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

Single-dose, Dose Escalation Study to Assess the Safety, Tolerability, Pharmacokinetics and Bronchodilatory Effects of Glycopyrrolate Inhalation Solution (GIS) Using a High Efficiency Nebulizer in Patients With COPD

The study assessed the safety and ability of several doses of an orally inhaled medicine [ie, Glycopyrrolate Inhalation Solution = GIS] to improve airflow in the lungs when delivered with an electronic eFlow nebulizer system in patients with Chronic Obstructive Pulmonary Disease (COPD). The study was conducted in 12 patients in 2 parts. Part 1 was designed to find the once-a- day GIS dose that produced the highest improvement in lung airflow. Part 2 tested the GIS dose with the highest improvement in lung airflow and a placebo (ie, no drug) delivered by a general purpose nebulizer. The airflow improvements of the same GIS dose were compared between the two nebulizer systems to determine what effect the device had on GIS delivery.

In Part I, 12 subjects were randomly allocated to one of 2 cohorts, running in parallel. The 6 cohort 1 subjects received 25 mg and then 200 mg during their treatment periods 1 and 2, respectively. The 6 cohort 2 subjects received 75mg, 500mg, and 1000 mg during their treatment periods 1, 2, and 3, respectively. During Part II of the study, the same 12 subjects from Part I were randomized to receive either 200 mg jet or placebo in a 1:1 ratio.

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 years, or 10 packs/day for 1 year)

4. Post-bronchodilator FEV1 40-80% of predicted normal

5. Post-bronchodilator FEV1/FVC ratio < 0.70

6. Improvement in FEV1 >12% (minimum 150 mL) following inhalation of ipratropium bromide

7. Ability to perform reproducible spirometry according to the ATS/ERS guidelines

8. If female and of childbearing potential, must have had a negative pregnancy test and was not lactating at the Screening Visit, and was using one of the following acceptable means of birth control throughout the study:

   • Post-menopausal for at least two years
   • Surgically sterile
   • 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

9. Willing and able to provide written informed consent

Exclusion Criteria:

1. 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 patients at risk or which would compromise the quality of the study data; including but not limited to cardiovascular disease, myocardial infraction, hypertension, arrhythmia, diabetes, neurological or neuromuscular disease, liver disease, gastrointestinal disease or electrolyte abnormalities.
2. Recent history of an exacerbation of airway disease within 3 months or need for increased treatments for COPD within 6 weeks prior to the Screening Visit.
3. Regular use of daily oxygen therapy.
4. Use of systemic (e.g., intramuscular or intravenous) steroids within 3 months prior to the Screening Visit
5. Respiratory tract infection within 6 weeks prior to the Screening Visit
6. History of tuberculosis, bronchiectasis or other non-specific pulmonary disease
7. History of urinary retention or bladder neck obstruction type symptoms
8. History of narrow-angle glaucoma
9. Current or recent history (previous 12 months) of excessive use or abuse of alcohol
10. Current evidence or history of abusing legal drugs or the use of illegal drugs or substances
11. History of hypersensitivity or intolerance to aerosol medications
12. Participation in another investigational drug study where drug was received within 30 days prior to the Screening Visit