Official Title: “A Double-Blind, Randomized, Multicenter, Two-Part Parallel-Group, Dose-Ranging Study of Twice-Daily and Once-Daily (R,R) Formoterol in the Treatment of Subjects With Chronic Obstructive Pulmonary Disease (COPD)”

A dose ranging study to evaluate the safety, tolerability and efficacy of arformoterol (given once or twice a day) in subjects with COPD.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Investigator), Parallel Assignment, Efficacy Study

Study Primary Completion Date: May 2004

This study is a double-blind, repeat-dose, randomized, multicenter, two-part, parallel-group, dose-ranging study of arformoterol and placebo in the treatment of subjects with COPD.

Approximately 215 subjects will be randomized in this study. Study participation will consist of a total of eight (8) study visits over approximately ten (10) weeks for each subject.

Intervention(s) in this Clinical Trial

• Drug: Arformoterol tartrate inhalation solution
  • Arformoterol 5 mcg BID
• Drug: Arformoterol tartrate inhalation solution
  • Arformoterol 15 mcg BID
• Drug: Arformoterol tartrate inhalation solution
  • Arformoterol 25 mcg BID
• Drug: Placebo
  • Placebo inhalation solution BID
• Drug: Arformoterol tartrate inhalation solution
  • Arformoterol 15 mcg QD
• Drug: Arformoterol tartrate inhalation solution
  • Arformoterol 25 mcg QD
• Drug: Arformoterol tartrate inhalation solution
  • Arformoterol 50 mcg QD
• Drug: Placebo
  • Placebo inhalation solution QD

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: A1
  • Arformoterol 5 mcg BID for 14 days
• Experimental: A2
  • Arformoterol 15 mcg BID for 14 days
• Experimental: A3
  • Arformoterol 25 mcg BID for 14 days
• Placebo Comparator: A4
  • Placebo inhalation solution BID for 14 days
• Experimental: B1
  • Arformoterol 15 mcg QD for 14 days
• Experimental: B2
  • Arformoterol 25 mcg QD for 14 days
• Experimental: B3
  • Arformoterol 50 mcg QD for 14 days
• Placebo Comparator: B4
  • Placebo inhalation solution QD for 14 days

Primary Measures

• Part A: The primary efficacy endpoint is the time-normalized area under the FEV1 percent change from pre-dose curve over 12 hours (nAUC0-12) after the first (AM) dose at the 24 hour clinic visit (Visit 4) following 14 days of double-blind treatment.
  • Time Frame: Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), Visit 5 (Day 21), Visit 6 (Day 28), Visit 7 (Day 42), Visit 8 (Day 48)
    Safety Issue?: No
• Part B: The primary efficacy endpoint is the time-normalized area under the FEV1 percent change from pre-dose curve over 24 hours (nAUC0-24) at the 24 hour clinic visit (Visit 7) following 14 days of double-blind treatment.
  • Time Frame: Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), Visit 5 (Day 21), Visit 6 (Day 28), Visit 7 (Day 42), Visit 8 (Day 48)
    Safety Issue?: No

Secondary Measures

• Relationship between plasma concentrations of arformoterol and changes in ECG QTc intervals at steady state throughout the dosing interval.
  • Time Frame: Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), Visit 5 (Day 21), Visit 6 (Day 28), Visit 7 (Day 42), Visit 8 (Day 48)
    Safety Issue?: Yes
• Part A only: Time-normalized area under the curve for FEV1 percent change from pre-dose over 24 hours (nAUC0-24) for each 24 hour clinic visit.
  • Time Frame: Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14),
    Safety Issue?: No
• Part B only: Time-normalized area under curve for the FEV1 percent change from pre-dose over 12 hours (nAUC0-12) for each 24 hour clinic visit.
  • Time Frame: Visit 5 (Day 21), Visit 6 (Day 28), Visit 7 (Day 42), Visit 8 (Day 48)
    Safety Issue?: No
• Time-normalized area under the curve for the percent change in FEV1 from pre-dose over 6 hours (nAUC0-6) for the 6 hour clinic visit (Visits 3 and 6).
  • Time Frame: Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), Visit 5 (Day 21), Visit 6 (Day 28), Visit 7 (Day 42), Visit 8 (Day 48)
    Safety Issue?: No
• Percent change in FEV1 from pre-dose to each post dose time point
  • Time Frame: Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), Visit 5 (Day 21), Visit 6 (Day 28), Visit 7 (Day 42), Visit 8 (Day 48)
    Safety Issue?: No
• Peak percent change in FEV1 post-dose
  • Time Frame: Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), Visit 5 (Day 21), Visit 6 (Day 28), Visit 7 (Day 42), Visit 8 (Day 48)
    Safety Issue?: No
• Ipratropium bromide metered-dose inhaler (MDI) use and racemic albuterol MDI use
  • Time Frame: Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), Visit 5 (Day 21), Visit 6 (Day 28), Visit 7 (Day 42), Visit 8 (Day 48)
    Safety Issue?: No
• Morning and evening peak expiratory flow rate (PEFR)
  • Time Frame: Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), Visit 5 (Day 21), Visit 6 (Day 28), Visit 7 (Day 42), Visit 8 (Day 48)
    Safety Issue?: No
• Exacerbations of COPD
  • Time Frame: Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), Visit 5 (Day 21), Visit 6 (Day 28), Visit 7 (Day 42), Visit 8 (Day 48)
    Safety Issue?: Yes
• COPD symptom ratings
  • Time Frame: Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), Visit 5 (Day 21), Visit 6 (Day 28), Visit 7 (Day 42), Visit 8 (Day 48)
    Safety Issue?: No
• Effects of withdrawal from therapy
  • Time Frame: Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), Visit 5 (Day 21), Visit 6 (Day 28), Visit 7 (Day 42), Visit 8 (Day 48)
    Safety Issue?: Yes
• Relationship between plasma concentrations of (R,R)-formoterol and selected pharmacodynamic parameters.
  • Time Frame: Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), Visit 5 (Day 21), Visit 6 (Day 28), Visit 7 (Day 42), Visit 8 (Day 48)
    Safety Issue?: No
• FEV1 percent change from pre-dose (24-hour trough) following 14 days of double-blind treatment.
  • Time Frame: Visit 2 (Day 0), Visit 3 (Day 7), Visit 4 (Day 14), Visit 5 (Day 21), Visit 6 (Day 28), Visit 7 (Day 42), Visit 8 (Day 48)
    Safety Issue?: No

