COMBINE: Study to Evaluate Efficacy/Safety of Combination Budesonide/Indacaterol vs Fluticasone/Salmeterol in Patients With COPD

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02055352
• Collaborator: (none)
• Enrollment: 222
• Locations: 25
• Arms: 2
• Actual Duration (Months): 19.9
• Patients Per Site: 8.9
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

To demonstrate the free combination of budesonide and indacaterol is as efficacious as fluticasone and salmeterol in patients with COPD

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease	Drug: Budesonide; Drug: Fluticasone; Drug: Indacaterol; Drug: Salmeterol	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 222 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 24-week Study to Evaluate Efficacy and Safety of the Combination Budesonide / Indacaterol vs Fluticasone / Salmeterol in Patients With COPD
• Actual Study Start Date: May 30, 2014
• Actual Primary Completion Date: Jan 26, 2016
• Actual Study Completion Date: Jan 26, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Budesonide/indacaterol Participants will receive a fixed combination of fluticasone and salmeterol during 4 weeks followed by a free combination of budesonide and indacaterol for the remainig of study.	Drug: Budesonide; Budesonide 400 mcg twice a day via Breezhaler® device; Drug: Fluticasone; Fluticasone 250 mcg twice daily via Accuhaler® device; Drug: Indacaterol; Indacaterol 150 mcg once daily via Breezhaler® device; Drug: Salmeterol; Salmeterol 50 mcg twice daily via Diskus® device
Active Comparator: Fluticasone / salmeterol Fixed combination of fluticasone and salmeterol	Drug: Fluticasone; Fluticasone 250 mcg twice daily via Accuhaler® device; Drug: Salmeterol; Salmeterol 50 mcg twice daily via Diskus® device

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Trough Forced Expiratory Volume in 1 Second (Non-inferiority Analysis). [Baseline and week 12]

   Forced Expiratory Volume in 1 second (FEV1) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation.

Secondary Outcome Measures

1. Change in Health Status - mMRC [Baseline, week 12 and week 24]

   Modified Medical Research Council scale (mMRC) questionnaire will be completed by participants. 0 Not troubled with breathlessness except with strenuous exercise; 1 Troubled by shortness of breath when hurrying on the level or walking up a slight hill; 2 Walks slower than people of the same age on the level because of breathlessness or has to stop for breath when walking at own pace on the level; 3 Stops for breath after walking about 100 yards or after a few minutes on the level; 4 Too breathless to leave the house or breathless when dressing or undressing

2. Change From Baseline in Mean Daily Number of Puffs of Rescue Medication Used Over the 24 Week Treatment [24 weeks]

   A day with no rescue medication use is defined from the diary data as any day where the patient recorded no rescue medicine use during the previous 12 hours.

3. Change From Baseline in Trough Forced Expiratory Volume in 1 Second at Week 24 (Analysis of Superiority) [Baseline and week 24]

   Forced Expiratory Volume in 1 second (FEV1) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing.

4. Change in Health Status - SGRQ-C [Baseline, week 12 and week 24]

   St George's Respiratory Questionnaire short version questionnaire will be completed by participants. The SGRQ ranges from 0 (no impairment of quality of life) to 100 (highest impairment of quality of life)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Written informed consent must be obtained before any assessment is performed

• Outpatients with stable COPD groups C and D according to the 2011 GOLD Guidelines.

• Current or ex-smokers who have a smoking history of at least 10 pack years

• Patients with a history of at least one exacerbation.

• Patients able to read and complete

Exclusion Criteria:

• Use of other investigational drugs within 30 days

• Patients with a history of hypersensitivity to any of the study drugs

• History or current diagnosis of ECG abnormalities

• Patients with diabetes Type I or uncontrolled diabetes Type II including patients with a history of blood glucose levels consistently outside the normal range

• Patients who have not achieved an acceptable spirometry result at Visit 1

• Patients with a body mass index (BMI) of more than 40 kg/m2

• Patients with lung cancer or a history of lung cancer

• Patients with a history of malignancy of any organ system

• Pregnant or nursing (lactating) women

• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment

• Patients who do not maintain regular day/night, waking/sleeping cycles (e.g., night shift workers)

