Confirmatory Dose Finding Study of 2 Dosages of CHF 4226 pMDI (Carmoterol) in Patients With COPD

Study Overview
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Brief Summary
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The purpose of this study is to confirm the dose of CHF 4226 (carmoterol) that should be given once a day to patients with COPD in order for the effect to last for 24 hours.

Official Title
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Evaluation of the Effect of 2 Weeks Treatment With CHF 4226 pMDI 2µg and 4µg, Given Once Daily in the Morning, on 24-Hour FEV1 in Patients With COPD

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: carmoterol (CHF 4226)
* Drug: carmoterol (CHF 4226)
* Drug: placebo
* Drug: salmeterol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed IRB approved Informed Consent form Male or non-pregnant female, 40 -75 years old, inclusive Current or past cigarette smoking history of at least 15 pack-years Clinical diagnosis of COPD in accordance with recommendations of the National Heart Lung and Blood Institute/World Health Organization (NHLBI/WHO) Global Initiative for Chronic Obstructive Lung Disease (GOLD) Patient meets following requirements after FEV1 albuterol reversibility test (i.e., 30 minutes after 200μg (metered dose) albuterol MDI): FEV1/FVC < 70% FEV1 is at least 0.9L FEV1 30% - 80%, inclusive, of patient's predicted normal value; ∆FEV1 > 5% of pre-albuterol value If ∆FEV1 < 5% of pre-albuterol value, requirement must be met after retesting during run-in period, at least 24 hours prior to Period 1/Visit 1. Exclusion Criteria: History of asthma Blood eosinophil count > 500/microliters History of allergic rhinitis or atopy COPD exacerbation or lower respiratory tract infection within 8 weeks prior to screening, or during run-in period, that resulted in use of an antibiotic, or oral or parenteral corticosteroids Inhaled corticosteroid that has been initiated, or effective dose has been changed, within 4 weeks prior to screening or during run-in period Uncontrolled cardiovascular (e.g., uncontrolled hypertension), respiratory, hematologic, immunologic, renal, neurologic, hepatic, endocrine (e.g., uncontrolled diabetes mellitus) or other disease, or any condition that might, in Investigator's judgment, place patient at undue risk or potentially compromise study results or interpretation History of coronary artery disease, cerebrovascular disease, cardiac arrhythmias Lung cancer or history of lung cancer Active cancer or history of cancer with < 5 years disease free survival time (with or without evidence of local recurrence or metastases). Localized basal cell carcinoma (without metastases) of skin is acceptable. Serum potassium value ≤ 3.5 mEq/L or > 5.5mEq/L and/or fasting serum glucose value ≥ 140 mg/dL Abnormal QTcF interval value in Screening visit ECG test (i.e., > 450 msec in males or > 470 msec in females) Cor Pulmonale Long term oxygen therapy, i.e., > 16 hours/24-hour period, every day, unless patient resides at elevation > 4000ft Use of any of the following medications prior to Screening, without meeting specified minimum washout period: Long acting anti-cholinergic agent (i.e., tiotropium): 7 days Short acting anti-cholinergics: 8 hours Fixed combinations of β2-agonists and inhaled corticosteroids: 48 hours Fixed combinations of an anti-cholinergic and short acting β2-agonist: 8 hours Long-acting β2-agonists: 48 hours Short acting β2-agonists (other than those prescribed in the study): 6 hours Theophylline and other xanthines: 1 week Parenteral or oral corticosteroids: 1 month Patient has taken any non-permitted medication Patient has received live-attenuated virus vaccination within two weeks prior to screening or during run-in (inactivated Influenza vaccination is acceptable if given > 48 hours prior to Screening) Known intolerance/hypersensitivity to β2-adrenergic agonists, propellant gases/excipients Patient is pregnant or lactating female, or female at risk of pregnancy (i.e., not using adequate contraceptive method: surgical sterilization [e.g., bilateral tubal ligation], hormonal contraception [implantable, patch, oral], IUD, and double-barrier methods [any double combination of: male or female condom with spermicidal gel, diaphragm, sponge, cervical cap]). Patient is mentally or legally incapacitated Patient has participated in another investigational study within 30 days prior to screening Abuse of alcohol or other substances Patient does not maintain regular day/night, waking/sleeping cycles (e.g., night shift worker) Patient is potentially non-compliant or unable to perform required protocol outcome measurements

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>CHF 4226 (carmoterol) 2 μg once a day, in the morning | Drug: carmoterol (CHF 4226)<br>* carmoterol (CHF 4226) 2 μg once a day, in the morning (1 puff of carmoterol 2 μg + 1 puff of placebo pMDI)<br>* Other names: TA2005;|
| Experimental: B<br>CHF 4226 (carmoterol) 4 μg once a day, in the morning | Drug: carmoterol (CHF 4226)<br>* carmoterol (CHF 4226) 4 μg once a day, in the morning (1 puff of carmoterol 2 µg + 1 puff of carmoterol 2µg)<br>* Other names: TA2005;|
| Placebo Comparator: C<br>placebo once a day, in the morning | Drug: placebo<br>* placebo once a day, in the morning (1 puff of placebo pMDI + 1 puff of placebo pMDI)<br>|
| Active Comparator: D<br>salmeterol 50 μg twice daily, in the morning and in the evening | Drug: salmeterol<br>* Salmeterol 50 μg twice daily, in the morning and in the evening (1 blister of Serevent Diskus BID)<br>* Other names: Serevent Diskus/Accuhaler;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FEV1 AUC0-24 standardized by time |  | on Day 15 (after 14 days of dosing) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FEV1(L) |  | 30 min, 1, 2 ,3, 4, 6, 10, 12, 14, 16, 22, 23, and 24 hrs post dose at Visit 2 at all treatment periods | 
| blood pressure |  | at the beginning and end of each of the four 14-day treatment periods | 
| heart rate |  | at the beginning and end of each of the four 14-day treatment periods | 
| FEV1 percent change |  | 30 min, 1, 2 ,3, 4, 6, 10, 12, 14, 16, 22, 23, and 24 hrs post dose at Visit 2 at all treatment periods |