician,
             contraindicates study participation or use of an inhaled anticholinergic or beta 2
             agonist.

          -  Hospitalisation: Hospitalisation for COPD or pneumonia within 12 weeks prior to Visit
             1.

          -  Lung Resection: Participants with lung volume reduction surgery within the 12 months
             prior to Screening (Visit 1).

          -  12-Lead ECG: An abnormal and significant ECG finding from the 12-lead ECG conducted at
             Visit 1. Specific ECG findings that preclude subject eligibility will be listed in
             protocol The study investigator will determine the medical significance of any ECG
             abnormalities not listed.

          -  Screening labs: Significantly abnormal finding from clinical chemistry or haematology
             tests at Visit 1 as determined by the study investigator.

          -  Medication Prior to Spirometry: Unable to withhold albuterol/salbutamol for the 4 hour
             period required prior to spirometry testing at each study visit.

          -  Medications prior to Screening: Use of the following medications according to the
             following defined time intervals prior to Visit 1: Depot corticosteroids (12 weeks);
             Oral or parenteral corticosteroids (6 weeks); Antibiotics (for lower respiratory tract
             infection) (6 weeks); Cytochrome P450 3A4 strong inhibitors ( 6 weeks); Long Acting
             Beta-Agonist (LABA)/ inhaled corticosteroids (ICS) combination products (e.g.
             fluticasone/salmeterol, mometasone, furoate/formoterol fumarate,
             budesonide/formoterol, fumarate), If LABA/ICS therapy is discontinued completely (30
             days); If discontinuing LABA therapy and switching to ICS monotherapy (48 hours for
             salmeterol or formoterol, 14 days for Olodaterol, Indacaterol or, Vilanterol); Use of
             ICS at a dose >1000 mcg/day of fluticasone propionate or equivalent (30 days);
             Initiation or discontinuation of ICS use (30 days); Inhaled long acting beta2-agonists
             (LABA): Salmeterol, Formoterol (48 hours), Olodaterol, Indacaterol and Vilanterol (14
             days); Long acting muscarinic antagonists (LAMA) (Tiotropium, Aclidinium,
             Glycopyrronium, Umeclidinium) (7 days); LABA/LAMA combination products (Whichever mono
             component has the longest washout); Roflumilast (14 days); Oral beta-agonists-
             Long-acting (48 hours), Short-acting(12 hours); Theophyllines (48 hours); Oral
             leukotriene inhibitors (zafirlukast, montelukast, zileuton) (48 hours); Inhaled sodium
             cromoglycate or nedocromil sodium (24 hours); Inhaled short acting beta2-agonists (4
             hours); Inhaled short-acting anticholinergic (short acting muscarinic antagonist
             [SAMA]) products eg ipratropium (4 hours); Inhaled short-acting
             anticholinergic/short-acting beta2-agonist combination products (SAMA/Short Acting
             beta2-agonists [SABA]) (4 hours); Any other investigational medication (30 days or
             within 5 drug half-lives)

          -  Oxygen: Use of Long Term Oxygen Therapy (LTOT).This is defined as oxygen therapy
             prescribed for greater than 12 hours per day. As needed oxygen use (i.e. <=12 hours
             per day) is not exclusionary.

          -  Nebulized Therapy: Regular use (prescribed for use every day, not for as-needed use)
             of short-acting bronchodilators (e.g., albuterol/salbutamol) via nebulized therapy.

          -  Pulmonary Rehabilitation Program: Participation in the acute phase of a pulmonary
             rehabilitation program within 12 weeks prior to Visit 1. Participants who are in the
             maintenance phase of a pulmonary rehabilitation program are not excluded.

          -  Drug or Alcohol Abuse: A known or suspected history of alcohol or drug abuse within 2
             years prior to Visit 1.

          -  Affiliation with Investigator Site: Is an investigator, sub-investigator, study
             coordinator, employee of a participating investigator or study site, or immediate
             family member of the aforementioned that is involved in this study.

          -  Inability to read: In the opinion of the investigator, any subject who is unable to
             read and/or would not be able to complete a questionnaire.

          -  Participants who are pre-screen or screen failures cannot be re-screened.