• Patients that are uncontrolled or unstable on permitted therapy, who in the opinion of the investigator, have clinically significant renal, cardiovascular, neurological, endocrine, immunological, psychiatric, gastrointestinal, hepatic, or haematological abnormalities which could interfere with the assessment of the efficacy and safety of the study treatment

• Patients requiring oxygen therapy for chronic hypoxemia

• Patients who have had a respiratory tract infection within 6 weeks prior to Visit 1

• Patients with concomitant pulmonary disease, e.g. pulmonary tuberculosis, bronchiectasis, sarcoidosis, interstitial lung disorder or pulmonary hypertension

• Patients with a known diagnosis of Alpha-1 Antitrypsin deficiency.

• Patients with history of lung surgery

• Patients who are participating in the active phase of a supervised pulmonary rehabilitation program.

• Patients with a history of asthma Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1056ABJ
2	Novartis Investigative Site	Florida	Buenos Aires	Argentina	B1602DQD
3	Novartis Investigative Site	La Plata	Buenos Aires	Argentina	1900
4	Novartis Investigative Site	Vicente Lopez	Buenos Aires	Argentina	B1638AAI
5	Novartis Investigative Site	Zarate	Buenos Aires	Argentina	2800
6	Novartis Investigative Site	Santa Rosa	La Pampa	Argentina
7	Novartis Investigative Site	Buenos Aires		Argentina	C1125ABE
8	Novartis Investigative Site	Ciudad Autonoma de Bs As		Argentina	C1425FVH
9	Novartis Investigative Site	Salta		Argentina	4000
10	Novartis Investigative Site	Rio de Janeiro	RJ	Brazil	021941-617
11	Novartis Investigative Site	Porto Alegre	RS	Brazil	90880-480
12	Novartis Investigative Site	Sao Bernardo do Campo	SP	Brazil	09750-420
13	Novartis Investigative Site	São Paulo	SP	Brazil	01244-030
14	Novartis Investigative Site	Santiago	Region Metropolitana	Chile	8431633
15	Novartis Investigative Site	Rancagua		Chile	2841959
16	Novartis Investigative Site	Santo Domingo	Republica Dominicana	Dominican Republic	10205
17	Novartis Investigative Site	Santo Domingo	Republica Dominicana	Dominican Republic
18	Novartis Investigative Site	Guayaquil	Guayas	Ecuador	412
19	Novartis Investigative Site	San Pedro Sula		Honduras	21102
20	Novartis Investigative Site	Tegucigalpa		Honduras
21	Novartis Investigative Site	Mexico	Distrito Federal	Mexico	03310
22	Novartis Investigative Site	Mexico	Distrito Federal	Mexico	06760
23	Novartis Investigative Site	Mexico	Distrito Federal	Mexico	14050
24	Novartis Investigative Site	León	Guanajuato	Mexico	37000
25	Novartis Investigative Site	Panama City	Panamá	Panama

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02055352
• Other Study ID Numbers: CQAB149BAR01
• First Posted: Feb 5, 2014
• Last Update Posted: Apr 18, 2017
• Last Verified: Apr 1, 2017

• Additional relevant MeSH terms: Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Fluticasone; Budesonide; Salmeterol Xinafoate

Study Results

Participant Flow

Arm/Group Title	Budesonide/Indacaterol	Fluticasone / Salmeterol
Arm/Group Description	Participants will receive a fixed combination of fluticasone and salmeterol during 4 weeks followed by a free combination of budesonide and indacaterol for the remainig of study.	Fixed combination of fluticasone and salmeterol
Period Title: Overall Study
STARTED	109	113
Per-Protocol Set (PPS)	108	111
COMPLETED	103	96
NOT COMPLETED	6	17

Baseline Characteristics

Arm/Group Title	Budesonide/Indacaterol	Fluticasone / Salmeterol	Total
Arm/Group Description	Participants will receive a fixed combination of fluticasone and salmeterol during 4 weeks followed by a free combination of budesonide and indacaterol for the remainig of study.	Fixed combination of fluticasone and salmeterol	Total of all reporting groups
Overall Participants	109	113	222
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	67.1 (9)	67.3 (8.45)	67.2 (8.70)
Sex: Female, Male (Count of Participants)
Female	41 37.6%	54 47.8%	95 42.8%
Male	68 62.4%	59 52.2%	127 57.2%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Trough Forced Expiratory Volume in 1 Second (Non-inferiority Analysis).
Description	Forced Expiratory Volume in 1 second (FEV1) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation.
Time Frame	Baseline and week 12

