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

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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

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

Condition or disease Intervention/treatment Phase
COPD Drug: RPL554 Suspension Drug: Placebo Drug: Tiotropium/olodaterol (Respimat) Phase 2

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).


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 79 participants
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
Official Title: 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
Actual Study Start Date : July 16, 2018
Actual Primary Completion Date : November 13, 2018
Actual Study Completion Date : November 13, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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
Drug: RPL554 Suspension
A PDE3/4 inhibitor

Drug: Tiotropium/olodaterol (Respimat)
An anticholinergic/β-agonist combination medication

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
Drug: RPL554 Suspension
A PDE3/4 inhibitor

Drug: Tiotropium/olodaterol (Respimat)
An anticholinergic/β-agonist combination medication

Experimental: Placebo and tiotropium/olodaterol
Placebo administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily
Drug: Placebo
A placebo solution

Drug: Tiotropium/olodaterol (Respimat)
An anticholinergic/β-agonist combination medication




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. Trough FEV1 on Day 4 [ Time Frame: Pre-dose on Day 4 ]
    FEV1 in the morning on Day 4

  2. 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

  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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. Biochemistry [ Time Frame: 3 days ]
    Number of patients with out of range results

  16. Hematology [ Time Frame: 3 days ]
    Number of patients with out of range results

  17. Urinalysis [ Time Frame: 3 days ]
    Number of patients with out of range results

  18. Blood pressure [ Time Frame: 3 days ]
    Change in systolic and diastolic blood pressure in each patient

  19. 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

  20. QT interval corrected for heart rate using Fridericia's formula (QTcF) [ Time Frame: 3 days ]
    Change in QTcF in each patient

  21. ECG heart rate [ Time Frame: 3 days ]
    Change in ECG heart rate in each patient

  22. Holter monitoring [ Time Frame: 24 hours on Day 3 ]
    Changes in Holter monitoring results in each patient



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   40 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03673670


Locations
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United States, Florida
Clinical Site Partners, LLC
Winter Park, Florida, United States, 32789
United States, South Carolina
Allied Biomedical Research Holdings, d/b/a Vitalink Research
Greenville, South Carolina, United States, 29615
United Kingdom
Respiratory Clinical Trials LTD,
London, United Kingdom, W1G8HU
Medicines Evaluation Unit
Manchester, United Kingdom, M23 9QZ
Sponsors and Collaborators
Verona Pharma plc
Investigators
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Principal Investigator: Dave Singh Medicines Evaluation Unit

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Responsible Party: Verona Pharma plc
ClinicalTrials.gov Identifier: NCT03673670     History of Changes
Other Study ID Numbers: RPL554-CO-204
First Posted: September 17, 2018    Key Record Dates
Last Update Posted: March 12, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Verona Pharma plc:
COPD
Bronchodilation
FEV1

Additional relevant MeSH terms:
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Tiotropium Bromide
Bronchodilator Agents
Olodaterol
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Parasympatholytics
Cholinergic Antagonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action