Long Term Safety Study of NVA237 vs QAB149 in COPD Patients

A Multi-center, Randomized, Double-blind, 52-week Study to Assess the Safety of NVA237 Compared to QAB149 in Patients With Chronic Obstructive Pulmonary Disease (COPD) Who Have Moderate to Severe Airflow Limitation

The purpose of the study is to provide long term safety data of NVA237. This study will assess the safety and tolerability of a single dose strength of NVA237.

Study Overview

• Status: Completed
• Conditions: Chronic Obstructive Pulmonary Disease (COPD)
• Intervention / Treatment: Drug: NVA237; Drug: Long-acting beta 2-agonist (LABA); Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 511
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Gulf Shores, Alabama, United States, 36547
      • Novartis Investigative Site
    • Mobile, Alabama, United States, 36608
      • Novartis Investigative Site
  • Arizona
    • Tucson, Arizona, United States, 85712
      • Novartis Investigative Site
  • California
    • Riverside, California, United States, 92506
      • Novartis Investigative Site
  • Colorado
    • Fort Collins, Colorado, United States, 80528
      • Novartis Investigative Site
    • Wheat Ridge, Colorado, United States, 80033
      • Novartis Investigative Site
  • Connecticut
    • Glastonbury, Connecticut, United States, 06033
      • Novartis Investigative Site
    • Stamford, Connecticut, United States, 06902
      • Novartis Investigative Site
    • Waterbury, Connecticut, United States, 06708
      • Novartis Investigative Site
  • Florida
    • Clearwater, Florida, United States, 33765
      • Novartis Investigative Site
    • Hialeah, Florida, United States, 33016
      • Novartis Investigative Site
    • Miami, Florida, United States, 33175
      • Novartis Investigative Site
    • Miami, Florida, United States, 33165
      • Novartis Investigative Site
    • Miami, Florida, United States, 33172
      • Novartis Investigative Site
    • Oakland Park, Florida, United States, 33334
      • Novartis Investigative Site
    • Pensacola, Florida, United States, 32503
      • Novartis Investigative Site
  • Idaho
    • Couer D'Alene, Idaho, United States, 83814
      • Novartis Investigative Site
  • Indiana
    • Newburgh, Indiana, United States, 47630
      • Novartis Investigative Site
  • Kansas
    • Topeka, Kansas, United States, 66606
      • Novartis Investigative Site
  • Kentucky
    • Florence, Kentucky, United States, 41042
      • Novartis Investigative Site
    • Madisonville, Kentucky, United States, 42431
      • Novartis Investigative Site
  • Louisiana
    • New Orleans, Louisiana, United States, 70119
      • Novartis Investigative Site
    • Opelousas, Louisiana, United States, 70570
      • Novartis Investigative Site
  • Maine
    • Biddeford, Maine, United States, 04005
      • Novartis Investigative Site
  • Massachusetts
    • Worchester, Massachusetts, United States, 01608
      • Novartis Investigative Site
  • Minnesota
    • Edina, Minnesota, United States, 55435
      • Novartis Investigative Site
    • Fridley, Minnesota, United States, 55432
      • Novartis Investigative Site
    • Minneapolis, Minnesota, United States, 55402
      • Novartis Investigative Site
    • Minneapolis, Minnesota, United States, 55407
      • Novartis Investigative Site
  • Nebraska
    • Fremont, Nebraska, United States, 68025
      • Novartis Investigative Site
    • Omaha, Nebraska, United States, 68134
      • Novartis Investigative Site
  • Nevada
    • Henderson, Nevada, United States, 89014
      • Novartis Investigative Site
    • Las Vegas, Nevada, United States, 89119
      • Novartis Investigative Site
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Novartis Investigative Site
  • North Carolina
    • Calabash, North Carolina, United States, 28467
      • Novartis Investigative Site
    • Tabor City, North Carolina, United States, 28463
      • Novartis Investigative Site
  • Ohio
    • Columbus, Ohio, United States, 43215
      • Novartis Investigative Site
    • Columbus, Ohio, United States, 43235
      • Novartis Investigative Site
    • Marion, Ohio, United States, 43302
      • Novartis Investigative Site
    • Zanesville, Ohio, United States, 43701
      • Novartis Investigative Site
  • Oregon
    • Eugene, Oregon, United States, 97404-3233
      • Novartis Investigative Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Novartis Investigative Site
  • Rhode Island
    • Warwick, Rhode Island, United States, 02886
      • Novartis Investigative Site
  • South Carolina
    • Charleston, South Carolina, United States, 29412
      • Novartis Investigative Site
    • Columbia, South Carolina, United States, 29204
      • Novartis Investigative Site
    • Greenville, South Carolina, United States, 29605
      • Novartis Investigative Site
    • Greer, South Carolina, United States, 29651
      • Novartis Investigative Site
    • N. Myrtle Beach, South Carolina, United States, 29582
      • Novartis Investigative Site
  • Texas
    • Boerne, Texas, United States, 78006
      • Novartis Investigative Site
    • El Paso, Texas, United States, 79902
      • Novartis Investigative Site
    • Houston, Texas, United States, 77081
      • Novartis Investigative Site
    • Houston, Texas, United States, 77043
      • Novartis Investigative Site
    • Kingwood, Texas, United States, 77339
      • Novartis Investigative Site
    • San Antonio, Texas, United States, 78229
      • Novartis Investigative Site
  • Vermont
    • White River Junction, Vermont, United States, 05009
      • Novartis Investigative Site
  • Virginia
    • Burke, Virginia, United States, 22015
      • Novartis Investigative Site
    • Fredericksburg, Virginia, United States, 22401
      • Novartis Investigative Site
    • Manassas, Virginia, United States, 20110
      • Novartis Investigative Site
    • Richmond, Virginia, United States, 23229
      • Novartis Investigative Site
    • Richmond, Virginia, United States, 23225
      • Novartis Investigative Site
  • Wisconsin
    • Oregon, Wisconsin, United States, 53575
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female patients with COPD according to GOLD 2011 who have signed informed consent.
2. Patients with airflow limitation of 30-80% post-bronchodilator FEV1 at run-in.
3. Current or ex-smokers with a smoking history of at least 10 pack years
4. Patients with a mMRC score of at least 2 at run-in.