Outcome Measure Data

Analysis Population Description

Per-protocol set (PPS) included all patients in the FAS without any major protocol deviations. Major protocol deviations were defined in the validation analysis plan prior to database lock and the unblinding of the study. Patients were analyzed according to the treatment they are randomized to

Arm/Group Title	Budesonide/Indacaterol	Fluticasone / Salmeterol
Arm/Group Description	Participants will receive a fixed combination of fluticasone and salmeterol during 4 weeks followed by a free combination of budesonide and indacaterol for the remainig of study.	Fixed combination of fluticasone and salmeterol
Measure Participants	108	111
Least Squares Mean (Standard Error) [Liters]	0.080 (0.027)	0.019 (0.028)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Budesonide/Indacaterol, Fluticasone / Salmeterol
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	A change of 5-10% from baseline values is considered to be clinically important. The estimated adjusted treatment difference for budesonide 400 μg twice a day/ indacaterol 150 μg once daily minus fixed combination of fluticasone/ salmeterol 250/ 50 μg twice daily was displayed along with the associated one-sided 97.5% confidence interval. If the lower limit of this confidence interval was to the right (i.e. above) - 10 mL, then non-inferiority could be claimed.
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Mixed effects General linear model
	Comments

2. Secondary Outcome

Title	Change in Health Status - mMRC
Description	Modified Medical Research Council scale (mMRC) questionnaire will be completed by participants. 0 Not troubled with breathlessness except with strenuous exercise; 1 Troubled by shortness of breath when hurrying on the level or walking up a slight hill; 2 Walks slower than people of the same age on the level because of breathlessness or has to stop for breath when walking at own pace on the level; 3 Stops for breath after walking about 100 yards or after a few minutes on the level; 4 Too breathless to leave the house or breathless when dressing or undressing
Time Frame	Baseline, week 12 and week 24

Outcome Measure Data

Analysis Population Description

Per-protocol set (PPS) included all patients in the FAS without any major protocol deviations. Major protocol deviations were defined in the validation analysis plan prior to database lock and the unblinding of the study. Patients were analyzed according to the treatment they are randomized to

Arm/Group Title	Budesonide/Indacaterol	Fluticasone / Salmeterol
Arm/Group Description	Participants will receive a fixed combination of fluticasone and salmeterol during 4 weeks followed by a free combination of budesonide and indacaterol for the remainig of study.	Fixed combination of fluticasone and salmeterol
Measure Participants	108	111
Week 12	1.452 (0.111)	1.623 (0.113)
Week 24	1.315 (0.112)	1.414 (0.115)

3. Secondary Outcome

Title	Change From Baseline in Mean Daily Number of Puffs of Rescue Medication Used Over the 24 Week Treatment
Description	A day with no rescue medication use is defined from the diary data as any day where the patient recorded no rescue medicine use during the previous 12 hours.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

Per-protocol set (PPS) included all patients in the FAS without any major protocol deviations. Major protocol deviations were defined in the validation analysis plan prior to database lock and the unblinding of the study. Patients that were not discontinued before Visit 3 (day 28±3).

Arm/Group Title	Budesonide/Indacaterol	Fluticasone / Salmeterol
Arm/Group Description	Participants will receive a fixed combination of fluticasone and salmeterol during 4 weeks followed by a free combination of budesonide and indacaterol for the remainig of study.	Fixed combination of fluticasone and salmeterol
Measure Participants	105	105
Mean (Standard Deviation) [Puffs]	10.5 (9.53)	12.9 (12.34)

4. Secondary Outcome

Title	Change From Baseline in Trough Forced Expiratory Volume in 1 Second at Week 24 (Analysis of Superiority)
Description	Forced Expiratory Volume in 1 second (FEV1) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing.
Time Frame	Baseline and week 24

