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Dose Ranging Study of RPL554 in Chronic Obstructive Pulmonary Disease (COPD) Patients

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ClinicalTrials.gov Identifier: NCT03443414
Recruitment Status : Completed
First Posted : February 23, 2018
Last Update Posted : May 8, 2018
Sponsor:
Information provided by (Responsible Party):
Verona Pharma plc

Brief Summary:
The study investigates the effect of 4 weeks of twice daily treatment of four different doses of RPL554 (a phosphodiesterase [PDE]3/4 inhibitor) or placebo in patients with moderate to severe COPD. Patients will be equally allocated to one of the five treatment options.

Condition or disease Intervention/treatment Phase
COPD Drug: RPL554 suspension Drug: Placebo Phase 2

Detailed Description:

RPL554 is a dual inhibitor of PDE3 and 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. PDE4 inhibitors (administered orally) have, however been associated with unfavorable gastrointestinal side effects such as nausea, emesis, diarrhea, abdominal pain, loss of appetite and weight loss. Dual PDE3/PDE4 inhibitors (administered by inhalation) have exhibited both bronchodilator and ant-inflammatory actions, with a more favorable side effect profile. It is plausible that increased efficacy with reduced side effects may be achievable with administration of a dual PDE3/4 inhibitor by the inhaled route compared to orally administered PDE3 or PDE4 inhibitors.

The purpose of this study is to investigate the dose response of RPL554 in patients with COPD over 4 weeks. This length of time should allow for study of the bronchodilator response, measured predominantly by the peak forced expired volume in one second (FEV1), and the anti-inflammatory response, as measured predominantly by trough FEV1.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 403 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Investigator, Outcomes Assessor)
Masking Description: The nebuliser cup will be obscured to prevent the Investigator or outcomes assessor so the contents are not visible to the Investigator our outcomes assessor. The visual appearance of the study medication will not be discussed with the subject
Primary Purpose: Treatment
Official Title: Phase IIb, Randomized, Double Blind, Placebo Controlled, Dose Ranging Study to Assess the Effect of RPL554 in Patients With Moderate to Severe COPD.
Actual Study Start Date : June 1, 2017
Actual Primary Completion Date : January 23, 2018
Actual Study Completion Date : February 7, 2018

Arm Intervention/treatment
Experimental: 0.75 mg RPL554 Drug: RPL554 suspension
A dual PDE3/PDE 4 inhibitor

Experimental: 1.5 mg RPL554 Drug: RPL554 suspension
A dual PDE3/PDE 4 inhibitor

Experimental: 3 mg RPL554 Drug: RPL554 suspension
A dual PDE3/PDE 4 inhibitor

Experimental: 6 mg RPL554 Drug: RPL554 suspension
A dual PDE3/PDE 4 inhibitor

Placebo Comparator: Placebo Drug: Placebo
Placebo solution




Primary Outcome Measures :
  1. Peak FEV1 change from baseline at end of treatment [ Time Frame: 4 weeks ]
    Maximum FEV1 in the 3 hours post-dose after 4 weeks of treatment


Secondary Outcome Measures :
  1. Trough FEV1 change from baseline at end of treatment [ Time Frame: 4 weeks ]
    Morning pre-dose FEV1 after 4 weeks of treatment

  2. Average FEV1 change from baseline over 12 hours [ Time Frame: 4 weeks ]
    Area under the curve (AUC) over 12 hours at the start of treatment and after 4 weeks treatment

  3. Peak FEV1 change from baseline over 3 hours at the start and end of treatment [ Time Frame: 4 weeks ]
    Maximum FEV1 over 3 hours at the start of treatment and after 4 weeks treatment

  4. Average FEV1 change from baseline over 3 hours at the start and end of treatment [ Time Frame: 4 weeks ]
    AUC FEV1 over 3 hours at the start of treatment and after 4 weeks treatment

  5. Change in COPD symptoms [ Time Frame: Daily for 4 weeks ]
    Change from baseline in COPD symptoms using The Exacerbations of Chronic Pulmonary Disease Tool Patient-Reported Outcome scoring

  6. Change in breathlessness using the St George's Respiratory Questionnaire-COPD specific [ Time Frame: After 2 and 4 weeks of treatment ]
    Change from baseline in breathlessness using the St George's Respiratory Questionnaire-COPD specific

  7. Change in breathlessness using Medical Research Council Questionnaire [ Time Frame: After 2 and 4 weeks of treatment ]
    Change from baseline in breathlessness using the Medical Research Council Questionnaire

  8. Severity of dyspnea [ Time Frame: After 2 and 4 weeks of treatment ]
    Assessment of dyspnea using the Traditional Dyspnea Index

  9. Patient assessment of change in breathing [ Time Frame: After 2 and 4 weeks of treatment ]
    Assessment of breathing compared to baseline using the Patient Global Assessment of Change Questionnaire

  10. Rescue medication use [ Time Frame: 4 weeks ]
    Change from baseline in albuterol/salbutamol use

  11. Adverse events [ Time Frame: 4 weeks ]
    Incidence of adverse events by system organ class and preferred term

  12. Biochemistry [ Time Frame: After 2 and 4 weeks of treatment ]
    Number of patients with out of range results

  13. Haematology [ Time Frame: After 2 and 4 weeks of treatment ]
    Number of patients with out of range results

  14. 12-lead electrocardiogram (ECG) [ Time Frame: Pre-dose and 2 hours after the first dose and after 1, 2, 3 and 4 weeks of treatment ]
  15. Vital signs [ Time Frame: Up to 12 hours post dose after the first dose and after 1, 2, 3 and 4 weeks of treatment ]
  16. Holter monitoring [ Time Frame: After 4 weeks of treatment ]


Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Provide informed consent
  • Male or female aged 40 to 75 years
  • Meeting specified contraception requirements
  • 12-lead ECG with heart rate 50-90 beats per minute, QT interval corrected using Fridericia's formula (QTcF) ≤450 msec (males) or ≤470 msec (females), QRS interval ≤120 msec, PR interval ≤200 msec and no clinically significant abnormalities
  • Capable of complying with all study restrictions and procedures, including ability to use the study nebulizer correctly.
  • Body mass index (BMI) 18 to 35 kg/m2 and minimum weight 45 kg.
  • COPD diagnosis with symptoms compatible with COPD for at least 1 year
  • Clinically stable COPD in the previous 4 weeks
  • Ability to perform acceptable and reproducible spirometry.
  • Post-bronchodilator spirometry at screening must demonstrate FEV1/forced vital capacity (FVC) ratio of ≤0.70 and FEV1 must be ≥40 % to ≤80% of predicted normal
  • Chest X-ray (posterior-anterior) at screening, or chest X-ray, magnetic resonance imaging (MRI) or computed tomography (CT) scan in the last 12 months, showing no abnormalities which are both clinically significant and unrelated to COPD.
  • Meet the concomitant medication restrictions and be expected to do so for the rest of the study.
  • Current and former smokers with a smoking history of ