Comparison of RPL554 With Placebo and Salbutamol in Asthmatic Patients

Study Overview
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Brief Summary
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The number of people with of asthma and allergy is still increasing and a large number of patients still do not have their asthma well controlled. There is therefore a need for new asthma treatments that work well and have less side effects. The study compares a new experimental drug RPL554 with a marketed asthma drug (salbutamol) and placebo.

Detailed Description
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A seven way crossover study to investigate the pharmacodynamics, pharmacokinetics, safety and tolerability of inhaled RPL554 compared to salbutamol and placebo in patients with mild to moderate chronic asthma. Salbutamol is a marketed beta-2 agonist typically used to treat bronchospasm (due to any cause, allergen asthma or exercise-induced), as well as chronic obstructive pulmonary disease but has associated dose-related systemic side effects. RPL554 is a dual PDE3 and PDE4 inhibitor that has bronchodilatory and anti-inflammatory actions and also the potential to stimulate increases in mucociliary clearance via its proven ability to activate CFTR. Four different doses of RPL554 will be compared with placebo and a two doses of salbutamol as benchmarks for bronchodilation and systemic side effects.

Official Title
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A Phase II, Randomised, Double Blind, Placebo Controlled, Seven Way Crossover Study to Assess the Effect of Single Doses of RPL554 Compared to Salbutamol and Placebo Administered by Nebuliser on Lung Function of Patients With Chronic Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: RPL554
* Drug: Salbutamol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provided written informed consent Males agree not to donate sperm and either be abstinent or use adequate contraception. Females to be post-menopausal or surgically sterile Non-smoker or ex-smoker >6 months Diagnosed asthma for at least 6 months Pre-bronchodilator FEV1 ≥60% and ≤90% of predicted normal value and ≥1.5 L at screening Increase in FEV1 of 15% within 30 minutes after a 2.5mg dose of nebulised salbutamol Systolic blood pressure 90 to 145 mmHg, diastolic blood pressure 50 to 90 mmHg and heart rate 45 to 80 beats per minute (bpm) after resting for 5 minutes in a supine position (average from two measurements) Capable of withdrawing from LABAs, LAMAs and SAMAs before screening and during study and SABAs before screening and for 8 hours before each dose Exclusion Criteria: Asthma exacerbation in the last 3 months Any prior life threatening episode of asthma (intensive care admission) Any clinically significant disease or disorder or clinically relevant screening result QTcF interval >450 ms or QT interval >500 ms or other abnormality in ECG History of ischemic heart disease or heart failure. History of recurrent or current clinically significant arrhythmia or ECG abnormality as judged by the investigator Treatment with systemic glucocorticosteroids within 30 days before screening A suspected/manifested infection according to WHO risk classification 2, 3 or 4

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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 |
| --- | --- |
| Placebo Comparator: Placebo<br>Single dose of nebulised placebo solution | Drug: Placebo<br>* RPL554 placebo containing no active ingredients<br>|
| Experimental: RPL554 Dose 1<br>0.4 mg single dose nebulised RPL554 | Drug: RPL554<br>* A dual PDE3 and PDE4 inhibitor<br>* Other names: VRP554;|
| Experimental: RPL554 Dose 2<br>1.5 mg single dose nebulised RPL554 | Drug: RPL554<br>* A dual PDE3 and PDE4 inhibitor<br>* Other names: VRP554;|
| Experimental: RPL554 Dose 3<br>6 mg single dose nebulised RPL554 | Drug: RPL554<br>* A dual PDE3 and PDE4 inhibitor<br>* Other names: VRP554;|
| Experimental: RPL554 Dose 4<br>24 mg single dose nebulised RPL554 | Drug: RPL554<br>* A dual PDE3 and PDE4 inhibitor<br>* Other names: VRP554;|
| Active Comparator: Salbutamol Dose 1<br>2.5 mg single dose nebulised salbutamol | Drug: Salbutamol<br>* a beta-2 receptor agonist<br>|
| Active Comparator: Salbutamol Dose 2<br>7.5 mg single dose nebulised salbutamol | Drug: Salbutamol<br>* a beta-2 receptor agonist<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Spirometry | FEV1 | 12 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Spirometry | FEV1 | 4, 6 and 8 hours | 
| Systemic pharmacodynamic effect on blood pressure | Supine blood pressure in the 4 hours after nebulisation | 4 hours | 
| Systemic pharmacodynamic effect on pulse rate | Supine Pulse rate in the 4 hours after nebulisation | 4 hours | 
| Systemic pharmacodynamic effect on ECG heart rate | ECG heart rate in the 4 hours after nebulisation | 4 hours | 
| Vital signs (Supine pulse rate) | Supine pulse rate | 12 hours | 
| Vital signs (Supine blood pressure) | Supine systolic and diastolic blood pressure | 12 hours | 
| ECG | 12-lead ECG parameters | 12 hours | 
| Pharmacokinetics (AUC) | RPL554 AUC | 12 hours | 
| Pharmacokinetics (Cmax) | RPL554 Cmax | 12 hours | 
| Pharmacokinetics (tmax) | RPL554 tmax | 12 hours | 
| Pharmacokinetics (half life) | RPL554 half life | 12 hours | 
| Pharmacokinetics (MRT) | RPL554 MRT | 12 hours |