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The Effects of RPL554 on Top of Standard COPD Reliever Medications

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

Tracking Information
First Submitted Date  ICMJE August 30, 2015
First Posted Date  ICMJE September 4, 2015
Last Update Posted Date September 9, 2016
Study Start Date  ICMJE October 2015
Actual Primary Completion Date December 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 3, 2015)
8 hour spirometry [ Time Frame: 8 hours ]
Forced expired volume in one second (FEV1) over 8 hours post-dose
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02542254 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 3, 2015)
  • 12 hour spirometry [ Time Frame: 12 hours ]
    FEV1 over 4, 6 and 12 hours post-dose
  • 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
  • Area under the curve (AUC) [ Time Frame: 12 hours ]
    AUC for RPL554 plasma concentration
  • Maximum plasma concentration (Cmax) [ Time Frame: 12 hours ]
    Cmax for RPL554 plasma concentration
  • Time to maximum plasma concentration (Tmax) [ Time Frame: 12 hours ]
    Tmax for RPL554 plasma concentration
  • Adverse events [ Time Frame: Up to 94 days ]
    Continuous measurement of adverse events throughout the study
  • Safety laboratory tests [ Time Frame: Up to 94 days ]
    Laboratory safety tests at screening, before each treatment and end of study
  • 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
  • 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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The Effects of RPL554 on Top of Standard COPD Reliever Medications
Official Title  ICMJE 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.
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
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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Chronic Obstructive Pulmonary Disease
Intervention  ICMJE
  • Drug: Salbutamol
    200 micrograms salbutamol administered using a pressurised metered dose inhaler (pMDI)
  • Drug: Ipratropium
    40 micrograms ipratropium administered using a pMDI
  • Drug: RPL554
    6 mg RPL554 administered using a nebuliser
  • Drug: Salbutamol matched placebo
    Placebo pMDI
  • Drug: Ipratropium matched placebo
    Placebo pMDI
  • Drug: RPL554 matched placebo
    Nebulised placebo
Study Arms  ICMJE
  • Active Comparator: Salbutamol alone
    200 micrograms salbutamol, ipratropium matched placebo and RPL554 matched placebo
    Interventions:
    • Drug: Salbutamol
    • Drug: Ipratropium matched placebo
    • Drug: RPL554 matched placebo
  • Experimental: Salbutamol and RPL554
    200 micrograms salbutamol, ipratropium matched placebo and 6 mg RPL554
    Interventions:
    • Drug: Salbutamol
    • Drug: RPL554
    • Drug: Ipratropium matched placebo
  • Active Comparator: Ipratropium
    Salbutamol matched placebo, 40 micrograms ipratropium and RPL554 matched placebo
    Interventions:
    • Drug: Ipratropium
    • Drug: Salbutamol matched placebo
    • Drug: RPL554 matched placebo
  • Experimental: Ipratropium and RPL554
    Salbutamol matched placebo, 40 micrograms ipratropium and 6 mg RPL554
    Interventions:
    • Drug: Ipratropium
    • Drug: RPL554
    • Drug: Salbutamol matched placebo
  • Experimental: RPL554
    Salbutamol matched placebo, ipratropium matched placebo and 6 mg RPL554
    Interventions:
    • Drug: RPL554
    • Drug: Salbutamol matched placebo
    • Drug: Ipratropium matched placebo
  • Placebo Comparator: Placebo
    Salbutamol matched placebo, ipratropium matched placebo and RPL554 matched placebo
    Interventions:
    • Drug: Salbutamol matched placebo
    • Drug: Ipratropium matched placebo
    • Drug: RPL554 matched placebo
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). pii: 1801074. doi: 10.1183/13993003.01074-2018. Print 2018 Nov.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 8, 2016)
36
Original Estimated Enrollment  ICMJE
 (submitted: September 3, 2015)
30
Actual Study Completion Date  ICMJE December 2015
Actual Primary Completion Date December 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02542254
Other Study ID Numbers  ICMJE RPL554-009-2015
2015-002536-41 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Verona Pharma plc
Study Sponsor  ICMJE Verona Pharma plc
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Dave Singh Medicines Evaluation Unit
PRS Account Verona Pharma plc
Verification Date September 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP