Efficacy, Tolerability and Safety of NVA237 in Patients With Chronic Obstructive Pulmonary Disease

A Multicenter, Randomized, Blinded, Active-controlled, Parallel-group Study to Compare the Efficacy, Tolerability and Safety of NVA237 Compared to Tiotropium Added on to Fluticasone/Salmeterol in Patients With Chronic Obstructive Pulmonary Disease

This study will assess the efficacy, tolerability and safety of NVA237 compared to tiotropium when added on to fluticasone/salmeterol in patients with chronic obstructive pulmonary disease.

Study Overview

• Status: Completed
• Conditions: Chronic Obstructive Pulmonary Disease
• Intervention / Treatment: Drug: NVA237 50µg once daily; Drug: Flu/Sal; Drug: NVA237 placebo + Tiotropium placebo.; Drug: Tiotropium 18µg once daily

• Study Type: Interventional
• Enrollment (Actual): 773
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Baulkham Hills, New South Wales, Australia, 2153
      • Novartis Investigative Site
    • Brookvale, New South Wales, Australia, 2100
      • Novartis Investigative Site
    • Castle Hill, New South Wales, Australia, 2067
      • Novartis Investigative Site
    • Dapto, New South Wales, Australia
      • Novartis Investigative Site
    • Darlinghurst, New South Wales, Australia, 2010
      • Novartis Investigative Site
    • Ermington, New South Wales, Australia
      • Novartis Investigative Site
    • Gosford, New South Wales, Australia, 2250
      • Novartis Investigative Site
    • Hinchinbrook, New South Wales, Australia, 2168
      • Novartis Investigative Site
    • Kingswood, New South Wales, Australia, 2747
      • Novartis Investigative Site
    • Sydney, New South Wales, Australia, 2089
      • Novartis Investigative Site
  • Queensland
    • Arundel, Queensland, Australia, 4214
      • Novartis Investigative Site
    • Aspley, Queensland, Australia, 4034
      • Novartis Investigative Site
    • Beenleigh, Queensland, Australia, 4207
      • Novartis Investigative Site
    • Browns Plains, Queensland, Australia, 4118
      • Novartis Investigative Site
    • Chemside, Queensland, Australia, 4032
      • Novartis Investigative Site
    • Deception Bay, Queensland, Australia, 4508
      • Novartis Investigative Site
    • Everton Plaza, Queensland, Australia, 4053
      • Novartis Investigative Site
    • Holland Park, Queensland, Australia, 4121
      • Novartis Investigative Site
    • Jimboomba, Queensland, Australia, 4032
      • Novartis Investigative Site
    • Kedron, Queensland, Australia
      • Novartis Investigative Site
    • Kenmore, Queensland, Australia, 4069
      • Novartis Investigative Site
    • Kippa Ring, Queensland, Australia, 4021
      • Novartis Investigative Site
    • Logan Central, Queensland, Australia, 4114
      • Novartis Investigative Site
    • Loganholme, Queensland, Australia, 4129
      • Novartis Investigative Site
    • Mermaid Beach, Queensland, Australia, 4218
      • Novartis Investigative Site
    • Morayfield, Queensland, Australia, 4506
      • Novartis Investigative Site
    • Nerang, Queensland, Australia, 4211
      • Novartis Investigative Site
    • Woolloongabba, Queensland, Australia, 4102
      • Novartis Investigative Site
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Novartis Investigative Site
    • Daw Park, South Australia, Australia, 5041
      • Novartis Investigative Site
    • Glenelg East, South Australia, Australia, 5045
      • Novartis Investigative Site
    • Golden Grove, South Australia, Australia, 5125
      • Novartis Investigative Site
    • Hamley Bridge, South Australia, Australia, 5401
      • Novartis Investigative Site
    • Kensington Gardens, South Australia, Australia, 5065
      • Novartis Investigative Site
    • Prospect, South Australia, Australia, 5082
      • Novartis Investigative Site
  • Victoria
    • Dandenong, Victoria, Australia
      • Novartis Investigative Site
    • Lalor, Victoria, Australia, 3075
      • Novartis Investigative Site
    • Malvern, Victoria, Australia, 3144
      • Novartis Investigative Site
    • Melbourne, Victoria, Australia
      • Novartis Investigative Site
    • Noble Park, Victoria, Australia, 3174
      • Novartis Investigative Site
    • Oakleigh East, Victoria, Australia, 3166
      • Novartis Investigative Site
    • Preston, Victoria, Australia
      • Novartis Investigative Site
    • Rosebud, Victoria, Australia, 3063
      • Novartis Investigative Site
  • Western Australia
    • Bicton, Western Australia, Australia
      • Novartis Investigative Site
    • East Fremantle, Western Australia, Australia, 6158
      • Novartis Investigative Site
    • East Victoria Park, Western Australia, Australia, 6101
      • Novartis Investigative Site
    • Fremantle, Western Australia, Australia, 6160
      • Novartis Investigative Site
    • Mirrabooka, Western Australia, Australia, 6061
      • Novartis Investigative Site
    • Morley, Western Australia, Australia, 6062
      • Novartis Investigative Site
    • Nedlands, Western Australia, Australia, 6009
      • Novartis Investigative Site
    • Noranda, Western Australia, Australia
      • Novartis Investigative Site
    • Perth, Western Australia, Australia, 6000
      • Novartis Investigative Site
    • Perth, Western Australia, Australia, 6069
      • Novartis Investigative Site
    • Perth, Western Australia, Australia
      • Novartis Investigative Site
    • Pinjarra, Western Australia, Australia
      • Novartis Investigative Site
    • Spearwood, Western Australia, Australia, 6163
      • Novartis Investigative Site
    • Woodvale, Western Australia, Australia, 6026
      • Novartis Investigative Site
    • Yokine, Western Australia, Australia, 6060
      • Novartis Investigative Site
• New Zealand
  • Auckland, New Zealand
    • Novartis Investigative Site
  • Auckland, New Zealand, 1051
    • Novartis Investigative Site
  • Christchurch, New Zealand
    • Novartis Investigative Site
  • Dunedin, New Zealand
    • Novartis Investigative Site
  • Grafton, Auckland, New Zealand, 1010
    • Novartis Investigative Site
  • Hamilton, New Zealand, 3240
    • Novartis Investigative Site
  • Tauranga, New Zealand
    • Novartis Investigative Site
  • Tauranga, New Zealand, 3143
    • Novartis Investigative Site
  • Wellington, New Zealand, 6021
    • Novartis Investigative Site
  • Wellington, New Zealand
    • 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:

• Patients with Moderate to Severe COPD (Stage II or Stage III) according to the GOLD 2010 guideline
• Current or ex-smokers who have a smoking history of at least 10 pack years
• Qualifying FEV1 at Visit 2 (day -7)

Exclusion Criteria:

• Patients with a history of asthma or a history of high blood eosinophil count (>600/mm³)
• Patients with concomitant pulmonary disease
• Patients with lung lobectomy or lung volume reduction or lung transplantation
• Patients with α-1 antitrypsin deficiency
• Patients who have had live attenuated vaccinations within 30 days prior to screening visit or during run-in period

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NVA237 + Fluticasone/Salmeterol (Flu/Sal); NVA237 50 µg once daily (NVA237 + Tiotropium placebo + Flu/Sal). NVA237 50 μg o.d., delivered via single-dose dry-powder inhaler (SDDPI) o.d. plus Placebo to tiotropium o.d. delivered via a proprietary inhalation device plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.	Drug: NVA237 50µg once daily; NVA237 50 μg o.d., delivered via single-dose dry-powder inhaler (SDDPI); Drug: Flu/Sal; Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device; Drug: NVA237 placebo + Tiotropium placebo.; Tiotropium 18 μg o.d. delivered via a proprietary inhalation device
Active Comparator: Tiotropium + Flu/Sal; Tiotropium 18µg once daily (NVA237 placebo + Tiotropium + Flu/Sal). Tiotropium 18 μg o.d. delivered via a proprietary inhalation device plus Placebo to NVA237 o.d. delivered via single-dose dry-powder inhaler (SDDPI) plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.	Drug: Flu/Sal; Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device; Drug: NVA237 placebo + Tiotropium placebo.; Tiotropium 18 μg o.d. delivered via a proprietary inhalation device; Drug: Tiotropium 18µg once daily; Tiotropium 18 μg o.d. delivered via a proprietary inhalation device
Placebo Comparator: Flu/Sal; Placebo (NVA237 placebo + Tiotropium placebo + Flu/Sal). Placebo to tiotropium o.d. delivered via a proprietary inhalation device plus Placebo to NVA237 o.d. delivered via single-dose dry-powder inhaler (SDDPI) plus Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device. In addition, at Visit 1, all participants were provided with a short acting β2-agonist (salbutamol) which they were instructed to use throughout the study as rescue medication.	Drug: Flu/Sal; Flu/Sal 500/50 μg b.i.d. delivered via a proprietary inhalation device; Drug: NVA237 placebo + Tiotropium placebo.; Tiotropium 18 μg o.d. delivered via a proprietary inhalation device

