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Comparison of Indacaterol 150 mcg Once Daily (o.d.) With Salmeterol/Fluticasone Propionate 50 mcg/500 mcg Twice Daily (b.i.d.) (INSTEAD)

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ClinicalTrials.gov Identifier: NCT01555138
Recruitment Status : Completed
First Posted : March 15, 2012
Results First Posted : April 28, 2015
Last Update Posted : April 28, 2015
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Chronic Obstructive Pulmonary Disease
Interventions Drug: Indacaterol
Drug: Salmeterol
Enrollment 581
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Indacaterol Salmeterol/Fluticasone Propionate
Hide Arm/Group Description Indacaterol 150 mcg once daily (o.d.) delivered via the Novartis single dose dry power inhaler (SDDPI) (Onbrez® Breezhaler®) Salmeterol 50 mcg /fluticasone propionate 500 mcg for inhalation delivered via a proprietary multi dose dry powder inhaler (MDDPI) device (Seretide® Accuhaler®) twice daily (b.i.d.)
Period Title: Overall Study
Started 293 288
Completed 246 250
Not Completed 47 38
Reason Not Completed
Death             0             1
Lost to Follow-up             1             0
Abnormal Lab reults             1             3
Lack of Efficacy             2             2
Protocol Violation             5             3
Administrative problems             8             0
Withdrawal by Subject             16             15
Adverse Event             14             14
Arm/Group Title Indacaterol Salmeterol/Fluticasone Propionate Total
Hide Arm/Group Description Indacaterol 150 mcg once daily (o.d.) delivered via the Novartis single dose dry power inhaler (SDDPI) (Onbrez® Breezhaler®) Salmeterol 50 mcg /fluticasone propionate 500 mcg for inhalation delivered via a proprietary multi dose dry powder inhaler (MDDPI) device (Seretide® Accuhaler®) twice daily (b.i.d.) Total of all reporting groups
Overall Number of Baseline Participants 293 288 581
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 293 participants 288 participants 581 participants
65.3  (8.39) 66.8  (8.53) 66.0  (8.49)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 293 participants 288 participants 581 participants
Female
89
  30.4%
91
  31.6%
180
  31.0%
Male
204
  69.6%
197
  68.4%
401
  69.0%
1.Primary Outcome
Title Trough Forced Expiratory Volume in One Second (FEV1) at 12 Weeks (Imputed With LOCF): Treatment Comparisons
Hide Description Spirometry conducted to internationally accepted standards. Trough FEV1 defined as the mean of the FEV1 measurements at 23 h 10 min and 23 h 45 min post the Day 84 morning dose. The primary variable (imputed with last observation carried forward) will be analysed using a mixed model for the Per Protocol Set (PPS). The model will contain treatment as a fixed effect with the baseline FEV1 measurement, FEV1 prior to inhalation and FEV1 10-15 min post inhalation of salbutamol (components of reversibility at Visit 1) as covariates.
Time Frame 12 weeks
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full analysis set
Arm/Group Title Indacaterol Salmeterol/Fluticasone Propionate
Hide Arm/Group Description:
Indacaterol 150 mcg once daily (o.d.) delivered via the Novartis single dose dry power inhaler (SDDPI) (Onbrez® Breezhaler®)
Salmeterol 50 mcg /fluticasone propionate 500 mcg for inhalation delivered via a proprietary multi dose dry powder inhaler (MDDPI) device (Seretide® Accuhaler®) twice daily (b.i.d.)
Overall Number of Participants Analyzed 293 288
Least Squares Mean (Standard Error)
Unit of Measure: Liters
1.591  (0.0276) 1.604  (0.0281)
2.Secondary Outcome
Title Trough FEV1 (L) at Week 26 (Imputed With LOCF): Treatment Comparisons
Hide Description Trough FEV1 is defined as the average of the 23 h 10 min and the 23 h 45 min values taken in the clinic at Visit 11.
