Efficacy and safety of aclidinium bromide for treatment of moderate to severe chronic obstructive pulmonary disease (COPD) (LAS-MD-33)

Study identifier:LAS-MD-33

ClinicalTrials.gov identifier:NCT00891462

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

Efficacy and Safety of Aclidinium Bromide at Two Dose Levels (200 μg Twice Daily, 400 μg Twice Daily) vs. Placebo When Administered to Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD)

Medical condition

Chronic Obstructive Pulmonary Disease

Phase

Phase 3

Healthy volunteers

Study drug

Aclidinium bromide, Placebo

Sex

All

Actual Enrollment

561

Study type

Interventional

Age

40 Years +

Date

Study Start Date: 01 Apr 2009

Primary Completion Date: 01 Nov 2009

Study Completion Date: 01 Nov 2009

Study design

Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind
Primary Purpose: Treatment

Verification:

Verified 01 Nov 2016 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

Location

Forest Investigative Site

Hagerstown, MD, United States, 21740

Location

Forest Investigative Site

Bangor, ME, United States, 04401

Location

Forest Investigative Site

Niagara Falls, Canada, L2G 1J4

Location

Forest Investigative Site

Waco, TX, United States, 76712

Location

Forest Investigative Site

Melbourne, FL, United States, 32901

Location

Forest Investigative Site

Kelowna, Canada, V1Y 8E7

Location

Forest Investigative Site

Columbus, OH, United States, 43215

Location

Forest Investigative Site

Pittsburgh, PA, United States, 15243

Arms	Assigned Interventions
Experimental: 1 Aclidinium bromide dose, inhaled, for 12 weeks of treatment	Drug: Aclidinium bromide Aclidinium bromide 200 μg, oral inhalation twice per day for 12 weeks of treatment
Experimental: 2 Aclidinium bromide dose, inhaled, for 12 weeks of treatment	Drug: Aclidinium bromide Aclidinium bromide 400 μg, oral inhalation twice per day for 12 weeks of treatment
Placebo Comparator: 3 Inhaled placebo for 12 weeks	Drug: Placebo Dose-matched placebo, oral inhalation twice per day for 12 weeks of treatment

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Patient recruitment occurred from April to July of 2009 at 106 study sites, (100 in the United States and 6 additional sites in Canada.) A total of 99 study sites randomized patients.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
From the total of 561 patients randomized, 560 patients received at least 1 dose of double-blind treatment and therefore were included in the Safety Population. Of these patients, 559 had at least 1 postbaseline FEV1 assessment and qualified for the Intent to Treat (ITT) Population.

Reporting Groups

	Description
Placebo	Inhaled placebo for 12 weeks
Aclidinium bromide, 200µg	Aclidinium bromide, 200 microgram dose. Oral inhalation, twice per day, for 12 weeks of treatment
Aclidinium bromide, 400µg	Aclidinium bromide 400 microgram dose. Oral inhalation, twice per day, for 12 weeks of treatment.

Participant Flow: Overall Study

	Placebo	Aclidinium bromide, 200µg	Aclidinium bromide, 400µg
STARTED	186	185	190
COMPLETED	149	152	166
NOT COMPLETED	37	33	24
Withdrawal by Subject	9	6	7
Adverse Event	7	8	7
Lack of Efficacy	10	5	1
COPD exacerbation	7	4	1
Other Reason	2	5	3
Protocol Violation	2	1	3
Inclusion/exclusion criteria	0	2	2
Lost to Follow-up	0	2	0

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

Reporting Groups

	Description
Placebo	Inhaled placebo for 12 weeks
Aclidinium bromide, 200µg	Aclidinium bromide, 200 microgram dose. Oral inhalation, twice per day, for 12 weeks of treatment
Aclidinium bromide, 400µg	Aclidinium bromide 400 microgram dose. Oral inhalation, twice per day, for 12 weeks of treatment.