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Mean Trough Forced Expiratory Volume in 1 Second (FEV1) (NVA237 Versus Tiotropium)	Spirometry was conducted according to internationally accepted standards. Trough FEV1 referred to the mean of FEV1 at 23:15 hours and 23:45 hours after the morning dose of study drug. The baseline was defined as the average of FEV1 values taken in the clinic 45 min and 15 min prior to the first dose of randomized treatment at Visit 3. A mixed model was used and contained treatment as a fixed effect with the baseline measurement of trough FEV1, FEV1 prior to inhalation of short acting bronchodilators, and FEV1 post-inhalation of bronchodilators and stratification factors as covariates. A positive change from baseline indicates improvement.	baseline, 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Mean Trough FEV1 (Flu/Sal Versus NVA237/Tiotropium+Flu/Sal)	Spirometry was conducted according to internationally accepted standards. Trough FEV1 referred to the mean of FEV1 at 23:15h and 23:45h after the morning dose of study drug. The baseline was defined as the average of FEV1 values taken in the clinic 45min and 15min prior to the first dose of randomized treatment at Visit 3. A mixed model was used and contained treatment as a fixed effect with the baseline measurement of trough FEV1, FEV1 prior to inhalation of short acting bronchodilators, and FEV1 post-inhalation of bronchodilators and stratification factors as covariates. A positive change from baseline indicates improvement.	baseline, 4 weeks, 8 weeks, 12 weeks
Change From Baseline in Mean Trough FEV1	Spirometry was conducted according to internationally accepted standards. Trough FEV1 referred to the mean of FEV1 at 23:15h and 23:45h after the morning dose of study drug. The baseline was defined as the average of FEV1 values taken in the clinic 45min and 15min prior to the first dose of randomized treatment at Visit 3. A mixed model was used and contained treatment as a fixed effect with the baseline measurement of trough FEV1, FEV1 prior to inhalation of short acting bronchodilators, and FEV1 post-inhalation of bronchodilators and stratification factors as covariates. A positive change from baseline indicates improvement.	baseline, 4 weeks, 8 weeks, 12 weeks
Change From Baseline in Total Score of the St George's Respiratory Questionnaire for COPD Patients (SGRQ-C) After 12 Weeks of Treatment	SGRQ-C is a health related quality of life questionnaire consisting of 40 items divided into two components: 1) symptoms, 2) activity& impacts. The lowest possible value is zero and the highest is 100. Higher values corresponded to greater impairment in quality of life. An analysis model included terms for treatment, baseline total SGRQ score, FEV1 and baseline smoking status. The model also contained as fixed effects the baseline total SGRQ score, FEV1 prior to inhalation of short acting bronchodilator, FEV1 post inhalation of short acting bronchodilator and stratification factors as covariates. A negative change from baseline indicates improvement.	12 weeks
Change From Baseline in the Mean Daily Number of Puffs of Rescue Medication Use	The total number of puffs of rescue medication used over the last 12 h recorded in the morning (nighttime use) and in the evening (daytime use) over the full 12 weeks was divided by the total number of days with non-missing rescue data to derive the mean daytime and nighttime number of puffs of rescue medication. Change from baseline in the mean daytime and nighttime number of puffs of rescue medication was analyzed as for the change from baseline in the mean daily number of puffs of rescue medication.	baseline, 12 weeks
Mean Percentage of Nights With 'no Nighttime Awakenings'	A night with 'no nighttime awakenings' is defined from diary data as any night where patient did not wake up due to symptoms. Total number of nights with 'no nighttime awakenings' over treatment period was divided by total number of nights where diary recordings have been made in order to derive percentage of 'no nighttime awakenings' which will be summarized by treatment and analyzed using a similar mixed model as specified for primary analysis. Diary data recorded during the 7 day run-in period was used to calculate baseline percentage of nights 'no nighttime awakenings'.	12 weeks
Mean Percentage of Days With Performance of Usual Activities	A 'day able to perform usual daily activities' was defined from diary data as any day where the patient was not prevented from performing their usual daily activities due to respiratory symptoms. The percentage of 'days able to perform usual daily activities' was derived and analyzed using a similar mixed model as specified for primary analysis as for the percentage of nights with 'no nighttime awakenings'.	12 weeks

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Frith PA, Thompson PJ, Ratnavadivel R, Chang CL, Bremner P, Day P, Frenzel C, Kurstjens N; Glisten Study Group. Glycopyrronium once-daily significantly improves lung function and health status when combined with salmeterol/fluticasone in patients with COPD: the GLISTEN study, a randomised controlled trial. Thorax. 2015 Jun;70(6):519-27. doi: 10.1136/thoraxjnl-2014-206670. Epub 2015 Apr 3.

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: January 16, 2012
• First Submitted That Met QC Criteria: January 19, 2012
• First Posted (Estimate): January 20, 2012

Study Record Updates

• Last Update Posted (Estimate): January 5, 2015
• Last Update Submitted That Met QC Criteria: December 23, 2014
• Last Verified: December 1, 2014

More Information

Terms related to this study

• Keywords: COPD; Chronic Obstructive Pulmonary Disease,; NVA 237,; glycopyrronium,
• 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; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Adjuvants, Anesthesia; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Glycopyrrolate; Tiotropium Bromide
• Other Study ID Numbers: CNVA237AAU01