The Effects of RPL554 on Top of Standard COPD Reliever Medications

• ClinicalTrials.gov Identifier: NCT02542254
• Recruitment Status: Completed
• First Posted: September 4, 2015
• Last Update Posted: September 9, 2016
• Sponsor: Verona Pharma plc
• Information provided by (Responsible Party): Verona Pharma plc

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Chronic Obstructive Pulmonary Disease	Drug: Salbutamol; Drug: Ipratropium; Drug: RPL554; Drug: Salbutamol matched placebo; Drug: Ipratropium matched placebo; Drug: RPL554 matched placebo	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 36 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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.
• Study Start Date: October 2015
• Actual Primary Completion Date: December 2015
• Actual Study Completion Date: December 2015

Arms and Interventions

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: RPL554; 6 mg RPL554 administered using a nebuliser; Drug: Ipratropium matched placebo; Placebo pMDI
Active Comparator: Ipratropium; Salbutamol matched placebo, 40 micrograms ipratropium and RPL554 matched placebo	Drug: Ipratropium; 40 micrograms ipratropium administered using a pMDI; Drug: Salbutamol matched placebo; Placebo pMDI; Drug: RPL554 matched placebo; Nebulised placebo
Experimental: Ipratropium and RPL554; Salbutamol matched placebo, 40 micrograms ipratropium and 6 mg RPL554	Drug: Ipratropium; 40 micrograms ipratropium administered using a pMDI; Drug: RPL554; 6 mg RPL554 administered using a nebuliser; Drug: Salbutamol matched placebo; Placebo pMDI
Experimental: RPL554; Salbutamol matched placebo, ipratropium matched placebo and 6 mg RPL554	Drug: RPL554; 6 mg RPL554 administered using a nebuliser; Drug: Salbutamol matched placebo; Placebo pMDI; Drug: Ipratropium matched placebo; Placebo pMDI
Placebo Comparator: Placebo; Salbutamol matched placebo, ipratropium matched placebo and RPL554 matched placebo	Drug: Salbutamol matched placebo; Placebo pMDI; Drug: Ipratropium matched placebo; Placebo pMDI; Drug: RPL554 matched placebo; Nebulised placebo

Outcome Measures

Primary Outcome Measures :

1. 8 hour spirometry [ Time Frame: 8 hours ]
   Forced expired volume in one second (FEV1) over 8 hours post-dose

Secondary Outcome Measures :

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

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United Kingdom

Medicines Evaluation Unit

Manchester, United Kingdom

Sponsors and Collaborators

Verona Pharma plc

Investigators

• Principal Investigator: Dave Singh; Medicines Evaluation Unit

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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). pii: 1801074. doi: 10.1183/13993003.01074-2018. Print 2018 Nov.

• Responsible Party: Verona Pharma plc
• ClinicalTrials.gov Identifier: NCT02542254 History of Changes
• Other Study ID Numbers: RPL554-009-2015; 2015-002536-41 ( EudraCT Number )
• First Posted: September 4, 2015
• Last Update Posted: September 9, 2016
• Last Verified: September 2016

Additional relevant MeSH terms:

Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Lung Diseases; Respiratory Tract Diseases; Albuterol; Ipratropium; Bronchodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Asthmatic Agents; Respiratory System Agents; Tocolytic Agents; Reproductive Control Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Adrenergic Agonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Cholinergic Antagonists; Cholinergic Agents