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Bronchodilator Effect of RPL554 Administered in Addition to Tiotropium/Olodaterol in Patients With COPD

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03673670
Recruitment Status : Completed
First Posted : September 17, 2018
Last Update Posted : March 12, 2019
Sponsor:
Information provided by (Responsible Party):
Verona Pharma plc

Tracking Information
First Submitted Date  ICMJE September 7, 2018
First Posted Date  ICMJE September 17, 2018
Last Update Posted Date March 12, 2019
Actual Study Start Date  ICMJE July 16, 2018
Actual Primary Completion Date November 13, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 14, 2018)
Peak FEV1 after morning dosing on Day 3 [ Time Frame: Pre-dose; 5, 15 and 30 minutes and 1, 1.5, 2, 4 on Day 3 (after the morning dose) ]
Maximum FEV1 in the 4 hours post-dose after the morning dose on Day 3
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03673670 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 14, 2018)
  • Trough FEV1 on Day 4 [ Time Frame: Pre-dose on Day 4 ]
    FEV1 in the morning on Day 4
  • Area under the curve (AUC)0-4h FEV1 after morning dosing on Day 3 [ Time Frame: Pre-dose; 5, 15 and 30 minutes and 1, 1.5, 2, 4 hours on Day 3 (after the morning dose) ]
    AUC over 4 hours after the morning dose on Day 3
  • Change from baseline in AUC0-12h on Day 3 [ Time Frame: Pre-dose; 5, 15 and 30 minutes and 1, 1.5, 2, 4, 6, 8, 12 hours on Day 3 (after the morning dose) ]
    Change from baseline in AUC over 12 hours after the morning dose on Day 3
  • Peak FEV1 on Day 1 [ Time Frame: Pre-dose; 5, 15 and 30 minutes and 1, 1.5, 2, 4 hours on Day 1 (after the morning dose) ]
    Maximum FEV1 in the 4 hours post dose after the morning dose on Day 1
  • Change from pre-evening dose FEV1 on Day 3 [ Time Frame: Pre-dose; 5, 15 and 30 minutes and 1, 1.5, 2, 4 hours on Day 3 (after the evening dose) ]
    Maximum FEV1 in the 4 hours post dose after the last dose of treatment in the evening on Day 3
  • AUC0-12h on Day 1 [ Time Frame: Pre-dose; 5, 15 and 30 minutes and 1, 1.5, 2, 4, 6, 8, 12 hours on Day 1 (after the morning dose) ]
    AUC over 12 hours after the morning dose on Day 1
  • Determination of onset of action on Day 1 [ Time Frame: Pre-dose; 5, 15 and 30 minutes and 1, 1.5, 2 hours on Day 1 (after the morning dose) ]
    Time to >10% increase in FEV1 from pre-first dose, censored at 2 hours
  • Residual volume [ Time Frame: Pre-dose, 1.25 hours on Day 1 and 1.25 hours, 8.25 hours and 12.25 hours on Day 3 (after the morning dose) ]
    Change in residual volume during treatment
  • Functional residual capacity [ Time Frame: Pre-dose, 1.25 hours on Day 1 and 1.25 hours, 8.25 hours and 12.25 hours on Day 3 (after the morning dose) ]
    Change in functional residual capacity during treatment
  • Specific airway conductance [ Time Frame: Pre-dose, 1.25 hours on Day 1and 1.25 hours, 8.25 hours and 12.25 hours on Day 3 (after the morning dose) ]
    Change in specific airway conductance during treatment
  • RPL554 steady state AUC [ Time Frame: Pre-dose, 5, 30 and 45 minutes and 1, 1.5, 2, 4, 8, and 12 hours on Day 3 (after the morning dose) ]
    AUC on Day 3
  • RPL554 steady state maximum concentration (Cmax) [ Time Frame: Pre-dose, 5, 30 and 45 minutes and 1, 1.5, 2, 4, 8, and 12 hours on Day 3 (after the morning dose) ]
    Cmax on Day 3
  • RPL554 steady state time to maximum concentration (Tmax) [ Time Frame: Pre-dose, 5, 30 and 45 minutes and 1, 1.5, 2, 4, 8, and 12 hours on Day 3 (after the morning dose) ]
    Tmax on Day 3
  • Adverse events [ Time Frame: From informed consent until 30 days after the follow-up visit ]
    Incidence of adverse events by system organ class and preferred term
  • Biochemistry [ Time Frame: 3 days ]
    Number of patients with out of range results
  • Hematology [ Time Frame: 3 days ]
    Number of patients with out of range results
  • Urinalysis [ Time Frame: 3 days ]
    Number of patients with out of range results
  • Blood pressure [ Time Frame: 3 days ]
    Change in systolic and diastolic blood pressure in each patient
  • AUC0-4h Pulse rate [ Time Frame: Pre-dose; 30 minutes and 1, 2, 4 hours on Days 1, 2 and 3 ]
    AUC pulse rate over 4 hours
  • QT interval corrected for heart rate using Fridericia's formula (QTcF) [ Time Frame: 3 days ]
    Change in QTcF in each patient
  • ECG heart rate [ Time Frame: 3 days ]
    Change in ECG heart rate in each patient
  • Holter monitoring [ Time Frame: 24 hours on Day 3 ]
    Changes in Holter monitoring results in each patient
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 Bronchodilator Effect of RPL554 Administered in Addition to Tiotropium/Olodaterol in Patients With COPD
Official Title  ICMJE A Phase II, Randomized, Double Blind, Placebo Controlled, Three-way Crossover Study to Assess the Bronchodilator Effect of RPL554 Administered in Addition to Open Label Tiotropium/Olodaterol in Patients With COPD
Brief Summary The study investigates the effect of 3 days of twice daily treatment of two different doses of RPL554 (a phosphodiesterase [PDE]3/4 inhibitor) or placebo, each administered in addition to once daily tiotropium/olodaterol (Respimat) in patients with moderate to severe chronic obstructive pulmonary disease (COPD). Patients will receive each of the three treatment combinations in a randomized sequence using a crossover design
Detailed Description

