Study Investigating the Effect of 4 Doses of RPL554 Given in Addition to Tiotropium to Patients With COPD

Inclusion Criteria

• Sign an informed consent document indicating they understand the purpose of and procedures required for the study and are willing to participate in the study.
• Male or female aged between 40 and 80 years inclusive, at the time of informed consent.
• Must agree to meet the following from the first dose up to 1 month after the last dose of study medication:
• If male:
• Not donate sperm
• Either: be sexually abstinent in accordance with a patient's usual and preferred lifestyle (but agree to abide by the contraception requirements below should their circumstances change)
• Or: use a condom with all sexual partners. If the partner is of childbearing potential the condom must be used with spermicide and a second reliable form of contraception must also be used (e.g., diaphragm/cap with spermicide, established hormonal contraception, intra-uterine device)
• If female:
• be of non-childbearing potential or use a highly effective form of contraception
• Have a 12-lead ECG recording at Screening showing the following (and no changes in the pre-dose value at the first treatment deemed clinically significant by the Investigator):
• Heart rate between 45 and 90 beats per minute
• QT interval corrected for heart rate using Fridericia's formula (QTcF) ≤450 msec for males, and ≤ 470 msec for females
• QRS interval ≤ 120 msec
• No clinically significant abnormality including morphology (e.g., left bundle branch block, atrio-ventricular nodal dysfunction, ST segment abnormalities consistent with ischemia)
• Capable of complying with study restrictions and procedures, including ability to use the nebulizer correctly.
• Body mass index (BMI) between 18 and 35 kg/m2 (inclusive) with a minimum weight of 45 kg.
• COPD diagnosis: Patients with a diagnosis of COPD as defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines (Celli and MacNee, 2004) with symptoms compatible with COPD for at least 1 year prior to Screening.
• Ability to perform acceptable and reproducible spirometry.
• Post-bronchodilator (four puffs of albuterol) spirometry at Screening demonstrating the following:
• FEV1/ FVC ratio of ≤0.70
• FEV1 ≥30% and ≤70% of predicted normal* *National Health and Nutrition Examination Survey (NHANES) III (Hankinson et al, 1999) will be used as the reference for normal predicted values.
• Clinically stable COPD in the 4 weeks prior to Screening (Visit 1) and during the period between Visits 1 and 2.
• A score of ≥2 on the modified Medical Research Council (mMRC) dyspnea scale at Screening.
• A chest X-ray (posterior-anterior) at Screening, or in the 12 months prior to Screening showing no clinically significant abnormalities unrelated to COPD.
• Meet the concomitant medication restrictions and be expected to do so for the rest of the study.
• Current and former smokers with smoking history of ≥10 pack years.
• Capable of withdrawing from long acting bronchodilators (other than tiotropium) for the duration of the study, and short acting bronchodilators for 6 hours prior to dosing.

Exclusion Criteria

• A history of life-threatening COPD including Intensive Care Unit admission and/or requiring intubation.
• COPD exacerbation requiring oral or parenteral steroids, or lower respiratory tract infection requiring antibiotics, within 3 months of Screening or prior to the first treatment.
• A history of one or more hospitalizations for COPD or pneumonia within 6 months of Screening or prior to the first treatment.
• Intolerance or hypersensitivity to albuterol, tiotropium or other muscarinic receptor antagonists.
• Other respiratory disorders: Patients with a current diagnosis of asthma, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, interstitial lung diseases, uncontrolled or unstable sleep apnea, known alpha-1 antitrypsin deficiency, core pulmonale, clinically significant pulmonary hypertension or other active pulmonary diseases.
• Previous lung resection