Baseline Measures

	Placebo	Aclidinium bromide, 200µg	Aclidinium bromide, 400µg	Total
Number of Participants [units: Participants]	186	184	190	560
Age Continuous [units: years] Mean ± Standard Deviation	65.1 ± 9.2	63.1 ± 9.5	64.9 ± 9.5	64.3 ± 9.4
Age, Customized [units: participants]
≥ 40 to < 60 years	46	64	44	154
≥ 60 to < 70 years	85	72	87	244
≥ 70 years	55	48	59	162
Gender, Male/Female [units: participants]
Female	90	83	90	263
Male	96	101	100	297
Region of Enrollment [units: participants]
United States	176	170	177	523
Canada	10	14	13	37

Outcome Measures

1. Primary Outcome Measure: Change from Baseline in Morning Pre-dose Forced Expiratory Volume in 1 Second (FEV1) [ Time Frame: Change from Baseline to 12 weeks ]

Measure Type	Primary
Measure Name	Change from Baseline in Morning Pre-dose Forced Expiratory Volume in 1 Second (FEV1)
Measure Description	Change from baseline in trough forced expiratory volume in 1 second before the morning dose of aclidinium bromide, Last Observation Carried Forward (LOCF)
Time Frame	Change from Baseline to 12 weeks
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Of 561 patients randomized, 560 patients received at least 1 dose of double-blind treatment and therefore were included in the Safety Population. Of these patients, 559 had a baseline and at least 1 postbaseline FEV1 assessment and qualified for the Intent to Treat (ITT) Population. The primary efficacy endpoint was based on ITT population.

Reporting Groups

	Description
Placebo	Dose-matched placebo twice per day, inhaled for 12 weeks of treatment
Aclidinium bromide, 200µg	Aclidinium bromide, 200 microgram dose. Oral inhalation, twice per day, for 12 weeks of treatment
Aclidinium bromide, 400µg	Aclidinium bromide 400 microgram dose. Oral inhalation, twice per day, for 12 weeks of treatment.

Measured Values

	Placebo	Aclidinium bromide, 200µg	Aclidinium bromide, 400µg
Number of Participants Analyzed [units:participants]	185	184	190
Change from Baseline in Morning Pre-dose Forced Expiratory Volume in 1 Second (FEV1) [units: L] Least Squares Mean (Standard Error)	-0.025 (0.015)	0.062 (0.015)	0.099 (0.015)

Statistical Analysis 1 for Change from Baseline in Morning Pre-dose Forced Expiratory Volume in 1 Second (FEV1)

Groups^[1]	Placebo, Aclidinium bromide, 200µg
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	0.086
95% Confidence Interval	( 0.05 to 0.13 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Change from Baseline in Morning Pre-dose Forced Expiratory Volume in 1 Second (FEV1)

Groups^[1]	Placebo, Aclidinium bromide, 400µg
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	0.124
95% Confidence Interval	( 0.08 to 0.16 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

2. Secondary Outcome Measure: Change from Baseline in Peak Forced Expiratory Volume in 1 Second (FEV1) [ Time Frame: Change from Baseline to 12 weeks ]

Measure Type	Secondary
Measure Name	Change from Baseline in Peak Forced Expiratory Volume in 1 Second (FEV1)
Measure Description	Change From Baseline in Peak FEV1 (L) at Week 12, Last Observation Carried Forward (LOCF)
Time Frame	Change from Baseline to 12 weeks
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Of 561 patients randomized, 560 patients received at least 1 dose of double-blind treatment and therefore were included in the Safety Population. Of these patients, 559 had a baseline and at least 1 postbaseline FEV1 assessment and qualified for the Intent to Treat (ITT) Population. The primary efficacy endpoint was based on ITT population.

Reporting Groups

	Description
Placebo	Dose matched placebo twice per day, inhaled for 12 weeks of treatment
Aclidinium bromide, 200 µg	Aclidinium bromide, 200 µg dose, Oral inhalation, twice per day, for 12 weeks of treatment
Aclidinium bromide, 400µg	Aclidinium bromide 400 microgram dose. Oral inhalation, twice per day, for 12 weeks of treatment.