RPL554 is a dual inhibitor of phosphodiesterase 3 (PDE3) and phosphodiesterase 4 (PDE4) which are known to have a role in modulating the inflammatory airway response in respiratory diseases, including COPD. PDE3 inhibitors act as bronchodilators whilst PDE4 inhibitors have anti-inflammatory properties and there is also evidence to suggest that combined inhibition of PDE3 and PDE4 can have additive or synergistic anti-inflammatory and bronchodilator. The two doses of RPL554 (1.5 mg and 6 mg)have been selected based on the results from prior studies investigating single and multiple ascending doses in healthy subjects, single doses in asthmatics, single/multiple ascending doses in COPD patients, and 3 days of dosing in COPD patients. These doses were demonstrated to be both effective as a bronchodilator and well tolerated.

The purpose of the study is to investigate if RPL554 has an additive bronchodilator effect when administered in combination with a commonly used anticholinergic/β-agonist combination medication, tiotropium/olodaterol (Respimat), in this patient population measured by the peak forced expiratory volume in one second (FEV1), and forced vital capacity (FVC).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description:
The nebulizer cup will be obscured so the contents are not visible to the subject and the blinded study staff.
Primary Purpose: Treatment
Condition  ICMJE COPD
Intervention  ICMJE
  • Drug: RPL554 Suspension
    A PDE3/4 inhibitor
  • Drug: Placebo
    A placebo solution
  • Drug: Tiotropium/olodaterol (Respimat)
    An anticholinergic/β-agonist combination medication
Study Arms  ICMJE
  • Experimental: 1.5 mg RPL554 and tiotropium/olodaterol
    1.5 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily
    Interventions:
    • Drug: RPL554 Suspension
    • Drug: Tiotropium/olodaterol (Respimat)
  • Experimental: 6 mg RPL554 and tiotropium/olodaterol
    6 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily
    Interventions:
    • Drug: RPL554 Suspension
    • Drug: Tiotropium/olodaterol (Respimat)
  • Experimental: Placebo and tiotropium/olodaterol
    Placebo administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily
    Interventions:
    • Drug: Placebo
    • Drug: Tiotropium/olodaterol (Respimat)
Publications * Not Provided

