The Effects of RPL554 in Addition to Tiotropium in COPD Patients

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 75 years inclusive, at the time of informed consent.
• If male: must agree to meet the following from the first dose up to 1 month after the last dose of study treatment:
• 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 highly effective form of contraception must also be used
• If female: either be:
• Of non-childbearing potential defined as being:
• Either: post-menopausal (being spontaneously amenorrhoeic for at least 1 year with an appropriate clinical profile [e.g. age appropriate, history of vasomotor symptoms]
• Or: permanently sterilised e.g. tubal occlusion, hysterectomy, bilateral oophorectomy, bilateral salpingectomy
• Of childbearing potential and agreeing to use a highly effective method of contraception until completion of the end of study visit.
• Have a 12-lead ECG recording at screening and randomisation (pre-dose in Treatment Period 1) showing the following:
• Heart rate between 45 and 90 beats per minute (bpm)
• QT interval corrected for heart rate using Fridericia's formula (QTcF) ≤450 msec for males and ≤470 ms for females
• QRS interval ≤120 msec
• No clinically significant abnormalities (as judged by the Investigator) including morphology (e.g. left bundle branch block, atrio-ventricular nodal dysfunction, ST segment abnormalities)
• Have a screening Holter report with a minimum of 18 hours recording that is able to be evaluated for rhythm analysis which shows no abnormality which indicates a significant impairment of patient safety or which may significantly impairs interpretation in the opinion of the Investigator including:
• Significant arrhythmias including atrial flutter, atrial fibrillation, ventricular tachycardia
• Any symptomatic arrhythmia (except isolated extra systoles)
• Any sustained second or third degree heart block
• Capable of complying with all study restrictions and procedures including ability to use the study nebuliser and HandiHaler® DPI correctly.
• Body mass index (BMI) between 18 and 33 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.
• Post-bronchodilator (four puffs of salbutamol) spirometry at screening:
• Post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio of ≤0.70
• Post-bronchodilator FEV1 ≥40 % and ≤80% of predicted normal
• Demonstrates ≥150 mL increase from pre-bronchodilator FEV1
• Clinically stable COPD in the 4 weeks prior to screening and randomisation (pre-dose in Treatment Period 1).
• A chest X-ray (post-anterior) at screening, or in the 12 months prior to screening 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.
• Smoking history of ≥10 pack years.
• Capable of withdrawing from long acting bronchodilators for the duration of the study, and short acting bronchodilators for 8 hours prior to spirometry.

Exclusion Criteria

• A history of life-threatening COPD exacerbation including Intensive Care Unit admission and/or requiring intubation.
• COPD exacerbation requiring oral steroids, or lower respiratory tract infection requiring antibiotics, in the 3 months prior to screening or randomisation (pre-do