Exclusion Criteria:

1. Patients contraindicated for muscarinic antagonist agents and beta-2 agonists
2. Patients with a history of malignancy of any organ system, treated or untreated, within the last five years
3. Patients with narrow-angle glaucoma, BPH or bladder-neck obstruction or moderate-severe renal impairment or urinary retention
4. Patients who had a COPD exacerbation within 6 weeks prior to screening.
5. Patients requiring long term oxygen therapy prescribed for more than 12 hr per day.
6. Patients with a history of asthma.
7. Patients with an onset of respiratory symptoms, including COPD diagnosis, prior to 40 years of age.
8. Patients with a blood eosinophil count of greater than 600 mm/3 during run-in
9. Patients with concomitant pulmonary disease
10. Patients with a history of certain cardiovascular co-morbid conditions
11. Patients with a diagnosis of alpha-1 anti-trypsin deficiency
12. Patients with active pulmonary tuberculosis
13. Patients in the active phase of a pulmonary rehabilitation programme
14. Other protocol-defined inclusion / exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NVA237 dose 1	Drug: NVA237; NVA237 will be supplied in capsule form in blister packs for use in the Novartis Concept 1 SDDPI
Active Comparator: Long-acting beta 2-agonist (LABA); QAB149	Drug: Long-acting beta 2-agonist (LABA); QAB149 and matching placebo will be supplied in capsule form in blister packs for use in the Novartis Concept 1 SDDPI; Drug: Placebo; Placebo to match QAB149

