NCT01437540

Safety and Tolerability of Aclidinium Bromide/Formoterol Fumarate Compared With Formoterol Fumarate in Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease

Completed Phase 3 Results posted Last updated 11 May 2017

What this trial tests

Phase 3 trial testing Aclidinium Bromide/Formoterol Fumarate in Chronic Obstructive Pulmonary Disease in 590 participants. Completed in 30 April 2013.

Timeline

19 September 2011

Primary endpoint
31 March 2013

30 April 2013

Quick facts

Lead sponsor	AstraZeneca
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	590
Start date	19 September 2011
Primary completion	31 March 2013
Estimated completion	30 April 2013
Sites	137 locations across United States

Drugs / interventions tested

• Aclidinium Bromide/Formoterol Fumarate
• Formoterol Fumarate — full drug profile →

Conditions studied

• Chronic Obstructive Pulmonary Disease — all drugs for Chronic Obstructive Pulmonary Disease →

Sponsor

AstraZeneca — full company profile →

Who can join

40 and older, any sex, with Chronic Obstructive Pulmonary Disease. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Patients to Experience at Least One Treatment-emergent Adverse Event (TEAE) Primary · Up to study Week 56 ± 3 days

TEAEs were coded Version 16.0 of the Medical Dictionary for Regulatory Activities (MedDRA)

Group	Value	95% CI
Aclidinium/Formoterol 400 μg/12 μg	71.4
Formoterol 12 μg	65.7

Percentage of Patients to Experience Any Potentially Clinically Significant (PCS) Post-baseline Change in Clinical Laboratory Values for Hematology, Chemistry or Urinalysis at the End of the Study Secondary · Up to study Week 52

\<0.85 x lower limit of normal (LLN) or \> 1.15 upper limit of normal (ULN) for hemoglobin, hematocrit, red blood cell, platelet, white blood cell, neutrophil and lymphocyte counts \>1.15 × ULN for eosinophil, basophil and monocyte counts \>1.15 x ULN for aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma glutamyl transferase, total bilirubin, creatinine kinase, lactate dehydrogenase, blood urea nitrogen, creatinine, uric acid, total cholesterol, triglycerides \<0.85 x LLN or \>1.15 ULN for fasting glucose, calcium, phosphorus, total protein and albumin \<0.95 x

Group	Value	95% CI
Aclidinium/Formoterol 400 μg/12 μg	63.9
Formoterol 12 μg	62.1

Percentage of Patients to Experience a Potentially Clinically Significant (PCS) Change in Pulse Rate, Systolic and Diastolic Blood Pressure Secondary · Up to study Week 56 ± 3 days

Systolic BP ≥180 mmHg and increase ≥20 mmHg from baseline or ≤90 mmHg and decrease ≥20 mmHg from baseline; Diastolic BP ≥105 mmHg and increase ≥15 mmHg from baseline or ≤50 mmHg and decrease ≥15 mmHg from baseline; Pulse rate ≥ 110 bpm and increase ≥ 15% from baseline or ≤ 50 bpm and decrease ≥15% from baseline

Systolic BP ≥180 mmHg and increase ≥20 mmHg

Group	Value	95% CI
Aclidinium/Formoterol 400 μg/12 μg	0.3
Formoterol 12 μg	0.5

Systolic BP ≤90 mmHg and decrease ≥20 mmHg

Group	Value	95% CI
Aclidinium/Formoterol 400 μg/12 μg	1.5
Formoterol 12 μg	1.0

Diastolic BP ≥105 mmHg and increase ≥15 mmHg

Group	Value	95% CI
Aclidinium/Formoterol 400 μg/12 μg	0
Formoterol 12 μg	0.5

Diastolic BP ≤50 mmHg and decrease ≥15 mmHg

Group	Value	95% CI
Aclidinium/Formoterol 400 μg/12 μg	0.3
Formoterol 12 μg	1.0

Pulse rate ≥ 110 bpm and increase ≥ 15%

Group	Value	95% CI
Aclidinium/Formoterol 400 μg/12 μg	0.8
Formoterol 12 μg	0.5

Pulse rate ≤ 50 bpm and decrease ≥15%

Group	Value	95% CI
Aclidinium/Formoterol 400 μg/12 μg	0
Formoterol 12 μg	0

Percentage of Patients to Experience Potentially Clinically Significant Changes in ECG From Baseline Secondary · Up to study Week 56 ± 3 days

Potentially clinically significant changes were defined as listed in the table below for QT interval, QTcB, QTcF, QRS interval, PR interval and heart rate (HR)

QT interval change from baseline >30 msec

Group	Value	95% CI
Aclidinium/Formoterol 400 μg/12 μg	42.0
Formoterol 12 μg	44.7

QT interval >480 msec

Group	Value	95% CI
Aclidinium/Formoterol 400 μg/12 μg	3.9
Formoterol 12 μg	2.0

QTcB change from baseline >30 msec

Group	Value	95% CI
Aclidinium/Formoterol 400 μg/12 μg	31.1
Formoterol 12 μg	30.3

QTcB value >480 msec

Group	Value	95% CI
Aclidinium/Formoterol 400 μg/12 μg	3.1
Formoterol 12 μg	4.5

QTcF change from baseline >30 msec

Group	Value	95% CI
Aclidinium/Formoterol 400 μg/12 μg	21.5
Formoterol 12 μg	22.7

QTcF value >480 msec

Group	Value	95% CI
Aclidinium/Formoterol 400 μg/12 μg	1.5
Formoterol 12 μg	1.5

QRS interval ≥100 msec and increase ≥25% from base

Group	Value	95% CI
Aclidinium/Formoterol 400 μg/12 μg	2.0
Formoterol 12 μg	1.0

PR interval ≥200 msec and increase ≥25% from base

Group	Value	95% CI
Aclidinium/Formoterol 400 μg/12 μg	2.8
Formoterol 12 μg	1.0

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to study Week 56 ± 3 days. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Aclidinium/Formoterol 400 μg/12 μg

