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Aclidinium bromide / Formoterol fumarate, a fixed dose combination for the maintenance treatment of COPD


Aclidinium bromide / Formoterol fumarate ( 400/12 mcg ) is a fixed dose combination of two approved long-acting bronchodilators with different mechanisms of action and similar pharmocodynamic profiles.
Aclidinium bromide is an anticholinergic or long acting muscarinic antagonist ( LAMA ) that produces bronchodilation by inhibiting the muscarinic M3 receptor in the airway smooth muscle.
Formoterol fumarate is a long-acting beta-agonist ( LABA ) that stimulates the B2-receptors in the bronchial smooth muscle resulting in bronchodilation.
Both Aclidinium bromide ( Elkira / Bretaris / Tudorza ) and Formoterol fumarate are separately approved for the maintenance treatment of COPD in the United States and Europe.

Bronchodilation

Aclidinium bromide / Formoterol fumarate 340/12 micrograms twice daily consistently provided clinically meaningful improvements in lung function ( as assessed by FEV1, forced vital capacity and inspiratory capacity ) compared with placebo.
In phase III studies, clinically meaningful bronchodilator effects were seen within 5 minutes of the first dose and were maintained over the dosing interval. There was a sustained effect over time in the six months and one year phase III studies.
In study ACLIFORM-COPD, Aclidinium bromide / Formoterol fumarate has shown improvements in FEV1 at 1 hour post-dose relative to placebo and Aclidinium of 299 ml and 125 ml, respectively ( both p less than 0.0001 ) and improvements in trough FEV1 relative to placebo and Formoterol of 143 ml and 85 ml, respectively ( both p less than 0.0001 ).
In study AUGMENT, Aclidinium bromide / Formoterol fumarate has shown improvements in FEV1 at 1 hour post-dose relative to placebo and Aclidinium of 284 ml and 108 ml ( both p less than 0.0001 ), respectively, and improvements in trough FEV1 relative to placebo and Formoterol of 130 ml ( p less than 0.0001 ) and 45 ml ( p=0.01 ), respectively.

Breathlessness and other symptomatic outcomes

Aclidinium bromide / Formoterol fumarate provided a clinically meaningful improvement in breathlessness ( assessed by the Transition Dyspnoea Index [ TDI ] ) with an improvement in the TDI focal score at 6 months compared to placebo of 1.29 units in study ACLIFORM-COPD ( p less than 0.0001 ) and 1.44 units in study AUGMENT ( p less than 0.0001 ). The percentages of patients with clinically meaningful improvements in TDI focal score ( defined as an increase of at least 1 unit ) were higher with Aclidinium bromide / Formoterol fumarate than with placebo in ACLIFORM-COPD ( 64.8% compared to 45.5%; p less than 0.001 ) and AUGMENT ( 58.1% compared to 36.6%; p less than 0.0001 ).
The pooled analysis of these two studies has shown Aclidinium bromide / Formoterol fumarate to be associated with statistically significant greater improvements in TDI focal score compared to Aclidinium ( 0.4 units, p=0.016 ) or Formoterol ( 0.5 units, p=0.009 ). In addition, a higher percentage of patients receiving Aclidinium bromide / Formoterol fumarate responded with a clinically meaningful improvement in TDI focal score compared to either Aclidinium or Formoterol ( 61.9% compared to 55.7% and 57.0%, respectively; p=0.056 and p=0.100, respectively ).
Aclidinium bromide / Formoterol fumarate improved daily symptoms of COPD such as breathlessness, chest symptoms, cough and sputum ( assessed by E-RS total score ) as well as overall night-time symptoms, overall early morning symptoms and symptoms limiting early morning activities compared to placebo, Aclidinium and Formoterol but the improvements were not always statistically significant.

Health-related quality of life

Aclidinium bromide / Formoterol fumarate provided a clinically meaningful improvement in disease-specific health status ( as assessed by the St. George's Respiratory Questionnaire [ SGRQ ] ) in study AUGMENT, with an improvement in the SGRQ total score compared to placebo of -4.35 units ( p less than 0.0001 ). The percentage of patients in AUGMENT who achieved a clinically meaningful improvement from baseline in SGRQ total score ( defined as a decrease of at least 4 units ) was higher with Aclidinium and Formoterol than with placebo ( 58.2% compared to 38.7%, respectively; p less than 0.001 ). In study ACLIFORM-COPD, only a small decrease in SGRQ total score compared to placebo was observed due to an unexpectedly large placebo response ( p=0.598 ) and the percentages of patients who achieved clinically meaningful improvements from baseline were 55.3% with Aclidinium bromide / Formoterol and 53.2% with placebo ( p=0.669 ).
In the pooled analysis of the two 6-month phase III studies, Aclidinium bromide / Formoterol showed greater improvements in SGRQ total score compared to Formoterol ( -1.7 units; p=0.018 ) or Aclidinium ( -0.79 units, p=0.273 ).
In addition, a higher percentage of patients receiving Aclidinium bromide / Formoterol responded with a clinically meaningful improvement in SGRQ total score compared to Aclidinium and Formoterol ( 56.6% compared to 53.9% and 52.2%, respectively; p=0.603 and p=0.270, respectively ).

Exacerbations

Pooled efficacy analysis of the two 6-month phase III studies demonstrated a statistically significant reduction of 29% in the rate of moderate or severe exacerbations ( requiring treatment with antibiotics or corticosteroids or resulting in hospitalisations ) with Aclidinium bromide / Formoterol compared to placebo ( rates per patient per year: 0.29 vs. 0.42, respectively; p=0.036 ).
In addition, Aclidinium bromide / Formoterol statistically significantly delayed the time to first moderate or severe exacerbation compared to placebo ( hazard ratio, HR=0.70; p=0.027 ).

Use of rescue medication

Aclidinium bromide / Formoterol reduced the use of rescue medication over 6 months compared to placebo ( by 0.9 puffs per day [ p less than 0.0001 ] ), Aclidinium ( by 0.4 puffs/day [ p less than 0.001 ] ) and Formoterol ( by 0.2 puffs/day [ p=0.062 ] ).

Side effects

Adverse reactions associated with Aclidinium bromide / Formoterol were similar to those of the individual components. ( Xagena )

Source: Almirall, 2014

XagenaMedicine_2014



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