Time Frame 26 weeks
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Hide Analysis Population Description
Full analysis set
Arm/Group Title Indacaterol Salmeterol/Fluticasone Propionate
Hide Arm/Group Description:
Indacaterol 150 mcg once daily (o.d.) delivered via the Novartis single dose dry power inhaler (SDDPI) (Onbrez® Breezhaler®)
Salmeterol 50 mcg /fluticasone propionate 500 mcg for inhalation delivered via a proprietary multi dose dry powder inhaler (MDDPI) device (Seretide® Accuhaler®) twice daily (b.i.d.)
Overall Number of Participants Analyzed 293 288
Least Squares Mean (Standard Error)
Unit of Measure: Liters
1.567  (0.0302) 1.569  (0.0307)
3.Secondary Outcome
Title FEV1 (L) at Individual Time Points After 12 Weeks Treatment: Treatment Comparisons
Hide Description FEV1 at each time point, for each visit, will be analyzed using the same mixed model as specified for the primary analysis. Least squares means will be displayed by treatment group.
Time Frame 12 weeks
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Hide Analysis Population Description
Full analysis set
Arm/Group Title Indacaterol Salmeterol/Fluticasone Propionate
Hide Arm/Group Description:
Indacaterol 150 mcg once daily (o.d.) delivered via the Novartis single dose dry power inhaler (SDDPI) (Onbrez® Breezhaler®)
Salmeterol 50 mcg /fluticasone propionate 500 mcg for inhalation delivered via a proprietary multi dose dry powder inhaler (MDDPI) device (Seretide® Accuhaler®) twice daily (b.i.d.)
Overall Number of Participants Analyzed 293 288
Least Squares Mean (Standard Error)
Unit of Measure: Liters
-50 min pre-dose 1.601  (0.0281) 1.588  (0.0286)
30 min post-dose, 1.667  (0.0207) 1.656  (0.0208)
1h post-dose, 1.693  (0.0285) 1.684  (0.0293)
2h post-dose 1.705  (0.0291) 1.708  (0.0300)
4h post-dose 1.670  (0.0215) 1.699  (0.0216)
23h 10 min post-dose 1.577  (0.0277) 1.591  (0.0284)
23h 45 min post-dose 1.597  (0.0283) 1.613  (0.0291)
-15 min pre-dose 1.623  (0.0282) 1.616  (0.287)
5 min post-dose 1.631  (0.0209) 1.613  (0.0209)
4.Secondary Outcome
Title FEV1 (L) at Individual Time Points After 26 Weeks Treatment: Treatment Comparisons
Hide Description FEV1 at each time point, for each visit, will be analyzed using the same mixed model as specified for the primary analysis. Least squares means will be displayed by treatment group .
Time Frame 26 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set
Arm/Group Title Indacaterol Salmeterol/Fluticasone Propionate
Hide Arm/Group Description:
Indacaterol 150 mcg once daily (o.d.) delivered via the Novartis single dose dry power inhaler (SDDPI) (Onbrez® Breezhaler®)
Salmeterol 50 mcg /fluticasone propionate 500 mcg for inhalation delivered via a proprietary multi dose dry powder inhaler (MDDPI) device (Seretide® Accuhaler®) twice daily (b.i.d.)
Overall Number of Participants Analyzed 293 288
Least Squares Mean (Standard Error)
Unit of Measure: Liters
-50 min pre-dose 1.569  (0.0301) 1.582  (0.0304)
30 min post-dose, 1.670  (0.0244) 1.656  (0.0244)
1h post-dose, 1.676  (0.0317) 1.677  (0.0324)
2h post-dose 1.700  (0.0318) 1.693  (0.0325)
4h post-dose 1.664  (0.0320) 1.663  (0.0328)
23h 10 min post-dose 1.551  (0.0305) 1.559  (0.0310)
23h 45 min post-dose 1.574  (0.313) 1.575  (0.0318)
-15 min pre-dose 1.576  (0.0294) 1.595  (0.0300)
5 min post-dose 1.630  (0.0304) 1.630  (0.0310)
5.Secondary Outcome
Title FVC Over 26 Weeks of Treatment
Hide Description FVC at each time point, for each visit, will be analyzed using the same mixed model as specified for the primary analysis. Least squares means will be displayed by treatment group.