*   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: March 9, 2019)
79
Original Estimated Enrollment  ICMJE
 (submitted: September 14, 2018)
70
Actual Study Completion Date  ICMJE November 13, 2018
Actual Primary Completion Date November 13, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Written informed consent
  2. Male or female aged 40 and 80 years
  3. For males, not to donate sperm and either be sexually abstinent or use contraception as specified by the protocol. For females, be of non-childbearing potential or use a highly effective form of contraception
  4. 12-lead ECG with heart rate between 45 and 90 beats per minute, QTcF ≤450 msec for males, and ≤ 470 msec for females, QRS interval ≤120 msec and no clinically significant abnormality including morphology
  5. Screening Holter report with a minimum of 18 hours recording that is able to be evaluated for rhythm analysis showing no abnormality which indicates a significant impairment of patient safety or which may significantly impair interpretation
  6. Capable of complying with all study restrictions and procedures including ability to use the study nebulizer and Respimat® correctly.
  7. Body mass index (BMI) between 18 and 36 kg/m2 and minimum weight of 45 kg.
  8. COPD diagnosis for at least 1 year and clinically stable COPD for 4 week
  9. Post-bronchodilator (two puffs of salbutamol/albuterol followed by two puffs of ipratropium) spirometry at Screening:

    • Post-bronchodilator FEV1/forced vital capacity (FVC) ratio of ≤0.70
    • Post-bronchodilator FEV1 ≥30 % and ≤70% of predicted normal
    • Demonstrates ≥150 mL increase from pre-bronchodilator FEV1
  10. A chest X-ray showing no abnormalities, which are both clinically significant and unrelated to COPD.

12. Meet the concomitant medication restrictions and be expected to do so for the rest of the study.

13. Current and former smokers with smoking history of ≥10 pack years. 14. Capable of withdrawing from long acting bronchodilators for the duration of the study, and short acting bronchodilators for 8 hours prior to dosing.

Exclusion Criteria:

  1. A history of life-threatening COPD including Intensive Care Unit admission and/or requiring intubation.
  2. COPD exacerbation requiring oral or parenteral steroids, or lower respiratory tract infection requiring antibiotics, in the last 3 months
  3. A history of one or more hospitalizations for COPD in the last 12 months
  4. Intolerance or hypersensitivity to tiotropium, olodaterol, atropine, ipratropium, or RPL554.
  5. Evidence of cor pulmonale or clinically significant pulmonary hypertension.
  6. Other respiratory disorders
  7. Previous lung resection or lung reduction surgery.
  8. Use of oral COPD medications, except mucolytics, in the last 3 months
  9. Pulmonary rehabilitation, unless such treatment has been stable in the last 4 weeks
  10. History of, or reason to believe a patient has, drug or alcohol abuse within the past 5 years.
  11. Inability to perform acceptable spirometry or whole body plethysmography
  12. Received an experimental drug within 30 days or five half lives, whichever is longer.
  13. Patients with uncontrolled disease that the Investigator believes are clinically significant. This includes any hepatic disease, or an alanine aminotransferase or aspartate aminotransferase>2 x upper limit of normal (ULN).
  14. Documented cardiovascular disease: arrhythmias, angina, recent (<1 year) or suspected myocardial infarction, congestive heart failure, unstable or uncontrolled hypertension, or diagnosis of hypertension in the last 3 months
  15. Use of non-selective oral β-blockers.
  16. Major surgery (requiring general anesthesia) in the last 6 weeks or will not have fully recovered from surgery, or planned surgery through the end of the study.
  17. A disclosed history or one known to the Investigator, of significant non compliance in previous investigational studies or with prescribed medications.
  18. Required use of oxygen therapy, even on an occasional basis.
  19. Symptomatic prostatic hyperplasia or bladder-neck obstruction or with narrow-angle glaucoma.
  20. History of malignancy of any organ system within 5 years, with the exception of localized skin cancers (basal or squamous cell).
  21. Clinically significant abnormal values for safety laboratory tests (hematology, biochemistry, virology or urinalysis) as determined by the Investigator
  22. Any other reason that the Investigator considers makes the patient unsuitable to participate.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years to 80 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,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03673670
Other Study ID Numbers  ICMJE RPL554-CO-204
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
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 March 2019

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