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Reporting Safety and Tolerability in Terms of Adverse Event (AE) Reporting Rate	Adverse events are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal lab finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgments of the investigators represent significant hazards.	52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Treatment Discontinuation	Discontinuation rates are calculated using the Kaplan Meier method. The protocol allowed patients to discontinue outside the treatment window, hence we have a patient who discontinued at Day 388. Reasons for discontinuing treatment are Subject/guardian decision, Adverse event, Protocol deviation Lack of efficacy, Physician decision, Dosing error, Disease improvement under study, Pregnancy, Technical problems	52 Weeks
Change From Baseline in Mean Forced Expiratory Volume (Average of the Two FEV1 Measurements 45 and 15 Minutes Pre-dose) in One Second at Week 52	Change from baseline in pre-dose trough FEV1 was analyzed using a repeated measures analysis of covariance model which contained treatment, baseline FEV1, visit, baseline smoking status, baseline ICS use, COPD severity and treatment by visit, visit by baseline FEV1 interactions. An unstructured variance-covariance error matrix was used .Pulmonary function assessments were performed using centralized spirometry according to international standards. Pre-dose trough FEV1 was defined as the mean of FEV1 at -45 min and -15 min before the morning dose at Week 52. Baseline FEV1 was defined as the mean of the pre-dose FEV1 at -45 min and -15 min on Day 1.	-45 min and -15 minutes baseline and at Week 52
Change From Baseline in Pre-dose Forced Expiratory Volume (FEV1) in One Second at All Post Baseline Timepoints	Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1.	-45 min and -15 minutes baseline and at Week 52
Change From Baseline in Pre-dose Forced Vital Capacity (FVC) at All Post-baseline Timepoints	Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FVC was defined as the average of the pre-dose FVC measured at -45 minutes (min) and -15 min at day 1.	-45 min and -15 minutes baseline and at Week 52
Change From Baseline in COPD Symptoms	The total symptom score was defined as the sum of individual cores for respiratory symptoms, cough, wheeze, amount of sputum, color of sputum, and reathlessness. Where a patient had a morning score and an evening score for an individual symptom on one particular day then the worst score was to be taken as the daily score for that symptom. Each symptom scale ranged from 0-3 where 0 was no symptoms and 3 was the worst. The total daily/daytime/nighttime symptom score consists of looking at the score for 6 symptoms and can therefore have a minimum score of 0 or a maximum of 18.	52 weeks
Change From Baseline in COPD Symptoms	Percentage of days with 'no daytime symptoms' A day with 'no daytime symptoms' was defined from the diary data as any day where the patient had recorded in the evening no cough, no wheeze, no production of sputum and no feeling of breathlessness (other than when running) and no puffs of rescue medication during the past 12 hours (approximately 8 am to 8pm). However, a patient was not considered symptom free if they had used rescue medication that day even if his/her total daytime symptoms score was zero. Percentage of nights with 'no nighttime awakenings' A night with 'no nighttime awakenings' was defined from diary data as any night where the patient did not wake up due to symptoms. The total number of nights with 'no nighttime awakenings' over the treatment period was divided by the total number of nights where diary recordings had been made in order to derive the percentage nights with 'no nighttime awakenings'.	52 weeks
Change From Baseline in Mean Daily Number of Puffs of Rescue Medication	The number of puffs of rescue medication taken in the previous 12 hours was recorded by the patients in the eDiary in the morning and evening. The total number of puffs of rescue medication per day over the 52 week treatment period was calculated and divided by the total number of days with non-missing rescue data to derive the mean daily number of puffs of rescue medication taken for the patient. If the number of puffs was missing for part of the day (either morning or evening), then a half day was used in the denominator. Change from baseline in number of puffs were analyzed using a linear mixed model which contained treatment, baseline number of puffs, baseline smoking status, baseline ICS use and COPD disease severity as fixed effects with center as a random effect	52 weeks
Time to First COPD Exacerbation (Moderate or Severe).	COPD exacerbations are considered to be moderate if treatment with systemic corticosteroids and/or antibiotics was required. COPD exacerbations are considered to be severe if hospitalizations were required. Rates are calculated using the Kaplan Meier method.	52 weeks

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Mahler DA, Gifford AH, Satti A, Jessop N, Eckert JH, D'Andrea P, Mota F, Banerjee R. Long-term safety of glycopyrrolate: A randomized study in patients with moderate-to-severe COPD (GEM3). Respir Med. 2016 Jun;115:39-45. doi: 10.1016/j.rmed.2016.03.015. Epub 2016 Mar 22.

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (Actual): November 1, 2014
• Study Completion (Actual): November 1, 2014

Study Registration Dates

• First Submitted: September 28, 2012
• First Submitted That Met QC Criteria: September 28, 2012
• First Posted (Estimate): October 2, 2012

Study Record Updates

• Last Update Posted (Estimate): March 16, 2016
• Last Update Submitted That Met QC Criteria: February 17, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: COPD, NVA237, QAB149, glycopyrronium bromide
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Adjuvants, Anesthesia; Glycopyrrolate
• Other Study ID Numbers: CNVA237A2319; 2012-002728-34 (EudraCT Number)