Time Frame 12 and 26 weeks
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Hide Analysis Population Description
Full analysis set
Arm/Group Title Indacaterol Salmeterol/Fluticasone Propionate
Hide Arm/Group Description:
Indacaterol 150 mcg once daily (o.d.) delivered via the Novartis single dose dry power inhaler (SDDPI) (Onbrez® Breezhaler®)
Salmeterol 50 mcg /fluticasone propionate 500 mcg for inhalation delivered via a proprietary multi dose dry powder inhaler (MDDPI) device (Seretide® Accuhaler®) twice daily (b.i.d.)
Overall Number of Participants Analyzed 293 288
Least Squares Mean (Standard Error)
Unit of Measure: Liters
12 weeks 3.090  (0.0457) 3.064  (0.0466)
26 weeks 3.057  (0.0512) 3.062  (0.0520)
6.Secondary Outcome
Title Analysis of AUC (5 Min – 4 h) for FEV1 (L) at Week 12 and Week 26: Treatment Comparison
Hide Description The standardized (with respect to the length of time) AUC for FEV1 will be calculated between 5 min and 4 h post morning dose as the sum of trapezoids divided by the length of time at Day 84 (Visit 6) and Day 182 (Visit 10). Scheduled (not actual) time points are to be used. FEV1 measurements taken within 6 h of rescue use will be set to missing before the standardized AUC is calculated.
Time Frame 12 and 26 weeks
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Full analysis set
Arm/Group Title Indacaterol Salmeterol/Fluticasone Propionate
Hide Arm/Group Description:
Indacaterol 150 mcg once daily (o.d.) delivered via the Novartis single dose dry power inhaler (SDDPI) (Onbrez® Breezhaler®)
Salmeterol 50 mcg /fluticasone propionate 500 mcg for inhalation delivered via a proprietary multi dose dry powder inhaler (MDDPI) device (Seretide® Accuhaler®) twice daily (b.i.d.)
Overall Number of Participants Analyzed 293 288
Least Squares Mean (Standard Error)
Unit of Measure: Liters
Week 12 1.689  (0.0201) 1.689  (0.0203)
Week 26 1.683  (0.0304) 1.682  (0.0310)
7.Secondary Outcome
Title TDI Focal Score at Week 12 and Week 26: Treatment Comparisons
Hide Description The Transition Dyspnea Index (TDI) total score after 12 and 26 weeks of treatment will be analyzed using the same mixed model as specified for the primary analysis with the Baseline Dyspnea Index (BDI) total score as the baseline.Total score ranging - 9 to + 9. The lower the score, the more deterioration in severity of dyspnea. One additional option in each category, which does not contribute to the score, allows for circumstances in which impairment is due to reasons other than dyspnea.
Time Frame 12 and 26 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Indacaterol Salmeterol/Fluticasone Propionate
Hide Arm/Group Description:
Indacaterol 150 mcg once daily (o.d.) delivered via the Novartis single dose dry power inhaler (SDDPI) (Onbrez® Breezhaler®)
Salmeterol 50 mcg /fluticasone propionate 500 mcg for inhalation delivered via a proprietary multi dose dry powder inhaler (MDDPI) device (Seretide® Accuhaler®) twice daily (b.i.d.)
Overall Number of Participants Analyzed 293 288
Least Squares Mean (Standard Error)
Unit of Measure: Units on a scale
12 weeks 1.89  (0.499) 1.69  (0.509)
26 weeks 2.58  (0.543) 2.70  (0.552)
8.Secondary Outcome
Title Number of COPD Exacerbations Per Patient Over 26 Weeks: Treatment Comparisons (Without Imputation; Full Analysis Set)
Hide Description The number of exacerbations during the 26 week treatment period will be analyzed using a generalized linear model assuming a negative binomial distribution.
Time Frame 26 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Indacaterol Salmeterol/Fluticasone Propionate
Hide Arm/Group Description:
Indacaterol 150 mcg once daily (o.d.) delivered via the Novartis single dose dry power inhaler (SDDPI) (Onbrez® Breezhaler®)
Salmeterol 50 mcg /fluticasone propionate 500 mcg for inhalation delivered via a proprietary multi dose dry powder inhaler (MDDPI) device (Seretide® Accuhaler®) twice daily (b.i.d.)