Inclusion Criteria:

• Subject may be male or female and must be aged greater than or equal to 35 years on the day the informed consent is signed.
• Female subject less than or equal to 65 years of age must have a serum pregnancy test conducted at study start and confirmed negative. Subjects of childbearing potential must be using an acceptable method of birth control and agree to continue its use throughout the study.
• In order to be considered not of childbearing potential female subjects must be:
• documented surgically sterile (defined as status post-hysterectomy or bilateral tubal ligation) OR
• postmenopausal
• Subject must have a primary diagnosis of COPD, which may include components of chronic bronchitis and/or emphysema. Diagnosis can be made during the screening process.
• Subject must have a minimum smoking history of 15 pack-years (pack-years = the number of cigarette packs per day times the number of years).
• Subject must have a chest x-ray that is consistent with the diagnosis of COPD (e.g., not diagnostic of pneumonia, other infection, atelectasis, or pneumothorax) and taken less than or equal to 6 months before study start. If there is no chest x-ray taken less than or equal to 6 months before study start, a chest x-ray will be performed at Visit 1.
• Subject must be able to complete all study questionnaires and logs reliably.

Exclusion Criteria:

• A female who is pregnant or lactating.
• Subject who has participated in an investigational drug study within 30 days prior to study start, or who is currently participating in another investigational drug study.
• Subject's schedule or travel prevents the completion of all required visits.
• Subject is scheduled for in-patient hospitalization, including elective surgery (in patient or out-patient) during the trial.
• Subject has had a life-threatening/unstable respiratory status, including upper or lower respiratory tract infection, within the 30 days prior to study start.
• Subject has a known history of asthma (except childhood asthma) or any chronic respiratory disease (including a current history of sleep apnea) other than COPD (chronic bronchitis and/or emphysema).
• Subject has a known history of alpha 1 antitrypsin deficiency-related emphysema.
• Subject has a history of cancer except non-melanoma skin cancer. Subjects with a history of cancer that is considered surgically cured and without a recurrence within the past 5 years may participate in the study. History of hematologic/lymphatic malignancy treated with chemotherapy or radiation is not allowed, under any condition.
• Subject has a history of lung resection of more than one full lobe or being a recipient of a lung or major organ transplant.
• Subject requires continuous supplemental oxygen therapy (unless subject resides at elevation greater than or equal to 4,000 feet).
• Subject has had a change in dose or type of any medications for COPD within 14 days before the screening visit.
• Subject has a known sensitivity to arformoterol, ipratropium or albuterol or any of the excipients contained in any of these formulations.
• Subject has a history of substance abuse within 12 months of Visit 1, or with a positive urine drug screen at study start.
• Subject is using any prescription drug for which concomitant beta-agonist administration is contraindicated (e.g., beta-blockers).
• Subject has had significant blood loss (>500 cc) or donated blood within 60 days preceding screening or plans to donate blood during or within 60 days after completing the study.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 35 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Sepracor, Inc.

Information obtained from ClinicalTrials.gov on August 29, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00691405

Study ID Number: 091-026

ClinicalTrials.gov Identifier: NCT00691405

Health Authority: United States: Food and Drug Administration