Outcome Measure Data

Analysis Population Description

Per-protocol set (PPS) included all patients in the FAS without any major protocol deviations. Major protocol deviations were defined in the validation analysis plan prior to database lock and the unblinding of the study. Patients were analyzed according to the treatment they are randomized to

Arm/Group Title	Budesonide/Indacaterol	Fluticasone / Salmeterol
Arm/Group Description	Participants will receive a fixed combination of fluticasone and salmeterol during 4 weeks followed by a free combination of budesonide and indacaterol for the remainig of study.	Fixed combination of fluticasone and salmeterol
Measure Participants	108	111
Least Squares Mean (Standard Error) [Liters]	0.063 (0.033)	0.020 (0.034)

5. Secondary Outcome

Title	Change in Health Status - SGRQ-C
Description	St George's Respiratory Questionnaire short version questionnaire will be completed by participants. The SGRQ ranges from 0 (no impairment of quality of life) to 100 (highest impairment of quality of life)
Time Frame	Baseline, week 12 and week 24

Outcome Measure Data

Analysis Population Description

Per-protocol set (PPS) included all patients in the FAS without any major protocol deviations. Major protocol deviations were defined in the validation analysis plan prior to database lock and the unblinding of the study. Patients were analyzed according to the treatment they are randomized to

Arm/Group Title	Budesonide/Indacaterol	Fluticasone / Salmeterol
Arm/Group Description	Participants will receive a fixed combination of fluticasone and salmeterol during 4 weeks followed by a free combination of budesonide and indacaterol for the remainig of study.	Fixed combination of fluticasone and salmeterol
Measure Participants	108	111
Week 12	-8.703 (2.006)	-2.334 (2.053)
Week 24	-7.787 (2.308)	-2.523 (2.384)

Adverse Events

Arm/Group Title	Budesonide / Indacaterol (A)		Fluticasone / Salmeterol (B)
Arm/Group Description	Budesonide / Indacaterol (A)		Fluticasone / Salmeterol (B)
All Cause Mortality
	Budesonide / Indacaterol (A)		Fluticasone / Salmeterol (B)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Budesonide / Indacaterol (A)		Fluticasone / Salmeterol (B)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/109 (9.2%)		9/113 (8%)
Cardiac disorders
Acute myocardial infarction	0/109 (0%)		1/113 (0.9%)
Bradycardia	0/109 (0%)		1/113 (0.9%)
Cor pulmonale	0/109 (0%)		1/113 (0.9%)
Nodal arrhythmia	0/109 (0%)		1/113 (0.9%)
Infections and infestations
Cellulitis	0/109 (0%)		1/113 (0.9%)
Pneumonia	3/109 (2.8%)		1/113 (0.9%)
Injury, poisoning and procedural complications
Hip fracture	0/109 (0%)		1/113 (0.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bronchial carcinoma	1/109 (0.9%)		0/113 (0%)
Hepatocellular carcinoma	0/109 (0%)		1/113 (0.9%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	0/109 (0%)		1/113 (0.9%)
Chronic obstructive pulmonary disease	6/109 (5.5%)		2/113 (1.8%)
Haemoptysis	1/109 (0.9%)		0/113 (0%)
Pulmonary embolism	1/109 (0.9%)		0/113 (0%)
Vascular disorders
Peripheral arterial occlusive disease	0/109 (0%)		1/113 (0.9%)
Vascular insufficiency	0/109 (0%)		1/113 (0.9%)
Venous thrombosis limb	0/109 (0%)		1/113 (0.9%)
Other (Not Including Serious) Adverse Events
	Budesonide / Indacaterol (A)		Fluticasone / Salmeterol (B)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/109 (22%)		39/113 (34.5%)
Infections and infestations
Influenza	6/109 (5.5%)		10/113 (8.8%)
Nasopharyngitis	11/109 (10.1%)		10/113 (8.8%)
Urinary tract infection	3/109 (2.8%)		7/113 (6.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/109 (0.9%)		7/113 (6.2%)
Back pain	1/109 (0.9%)		6/113 (5.3%)
Nervous system disorders
Headache	1/109 (0.9%)		9/113 (8%)
Respiratory, thoracic and mediastinal disorders
Dysphonia	3/109 (2.8%)		8/113 (7.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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 (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.