Bronchodilator Effect of RPL554 Administered in Addition to Tiotropium/Olodaterol in Patients With COPD

RPL554 is a dual inhibitor of phosphodiesterase 3 (PDE3) and phosphodiesterase 4 (PDE4) which are known to have a role in modulating the inflammatory airway response in respiratory diseases, including COPD. PDE3 inhibitors act as bronchodilators whilst PDE4 inhibitors have anti-inflammatory properties and there is also evidence to suggest that combined inhibition of PDE3 and PDE4 can have additive or synergistic anti-inflammatory and bronchodilator. The two doses of RPL554 (1.5 mg and 6 mg)have been selected based on the results from prior studies investigating single and multiple ascending doses in healthy subjects, single doses in asthmatics, single/multiple ascending doses in COPD patients, and 3 days of dosing in COPD patients. These doses were demonstrated to be both effective as a bronchodilator and well tolerated.

The purpose of the study is to investigate if RPL554 has an additive bronchodilator effect when administered in combination with a commonly used anticholinergic/β-agonist combination medication, tiotropium/olodaterol (Respimat), in this patient population measured by the peak forced expiratory volume in one second (FEV1), and forced vital capacity (FVC).

Inclusion criteria

• Written informed consent
• Male or female aged 40 and 80 years
• For males, not to donate sperm and either be sexually abstinent or use contraception as specified by the protocol. For females, be of non-childbearing potential or use a highly effective form of contraception
• 12-lead ECG with heart rate between 45 and 90 beats per minute, QTcF ≤450 msec for males, and ≤ 470 msec for females, QRS interval ≤120 msec and no clinically significant abnormality including morphology
• Screening Holter report with a minimum of 18 hours recording that is able to be evaluated for rhythm analysis showing no abnormality which indicates a significant impairment of patient safety or which may significantly impair interpretation
• Capable of complying with all study restrictions and procedures including ability to use the study nebulizer and Respimat® correctly.
• Body mass index (BMI) between 18 and 36 kg/m2 and minimum weight of 45 kg.
• COPD diagnosis for at least 1 year and clinically stable COPD for 4 week
• Post-bronchodilator (two puffs of salbutamol/albuterol followed by two puffs of ipratropium) spirometry at Screening:

• Post-bronchodilator FEV1/forced vital capacity (FVC) ratio of ≤0.70
• Post-bronchodilator FEV1 ≥30 % and ≤70% of predicted normal
• Demonstrates ≥150 mL increase from pre-bronchodilator FEV1
• A chest X-ray showing no abnormalities, which are both clinically significant and 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. 14. Capable of withdrawing from long acting bronchodilators for the duration of the study, and short acting bronchodilators for 8 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, in the last 3 months
• A history of one or more hospitalizations for COPD in the last 12 months
• Intolerance or hypersensitivity to tiotropium, olodaterol, atropine, ipratropium, or RPL554.
• Evidence of cor pulmonale or clinically significant pulmonary hypertension.
• Other respiratory disorders
• Previous lung resection or lung reduction surgery.
• Use of oral COPD medications, except mucolytics, in the last 3 months
• Pulmonary rehabilitation, unless such treatment has been stable in the last 4 weeks
• History of, or reason to believe a patient has, drug or alcohol abuse within the past 5 years.
• Inability to perform acceptable spirometry or whole body plethysmography
• Received an experimental drug within 30 days or five half lives, whichever is longer.
• Patients with uncontrolled disease that the Investigator believes are clinically significant. This includes any hepatic disease, or an alanine aminotransferase or aspartate aminotransferase>2 x upper limit of normal (ULN).
• Documented cardiovascular disease: arrhythmias, angina, recent (<1 year) or suspected myocardial infarction, congestive heart failure, unstable or uncontrolled hypertension, or diagnosis of hypertension in the last 3 months
• Use of non-selective oral β-blockers.
• Major surgery (requiring general anesthesia) in the last 6 weeks or will not have fully recovered from surgery, or planned surgery through the end of the study.
• A disclosed history or one known to the Investigator, of significant non compliance in previous investigational studies or with prescribed medications.
• Required use of oxygen therapy, even on an occasional basis.
• Symptomatic prostatic hyperplasia or bladder-neck obstruction or with narrow-angle glaucoma.
• History of malignancy of any organ system within 5 years, with the exception of localized skin cancers (basal or squamous cell).
• Clinically significant abnormal values for safety laboratory tests (hematology, biochemistry, virology or urinalysis) as determined by the Investigator
• Any other reason that the Investigator considers makes the patient unsuitable to participate.