Serious: 38/392 (10%)

Deaths: —

Formoterol 12 μg

Serious: 21/198 (11%)

Deaths: —

Serious adverse events (81 terms)

Reaction	System	Aclidinium/Formoterol 400 …	Formoterol 12 μg
Pneumonia	Infections and infestations	—	—
Abdominal pain	Gastrointestinal disorders	—	—
Atrial fibrillation	Cardiac disorders	—	—
Death	General disorders	—	—
Non-cardiac chest pain	General disorders	—	—
Abscess intestinal	Infections and infestations	—	—
Adenocarcinoma of colon	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Angina pectoris	Cardiac disorders	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—
Atrial flutter	Cardiac disorders	—	—
Cardiac failure congestive	Cardiac disorders	—	—
Cardio-respiratory arrest	Cardiac disorders	—	—
Carotid artery disease	Nervous system disorders	—	—
Cellulitis	Infections and infestations	—	—
Chronic respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—
Colon cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Completed suicide	Psychiatric disorders	—	—
Coronary artery occlusion	Cardiac disorders	—	—
Cystocele	Reproductive system and breast disorders	—	—
Diverticulitis	Infections and infestations	—	—
Endometrial adenocarcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Epistaxis	Respiratory, thoracic and mediastinal disorders	—	—
Fall	Injury, poisoning and procedural complications	—	—
Flank pain	Musculoskeletal and connective tissue disorders	—	—
Gastric ulcer	Gastrointestinal disorders	—	—

Other adverse events (8 terms — click to expand)

Reaction	System	Aclidinium/Formoterol 400 …	Formoterol 12 μg
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	—	—
Urinary tract infection	Infections and infestations	—	—
Nasopharyngitis	Infections and infestations	—	—
Anxiety	Psychiatric disorders	—	—
Sinusitis	Infections and infestations	—	—
Upper respiratory tract infection	Infections and infestations	—	—
Nausea	Gastrointestinal disorders	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—

Most-reported serious reactions: Pneumonia, Abdominal pain, Atrial fibrillation, Death, Non-cardiac chest pain, Abscess intestinal, Adenocarcinoma of colon, Angina pectoris.

Data from ClinicalTrials.gov NCT01437540 adverse events section.

Sponsor's own description

The purpose of this study is to assess the long-term safety and tolerability of inhaled aclidinium bromide/formoterol in patients with moderate to severe, stable chronic obstructive pulmonary disease (COPD).

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Combination bronchodilator therapy in the management of chronic obstructive pulmonary disease.
   Tashkin DP, Ferguson GT. · · 2013 · cited 112× · PMID 23651244 · DOI 10.1186/1465-9921-14-49
2. Dual combination therapy versus long-acting bronchodilators alone for chronic obstructive pulmonary disease (COPD): a systematic review and network meta-analysis.
   Oba Y, Keeney E, Ghatehorde N, Dias S. · · 2018 · cited 67× · PMID 30521694 · DOI 10.1002/14651858.cd012620.pub2
3. LABA/LAMA fixed-dose combinations in patients with COPD: a systematic review.
   Rogliani P, Calzetta L, Braido F, Cazzola M, et al · · 2018 · cited 26× · PMID 30323582 · DOI 10.2147/copd.s170606
4. Aclidinium bromide for stable chronic obstructive pulmonary disease.
   Ni H, Soe Z, Moe S. · · 2014 · cited 24× · PMID 25234126 · DOI 10.1002/14651858.cd010509.pub2
5. The impact of dual bronchodilation on cardiovascular serious adverse events and mortality in COPD: a quantitative synthesis.
   Rogliani P, Matera MG, Ora J, Cazzola M, et al · · 2017 · cited 23× · PMID 29255354 · DOI 10.2147/copd.s146338
6. Once daily long-acting beta2-agonists and long-acting muscarinic antagonists in a combined inhaler versus placebo for chronic obstructive pulmonary disease.
   Maqsood U, Ho TN, Palmer K, Eccles FJ, et al · · 2019 · cited 17× · PMID 30839102 · DOI 10.1002/14651858.cd012930.pub2
7. Combined aclidinium bromide and long-acting beta2-agonist for chronic obstructive pulmonary disease (COPD).
   Ni H, Moe S, Soe Z, Myint KT, et al · · 2018 · cited 17× · PMID 30536566 · DOI 10.1002/14651858.cd011594.pub2
8. Comparisons of exacerbations and mortality among LAMA/LABA combinations in stable chronic obstructive pulmonary disease: systematic review and Bayesian network meta-analysis.
   Lee HW, Park J, Jang EJ, Lee CH. · · 2020 · cited 15× · PMID 33238986 · DOI 10.1186/s12931-020-01540-8