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

• ClinicalTrials.gov Identifier: NCT01513460
• Recruitment Status: Completed
• First Posted: January 20, 2012
• Results First Posted: January 5, 2015
• Last Update Posted: January 5, 2015
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: January 16, 2012
• First Posted Date: January 20, 2012
• Results First Submitted Date: December 10, 2014
• Results First Posted Date: January 5, 2015
• Last Update Posted Date: January 5, 2015
• Study Start Date: April 2012
• Actual Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 23, 2014)

Change From Baseline in Mean Trough Forced Expiratory Volume in 1 Second (FEV1) (NVA237 Versus Tiotropium) [ Time Frame: baseline, 12 weeks ]

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.

Original Primary Outcome Measures (submitted: January 19, 2012)

Mean trough forced expiratory volume in 1 second (FEV1) [ Time Frame: 12 weeks ]

Spirometry is conducted according to internationally accepted standards. Trough FEV1 refers to the mean of FEV1 at 23:15h and 23:45h after the morning dose of study drug. The baseline is 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. Mixed model used will contain 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.

Current Secondary Outcome Measures (submitted: December 23, 2014)

• Change From Baseline in Mean Trough FEV1 (Flu/Sal Versus NVA237/Tiotropium+Flu/Sal) [ Time Frame: baseline, 4 weeks, 8 weeks, 12 weeks ]
  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.
• Change From Baseline in Mean Trough FEV1 [ Time Frame: baseline, 4 weeks, 8 weeks, 12 weeks ]
  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.
• Change From Baseline in Total Score of the St George's Respiratory Questionnaire for COPD Patients (SGRQ-C) After 12 Weeks of Treatment [ Time Frame: 12 weeks ]
  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.
• Change From Baseline in the Mean Daily Number of Puffs of Rescue Medication Use [ Time Frame: baseline, 12 weeks ]
  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.
• Mean Percentage of Nights With 'no Nighttime Awakenings' [ Time Frame: 12 weeks ]
  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'.
• Mean Percentage of Days With Performance of Usual Activities [ Time Frame: 12 weeks ]
  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'.

Original Secondary Outcome Measures (submitted: January 19, 2012)

• Mean trough forced expiratory volume in 1 second (FEV1) [ Time Frame: Weeks 4 and 8 ]
  Spirometry is conducted according to internationally accepted standards. Trough FEV1 refers to the mean of FEV1 at 23:15h and 23:45h after the morning dose of study drug. The baseline is 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. Mixed model used will contain 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.
• Total score of the St George's Respiratory Questionnaire for COPD patients (SGRQ-C) After 12 weeks of treatment [ Time Frame: Week 12 ]
  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 100. Higher values correspond to greater impairment in quality of life. Model will include terms for treatment, baseline total SGRQ score, FEV1 and baseline smoking status. The model will also contain 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.
• Daily rescue Medication Use (number of puffs) Over the study duration (Baseline to Week 12) [ Time Frame: 12 weeks ]
  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 will be 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 will be analyzed as for the change from baseline in the mean daily number of puffs of rescue medication.
• Percentage of nights with 'no nighttime awakenings' over 12 weeks (Baseline to Week 12) [ Time Frame: 12 weeks ]
  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 will be 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 similar mixed model as specified for primary analysis. Diary data recorded during the 7 day run-in period will be used to calculate baseline percentage of nights 'no nighttime awakenings'.
• Performance of usual activities [ Time Frame: 12 weeks ]
  A 'day able to perform usual daily activities' is 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' will be derived and analyzed as for the percentage of nights with 'no nighttime awakenings'.
• Adverse Events, Death, and Serious or Clinically Significant Adverse Events or Related Discontinuations [ Time Frame: 12 weeks and 30 day follow-up (for SAE - 7 days for AE) ]
  Adverse events are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory 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 judgment of investigators represent significant hazards.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy, Tolerability and Safety of NVA237 in Patients With Chronic Obstructive Pulmonary Disease
• Official Title: 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
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Chronic Obstructive Pulmonary Disease

Intervention

• Drug: NVA237 50µg once daily
  NVA237 50 μg o.d., delivered via single-dose dry-powder inhaler (SDDPI)
• Drug: Tiotropium 18µg once daily
  Tiotropium 18 μg o.d. delivered via a proprietary inhalation device
• 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

Study Arms

• 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.
  Interventions:

  • Drug: NVA237 50µg once daily
  • Drug: Flu/Sal
  • Drug: NVA237 placebo + Tiotropium placebo.
• 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.
  Interventions:

  • Drug: Tiotropium 18µg once daily
  • Drug: Flu/Sal
  • Drug: NVA237 placebo + Tiotropium placebo.
• 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.
  Interventions:

  • Drug: Flu/Sal
  • Drug: NVA237 placebo + Tiotropium placebo.

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 23, 2014): 773
• Original Estimated Enrollment (submitted: January 19, 2012): 600
• Actual Study Completion Date: December 2013
• Actual Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 40 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, New Zealand

Administrative Information

• NCT Number: NCT01513460
• Other Study ID Numbers: CNVA237AAU01
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: December 2014