Comparison of RPL554 With Placebo and Salbutamol in Asthmatic Patients

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

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.

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Drug: Placebo; Drug: RPL554; Drug: Salbutamol

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 2

Contacts and Locations

Study Locations

• Sweden
  • Lund, Sweden
    • Skåne University Hospital
• United Kingdom
  • Belfast, United Kingdom
    • Celerion

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: TRIPLE

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo; Single dose of nebulised placebo solution	Drug: Placebo; RPL554 placebo containing no active ingredients
EXPERIMENTAL: RPL554 Dose 1; 0.4 mg single dose nebulised RPL554	Drug: RPL554; A dual PDE3 and PDE4 inhibitor; Other Names: VMX554; VRP554
EXPERIMENTAL: RPL554 Dose 2; 1.5 mg single dose nebulised RPL554	Drug: RPL554; A dual PDE3 and PDE4 inhibitor; Other Names: VMX554; VRP554
EXPERIMENTAL: RPL554 Dose 3; 6 mg single dose nebulised RPL554	Drug: RPL554; A dual PDE3 and PDE4 inhibitor; Other Names: VMX554; VRP554
EXPERIMENTAL: RPL554 Dose 4; 24 mg single dose nebulised RPL554	Drug: RPL554; A dual PDE3 and PDE4 inhibitor; Other Names: VMX554; VRP554
ACTIVE_COMPARATOR: Salbutamol Dose 1; 2.5 mg single dose nebulised salbutamol	Drug: Salbutamol; a beta-2 receptor agonist
ACTIVE_COMPARATOR: Salbutamol Dose 2; 7.5 mg single dose nebulised salbutamol	Drug: Salbutamol; a beta-2 receptor agonist

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Verona Pharma plc
• Investigators: Principal Investigator: Lief Bjermer, Skane University Hospital, Sweden; Principal Investigator: Johnston Stewart, Celerion, Northern Ireland

Publications and helpful links

General Publications

• Bjermer L, Abbott-Banner K, Newman K. Efficacy and safety of a first-in-class inhaled PDE3/4 inhibitor (ensifentrine) vs salbutamol in asthma. Pulm Pharmacol Ther. 2019 Oct;58:101814. doi: 10.1016/j.pupt.2019.101814. Epub 2019 Jun 14.

Study record dates

Study Major Dates

• Study Start: April 1, 2015
• Primary Completion (ACTUAL): November 1, 2015
• Study Completion (ACTUAL): November 1, 2015

Study Registration Dates

• First Submitted: April 14, 2015
• First Submitted That Met QC Criteria: April 24, 2015
• First Posted (ESTIMATE): April 27, 2015

Study Record Updates

• Last Update Posted (ESTIMATE): September 9, 2016
• Last Update Submitted That Met QC Criteria: September 8, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic Agonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Reproductive Control Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Tocolytic Agents; Albuterol
• Other Study ID Numbers: RPL554-008-2014