Assessment of the Safety and Ability of a Once-a-day Dose of an Orally Inhaled Medicine [i.e., Glycopyrrolate Inhalation Solution = GIS] to Improve Airflow in the Lungs When Delivered Using an eFlow Nebulizer in Patients With Chronic Obstructive Pulmonary Disease (COPD)

Randomized, Placebo-Controlled, Double-Blind, Dose Ranging, Single-Dose, 6-Way Crossover Study to Assess Safety, Efficacy and Pharmacokinetics of EP-101 Using eFlow Nebuliser in Patients With COPD

The study assessed the safety and ability of an orally inhaled medicine [i.e., Glycopyrrolate Inhalation Solution = GIS] to improve airflow in the lungs when delivered using an eFlow nebulizer in 42 patients with Chronic Obstructive Pulmonary Disease (COPD). Each patient randomly received several, single doses of GIS, or placebo, separated by approximately 1 to 2 weeks. After the dose was given, lung airflow was measured over 24 hours and blood was collected to measure how much GIS was in the bloodstream. The study was conducted to find the once-a- day GIS dose that produced the highest improvement in lung airflow using the eFlow nebulizer.

Inclusion Criteria:

1. Male and female patients aged 40 through 75 years, inclusive
2. A clinical diagnosis of COPD according to the GOLD guidelines
3. Current smokers or ex-smokers with at least 10 pack-year smoking history (e.g., at least 1 pack/day for 10
4. Post-bronchodilator FEV1 30-70% of predicted normal at the Screening Visit
5. Post-bronchodilator FEV1/FVC ratio < 0.70 at the Screening Visit
6. Improvement in FEV1 >12% and 150 mL following inhalation of ipratropium bromide at the Screening Visit
7. Ability to perform reproducible spirometry according to the ATS/ERS guidelines
8. Willing to stay at the study site for approximately 30 hours on each treatment visit
9. Willing and able to provide written informed consent

Exclusion Criteria:

1. Females who are pregnant or lactating at the Screening Visit, or if of childbearing potential not using one of the following acceptable means of birth control throughout the study:

   • Abstinence
   • Post-menopausal for at least two years
   • Surgically sterile (i.e., tubal ligation, hysterectomy)
   • Oral contraceptives (taken for at least one month prior to the Screening Visit)
   • Approved implantable or injectable contraceptives (e.g., Norplant®, Depo-Provera® or equivalent)
   • Barrier methods (e.g., condoms with spermicide)
   • Intrauterine device (i.e., IUD)
   • Vasectomy of male partner
   • Non-heterosexual life style

2. Current evidence or recent history of any clinically significant disease (other than COPD) or abnormality in the opinion of the Investigator that would put the subject at risk or which would compromise the quality of the study data; including but not limited to cardiovascular disease, myocardial infarction, cardiac failure, uncontrolled hypertension, life-threatening arrhythmias, uncontrolled diabetes, neurologic or neuromuscular disease, liver disease, gastrointestinal disease or electrolyte abnormalities

3. Recent history of hospitalization due to an exacerbation of airway disease within 3 months or need for increased treatments for COPD within 6 weeks prior to the Screening Visit

4. Primary diagnosis of asthma

5. Prior lung volume reduction surgery or history of chest/lung irradiation

6. Regular use of daily oxygen therapy

7. Use of systemic (eg, intramuscular or intravenous) steroids within 3 months prior to the Screening Visit

8. Respiratory tract infection within 6 weeks prior to the Screening Visit

9. History of tuberculosis, bronchiectasis or other non- specific pulmonary disease

10. History of urinary retention or bladder neck obstruction type symptoms

11. History of narrow-angle glaucoma

12. Clinically significant abnormal ECG

13. Positive Hepatitis B surface antigen or positive Hepatitis C antibody

14. Positive screening test for HIV antibodies

15. Current or recent history (previous 12 months) of excessive use or abuse of alcohol

16. Current evidence or history of abusing legal drugs or use of illegal drugs or substances

17. Donation of 450 mL of blood within 8 weeks of the Screening Visit

18. History of hypersensitivity or intolerance to aerosol medications

19. Participation in another investigational drug study was received within 30 days prior to the Screening Visit