The Effects of RPL554 on Top of Standard COPD Reliever Medications

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.

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

Study Overview

• Status: Completed
• Conditions: Chronic Obstructive Pulmonary Disease
• Intervention / Treatment: Drug: Salbutamol; Drug: Ipratropium matched placebo; Drug: RPL554 matched placebo; Drug: RPL554; Drug: Ipratropium; Drug: Salbutamol matched placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Manchester, United Kingdom
    • Medicines Evaluation Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

6

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Verona Pharma plc
• Investigators: Principal Investigator: Dave Singh, Medicines Evaluation Unit

Publications and helpful links

General Publications

• Singh D, Abbott-Banner K, Bengtsson T, Newman K. The short-term bronchodilator effects of the dual phosphodiesterase 3 and 4 inhibitor RPL554 in COPD. Eur Respir J. 2018 Nov 1;52(5):1801074. doi: 10.1183/13993003.01074-2018. Print 2018 Nov.

Study record dates

Study Major Dates

• Study Start: October 1, 2015
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: August 30, 2015
• First Submitted That Met QC Criteria: September 3, 2015
• First Posted (Estimate): September 4, 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; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Antagonists; Cholinergic 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; Ipratropium
• Other Study ID Numbers: RPL554-009-2015; 2015-002536-41 (EudraCT Number)