Overall Number of Participants Analyzed 293 288
Measure Type: Number
Unit of Measure: participants
none 233 215
one 47 57
two 11 15
three 2 1
Greater than or equal to four 0 0
9.Secondary Outcome
Title Mean Daily Number of Puffs of Rescue Medication Used Over 26 Weeks of Treatment
Hide Description The mean daily number of puffs of rescue medication taken by the patient will be derived. If the number of puffs is missing for part of the day (either morning or evening) then a half day will be used in the denominator. Rescue medication data recorded during the 14 day run-in period will be used to calculate the baseline. The mean change from baseline in the daily number of puffs of rescue medication will be analyzed using the same mixed model as specified for the primary analysis, with the baseline FEV1 replaced with the baseline daily rescue use.
Time Frame 12 and 26 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Indacaterol Salmeterol/Fluticasone Propionate
Hide Arm/Group Description:
Indacaterol 150 mcg once daily (o.d.) delivered via the Novartis single dose dry power inhaler (SDDPI) (Onbrez® Breezhaler®)
Salmeterol 50 mcg /fluticasone propionate 500 mcg for inhalation delivered via a proprietary multi dose dry powder inhaler (MDDPI) device (Seretide® Accuhaler®) twice daily (b.i.d.)
Overall Number of Participants Analyzed 293 288
Mean (Standard Deviation)
Unit of Measure: number of puffs
Baseline 1.82  (2.274) 1.83  (2.035)
Week 12 1.50  (1.883) 1.45  (1.697)
Week 26 1.37  (1.775) 1.37  (1.678)
10.Secondary Outcome
Title Rescue Medication Use Over 26 Weeks: Percentage of 'Days With no Rescue Use'
Hide Description A ‘day with no rescue use’ is defined from diary data as any day where the patient has taken no puffs of rescue medication. The percentage of ‘days with no rescue use’ will be derived and analyzed as for the percentage of ‘nights with no nighttime awakenings’.
Time Frame 26 weeks
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Hide Analysis Population Description
Full Analysis Set
Arm/Group Title Indacaterol Salmeterol/Fluticasone Propionate
Hide Arm/Group Description:
Indacaterol 150 mcg once daily (o.d.) delivered via the Novartis single dose dry power inhaler (SDDPI) (Onbrez® Breezhaler®)
Salmeterol 50 mcg /fluticasone propionate 500 mcg for inhalation delivered via a proprietary multi dose dry powder inhaler (MDDPI) device (Seretide® Accuhaler®) twice daily (b.i.d.)
Overall Number of Participants Analyzed 293 288
Least Squares Mean (Standard Error)
Unit of Measure: % of Days
52.8  (3.71) 54.6  (3.68)
11.Secondary Outcome
Title St Georges Respiratory Questionnaire for COPD
Hide Description A Total and three component scores are calculated: Symptoms; Activity; Impacts. Each component of the questionnaire is scored separately:The score for each component is calculated separately by dividing the summed weights by the maximum possible weight for that component and expressing the result as a percentage: Score = 100 x Summed weights from all positive items in that component divided by Sum of weights for all items in that component The Total score is calculated in similar way: Score = 100 x Summed weights from all positive items in the questionnaire divided by Sum of weights for all items in the questionnaire Sum of maximum possible weights for each component and Total: Symptoms 566.2 Activity 982.9 Impacts 1652.8 Total (sum of maximum for all three components) 3201.9 The proportion of patients who achieve a clinically important improvement of at least 4 units in the total SGRQ will be analyzed. The higher the score the more symptoms of disease are present.
Time Frame 12 and 26 weeks
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Hide Analysis Population Description
Full Analysis set
Arm/Group Title Indacaterol Salmeterol/Fluticasone Propionate
Hide Arm/Group Description:
Indacaterol 150 mcg once daily (o.d.) delivered via the Novartis single dose dry power inhaler (SDDPI) (Onbrez® Breezhaler®)
Salmeterol 50 mcg /fluticasone propionate 500 mcg for inhalation delivered via a proprietary multi dose dry powder inhaler (MDDPI) device (Seretide® Accuhaler®) twice daily (b.i.d.)
