The Effects of RPL554 on Top of Standard COPD Reliever Medications
The Effects of RPL554 on Top of Standard COPD Reliever Medications
This study evaluates the addition of RPL554 to standard reliever medications for chronic
 obstructive pulmonary disorder (COPD). All patients will receive the same six treatments in a
 randomised sequence:

 1. salbutamol,

 2. ipratropium,

 3. salbutamol + RPL554,

 4. ipratropium + RPL554,

 5. RPL554

 6. Placebo
The purpose of this study is to investigate if RPL554 has an additive bronchodilator effect
 when administered in combination with standard of care bronchodilators in patients with
 COPD.This study investigates the pharmacodynamic effect of RPL554 using spirometry and whole
 body plethysmography compared to placebo, when administered in addition to a beta2 agonist
 (salbutamol), a muscarinic antagonist (ipratropium) or placebo.
Inclusion Criteria:

 -  Provide informed consent

 -  Males not donating sperm and using adequate contraception or females who are
 surgically sterile or postmenopausal

 -  12-lead ECG showing:Heart rate 45 to 90 bpm, QTcF≤450 msec, QRS ≤120 msec, PR interval
 ≤220 msec, no clinically significant abnormality

 -  Capable of complying with all study restrictions and procedures including ability to
 use the study nebuliser correctly.

 -  BMI 18 to 33 kg/m2 with a minimum weight of 45 kg.

 -  COPD diagnosis for at least 1 year and clinically stable COPD in previous 4 weeks

 -  Demonstrates reversibility to bronchodilator (two puffs of salbutamol followed by two
 puffs of ipratropium) via spirometry:

 -  Post-bronchodilator FEV1/forced vital capacity (FVC) ratio of ≤0.70

 -  Post-bronchodilator FEV1 ≥40 % and ≤80% of predicted normal

 -  ≥150 mL increase from pre-bronchodilator FEV1

 -  Chest X-ray showing no abnormalities

 -  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 throughout the study and short
 acting bronchodilators for 8 hours prior to study treatment.

 Exclusion Criteria:

 -  History of life-threatening COPD including Intensive Care Unit admission and/or
 requiring intubation.

 -  COPD exacerbation requiring oral steroids in the previous 3 months

 -  History of one or more hospitalisations for COPD in the previous 12 months

 -  Respiratory tract infection (both upper and lower) treated with antibiotics in
 previous 12 weeks

 -  Evidence of cor pulmonale or clinically significant pulmonary hypertension.

 -  Other respiratory disorders

 -  Previous lung resection or lung reduction surgery.

 -  Oral therapies for COPD in the previous 3 months and throughout the study.

 -  Drug or alcohol abuse in the past 3 years

 -  Received an experimental drug within 3 months or five half lives, whichever is longer.

 -  Prior exposure to RPL554

 -  Patients with a history of chronic uncontrolled disease that the Investigator believes
 are clinically significant.

 -  Documented cardiovascular disease in last 3 months

 -  Major surgery, (requiring general anaesthesia) in the previous 6 weeks, or will not
 have fully recovered from surgery, or planned surgery through the end of the study.

 -  History of malignancy of any organ system within 5 years with the exception of
 localised skin cancers (basal or squamous cell)

 -  Clinically significant abnormal values for safety laboratory tests

 -  A disclosed history, or one known to the Investigator, of significant non compliance
 in previous investigational studies or with prescribed medications.

 -  Requires oxygen therapy, even on an occasional basis.

 -  Inability to adequately perform whole body plethysmography.

 -  Any other reason that the Investigator considers makes the subject unsuitable to
 participate.

 -  Patients with known hypersensitivity to atropine or its derivatives, or to ipratropium
 bromide, salbutamol or RPL554 or their excipients/components.