Measured Values

	Placebo	Aclidinium bromide, 200 µg	Aclidinium bromide, 400µg
Number of Participants Analyzed [units:participants]	185	184	190
Change from Baseline in Peak Forced Expiratory Volume in 1 Second (FEV1) [units: L] Least Squares Mean (Standard Error)	0.071 (0.016)	0.217 (0.016)	0.263 (0.016)

No statistical analysis provided for Change from Baseline in Peak Forced Expiratory Volume in 1 Second (FEV1)

Serious Adverse Events

Time Frame	Adverse events reporting occurred from April 28th, 2009 to December 3rd, 2009 at 99 study sites.
Additional Description	No text entered.

Reporting Groups

	Description
Placebo	Inhaled placebo for 12 weeks
Aclidinium bromide, 200µg	Aclidinium bromide, 200 microgram dose. Oral inhalation, twice per day, for 12 weeks of treatment
Aclidinium bromide, 400µg	Aclidinium bromide 400 microgram dose. Oral inhalation, twice per day, for 12 weeks of treatment.

Serious Adverse Events

Placebo

Aclidinium bromide, 200µg

Aclidinium bromide, 400µg

Total, serious adverse events

# participants affected / at risk

4/186 (2.15%)

8/184 (4.35%)

6/190 (3.16%)

Respiratory, thoracic and mediastinal disorders

Chronic obstructive pulmonary disease¹,^†

# participants affected / at risk

1/186 (0.54%)

1/184 (0.54%)

3/190 (1.58%)

Respiratory, thoracic and mediastinal disorders

Acute respiratory failure¹,^†

# participants affected / at risk

0/186 (0.00%)

0/184 (0.00%)

2/190 (1.05%)

Cardiac disorders

Cardiac failure congestive¹,^†

# participants affected / at risk

0/186 (0.00%)

0/184 (0.00%)

1/190 (0.53%)

Vascular disorders

Hypotension¹,^†

# participants affected / at risk

0/186 (0.00%)

0/184 (0.00%)

1/190 (0.53%)

Injury, poisoning and procedural complications

Intentional overdose¹,^†

# participants affected / at risk

0/186 (0.00%)

0/184 (0.00%)

1/190 (0.53%)

Nervous system disorders

Loss of consciousness¹,^†

# participants affected / at risk

0/186 (0.00%)

0/184 (0.00%)

1/190 (0.53%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Lung cancer metastatic¹,^†

# participants affected / at risk

0/186 (0.00%)

0/184 (0.00%)

1/190 (0.53%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Metastases to central nervous system¹,^†

# participants affected / at risk

0/186 (0.00%)

0/184 (0.00%)

1/190 (0.53%)

Renal and urinary disorders

Renal failure acute¹,^†

# participants affected / at risk

0/186 (0.00%)

0/184 (0.00%)

1/190 (0.53%)

Psychiatric disorders

Suicidal ideation¹,^†

# participants affected / at risk

0/186 (0.00%)

2/184 (1.09%)

1/190 (0.53%)

Psychiatric disorders

Suicide attempt¹,^†

# participants affected / at risk

0/186 (0.00%)

0/184 (0.00%)

1/190 (0.53%)

Nervous system disorders

Syncope¹,^†

# participants affected / at risk

0/186 (0.00%)

0/184 (0.00%)

1/190 (0.53%)

Gastrointestinal disorders

Abdominal hernia obstructive¹,^†

# participants affected / at risk

0/186 (0.00%)

1/184 (0.54%)

0/190 (0.00%)

Psychiatric disorders

Bipolar disorder¹,^†

# participants affected / at risk

0/186 (0.00%)

2/184 (1.09%)

0/190 (0.00%)

Respiratory, thoracic and mediastinal disorders

Bronchitis¹,^†

# participants affected / at risk

0/186 (0.00%)

1/184 (0.54%)

0/190 (0.00%)

