The Effects of RPL554 on Top of Standard COPD Reliever Medications

Study Overview
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Brief Summary
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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: salbutamol, ipratropium, salbutamol + RPL554, ipratropium + RPL554, RPL554 Placebo

Detailed Description
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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.

Official Title
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A Phase II, Randomised, Double Blind, Placebo Controlled, Six Way Crossover Study to Assess the Bronchodilator Effect of RPL554 Administered on Top of Salbutamol and Ipratropium in Patients With COPD.

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: Salbutamol
* Drug: Ipratropium
* Drug: RPL554
* Drug: Salbutamol matched placebo
* Drug: Ipratropium matched placebo
* Drug: RPL554 matched placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Salbutamol alone<br>200 micrograms salbutamol, ipratropium matched placebo and RPL554 matched placebo | Drug: Salbutamol<br>* 200 micrograms salbutamol administered using a pressurised metered dose inhaler (pMDI)<br>Drug: Ipratropium matched placebo<br>* Placebo pMDI<br>Drug: RPL554 matched placebo<br>* Nebulised placebo<br>|
| Experimental: Salbutamol and RPL554<br>200 micrograms salbutamol, ipratropium matched placebo and 6 mg RPL554 | Drug: Salbutamol<br>* 200 micrograms salbutamol administered using a pressurised metered dose inhaler (pMDI)<br>Drug: RPL554<br>* 6 mg RPL554 administered using a nebuliser<br>Drug: Ipratropium matched placebo<br>* Placebo pMDI<br>|
| Active Comparator: Ipratropium<br>Salbutamol matched placebo, 40 micrograms ipratropium and RPL554 matched placebo | Drug: Ipratropium<br>* 40 micrograms ipratropium administered using a pMDI<br>Drug: Salbutamol matched placebo<br>* Placebo pMDI<br>Drug: RPL554 matched placebo<br>* Nebulised placebo<br>|
| Experimental: Ipratropium and RPL554<br>Salbutamol matched placebo, 40 micrograms ipratropium and 6 mg RPL554 | Drug: Ipratropium<br>* 40 micrograms ipratropium administered using a pMDI<br>Drug: RPL554<br>* 6 mg RPL554 administered using a nebuliser<br>Drug: Salbutamol matched placebo<br>* Placebo pMDI<br>|
| Experimental: RPL554<br>Salbutamol matched placebo, ipratropium matched placebo and 6 mg RPL554 | Drug: RPL554<br>* 6 mg RPL554 administered using a nebuliser<br>Drug: Salbutamol matched placebo<br>* Placebo pMDI<br>Drug: Ipratropium matched placebo<br>* Placebo pMDI<br>|
| Placebo Comparator: Placebo<br>Salbutamol matched placebo, ipratropium matched placebo and RPL554 matched placebo | Drug: Salbutamol matched placebo<br>* Placebo pMDI<br>Drug: Ipratropium matched placebo<br>* Placebo pMDI<br>Drug: RPL554 matched placebo<br>* Nebulised placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 8 hour spirometry | Forced expired volume in one second (FEV1) over 8 hours post-dose | 8 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 12 hour spirometry | FEV1 over 4, 6 and 12 hours post-dose | 12 hours | 
| Whole body plethysmography | Functional residual capacity, residual volume, total lung capacity, specific airway conductance, specific airway resistance at 1 and 4 hours post-dose | 4 hours | 
| Area under the curve (AUC) | AUC for RPL554 plasma concentration | 12 hours | 
| Maximum plasma concentration (Cmax) | Cmax for RPL554 plasma concentration | 12 hours | 
| Time to maximum plasma concentration (Tmax) | Tmax for RPL554 plasma concentration | 12 hours | 
| Adverse events | Continuous measurement of adverse events throughout the study | Up to 94 days | 
| Safety laboratory tests | Laboratory safety tests at screening, before each treatment and end of study | Up to 94 days | 
| ECG | 12 lead ECG at screening, before and up to 12 hours after each treatment and end of study | Up to 94 days | 
| Vital signs | Blood pressure and pulse rate at screening, before and up to 12 hours after each treatment and end of study | Up to 94 days |