Overall Number of Participants Analyzed 293 288
Least Squares Mean (Standard Error)
Unit of Measure: scores on a scale
Week 12 32.8  (1.58) 32.9  (1.61)
Week 26 33.1  (1.87) 33.5  (1.93)
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Indacaterol Salmeterol/Fluticasone
Hide Arm/Group Description Indacaterol 150 μg once daily (o.d.) delivered via the Novartis single dose dry power inhaler (SDDPI) (Onbrez® Breezhaler®) Salmeterol 50 μg /fluticasone propionate 500 μg for inhalation delivered via a proprietary multi dose dry powder inhaler (MDDPI) device (Seretide® Accuhaler®) twice daily (b.i.d.)
All-Cause Mortality
Indacaterol Salmeterol/Fluticasone
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Indacaterol Salmeterol/Fluticasone
Affected / at Risk (%) Affected / at Risk (%)
Total   5/293 (1.71%)   17/288 (5.90%) 
Blood and lymphatic system disorders     
Anaemia  1  0/293 (0.00%)  1/288 (0.35%) 
Thrombocytopenia  1  0/293 (0.00%)  1/288 (0.35%) 
Cardiac disorders     
Atrial fibrillation  1  0/293 (0.00%)  2/288 (0.69%) 
Bradycardia  1  0/293 (0.00%)  1/288 (0.35%) 
Cardiac failure  1  1/293 (0.34%)  0/288 (0.00%) 
Coronary artery disease  1  0/293 (0.00%)  1/288 (0.35%) 
Supraventricular tachycardia  1  0/293 (0.00%)  1/288 (0.35%) 
Gastrointestinal disorders     
Duodenitis  1  0/293 (0.00%)  1/288 (0.35%) 
Dyspepsia  1  0/293 (0.00%)  1/288 (0.35%) 
Pancreatitis acute  1  1/293 (0.34%)  0/288 (0.00%) 
General disorders     
Non-cardiac chest pain  1  0/293 (0.00%)  1/288 (0.35%) 
Sudden death  1  0/293 (0.00%)  1/288 (0.35%) 
Hepatobiliary disorders     
Cholelithiasis  1  0/293 (0.00%)  1/288 (0.35%) 
Cholestasis  1  0/293 (0.00%)  1/288 (0.35%) 
Infections and infestations     
Pneumonia  1  0/293 (0.00%)  2/288 (0.69%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Gastric cancer  1  1/293 (0.34%)  0/288 (0.00%) 
Mesothelioma  1  0/293 (0.00%)  1/288 (0.35%) 
Neurilemmoma benign  1  0/293 (0.00%)  1/288 (0.35%) 
Renal cancer  1  0/293 (0.00%)  1/288 (0.35%) 
Nervous system disorders     
Transient ischaemic attack  1  0/293 (0.00%)  1/288 (0.35%) 
Respiratory, thoracic and mediastinal disorders     
Chronic obstructive pulmonary disease  1  1/293 (0.34%)  3/288 (1.04%) 
Pneumothorax spontaneous  1  1/293 (0.34%)  0/288 (0.00%) 
Vascular disorders     
Peripheral arterial occlusive disease  1  0/293 (0.00%)  1/288 (0.35%) 
Peripheral artery thrombosis  1  0/293 (0.00%)  1/288 (0.35%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Indacaterol Salmeterol/Fluticasone
Affected / at Risk (%) Affected / at Risk (%)
Total   70/293 (23.89%)   85/288 (29.51%) 
Infections and infestations     
Nasopharyngitis  1  15/293 (5.12%)  18/288 (6.25%) 
Respiratory, thoracic and mediastinal disorders     
Chronic obstructive pulmonary disease  1  60/293 (20.48%)  71/288 (24.65%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Study Director
Organization: Novartis Pharmaceuticals
Phone: 862-778-8300
Layout table for additonal information
Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01555138     History of Changes
Other Study ID Numbers: CQAB149B2401
2011-003732-31 ( EudraCT Number )
First Submitted: March 13, 2012
First Posted: March 15, 2012
Results First Submitted: February 10, 2015
Results First Posted: April 28, 2015
Last Update Posted: April 28, 2015