Nervous system disorders

Cerebrovascular accident¹,^†

# participants affected / at risk

1/186 (0.54%)

0/184 (0.00%)

0/190 (0.00%)

Hepatobiliary disorders

Cholecystitis¹,^†

# participants affected / at risk

1/186 (0.54%)

0/184 (0.00%)

0/190 (0.00%)

Hepatobiliary disorders

Cholelithiasis¹,^†

# participants affected / at risk

1/186 (0.54%)

0/184 (0.00%)

0/190 (0.00%)

Gastrointestinal disorders

Colitis ischaemic¹,^†

# participants affected / at risk

0/186 (0.00%)

1/184 (0.54%)

0/190 (0.00%)

Psychiatric disorders

Depression¹,^†

# participants affected / at risk

0/186 (0.00%)

2/184 (1.09%)

0/190 (0.00%)

Infections and infestations

Lobar pneumonia¹,^†

# participants affected / at risk

1/186 (0.54%)

0/184 (0.00%)

0/190 (0.00%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Lung adenocarcinoma¹,^†

# participants affected / at risk

0/186 (0.00%)

1/184 (0.54%)

0/190 (0.00%)

Infections and infestations

Pneumonia viral¹,^†

# participants affected / at risk

0/186 (0.00%)

1/184 (0.54%)

0/190 (0.00%)

General disorders and administration site conditions

Pyrexia¹,^†

# participants affected / at risk

0/186 (0.00%)

1/184 (0.54%)

0/190 (0.00%)

Injury, poisoning and procedural complications

Radius fracture¹,^†

# participants affected / at risk

0/186 (0.00%)

1/184 (0.54%)

0/190 (0.00%)

Musculoskeletal and connective tissue disorders

Still's disease adult onset¹,^†

# participants affected / at risk

0/186 (0.00%)

1/184 (0.54%)

0/190 (0.00%)

Psychiatric disorders

Substance abuse¹,^†

# participants affected / at risk

0/186 (0.00%)

1/184 (0.54%)

0/190 (0.00%)

Injury, poisoning and procedural complications

Ulna fracture¹,^†

# participants affected / at risk

0/186 (0.00%)

1/184 (0.54%)

0/190 (0.00%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA (12.1)

Other Adverse Events

Time Frame	Adverse events reporting occurred from April 28th, 2009 to December 3rd, 2009 at 99 study sites.
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
Placebo	Inhaled placebo for 12 weeks
Aclidinium bromide, 200µg	Aclidinium bromide, 200 microgram dose. Oral inhalation, twice per day, for 12 weeks of treatment
Aclidinium bromide, 400µg	Aclidinium bromide 400 microgram dose. Oral inhalation, twice per day, for 12 weeks of treatment.

Other Adverse Events

Placebo

Aclidinium bromide, 200µg

Aclidinium bromide, 400µg

Total, other (not including serious) adverse events

# participants affected / at risk

23/186 (12.37%)

17/184 (9.24%)

14/190 (7.37%)

Respiratory, thoracic and mediastinal disorders

Chronic obstructive pulmonary disease¹,^†

# participants affected / at risk

23/186 (12.37%)

17/184 (9.24%)

14/190 (7.37%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA (12.1)

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 agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: All data generated in this study will be the property of Forest Research Institute, Inc. An integrated clinical and statistical report will be prepared at the completion of the study. Publication of the results by the Investigator will be subject to mutual agreement between the Investigator and Forest Research Institute.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact

Name/Title:	AstraZeneca Clinical
Organization:	Study Information Center
Phone	1-877-240-9479
E-mail:	[email protected]

Documents available

las-md-33-synopsis
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Investigators

Principal Investigator

Esther Garcia

AstraZeneca

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Forest Investigative Site

Forest Investigative Site

Forest Investigative Site

Forest Investigative Site

Forest Investigative Site

Forest Investigative Site

Forest Investigative Site

Forest Investigative Site

las-md-33-synopsis

Trial Results Summaries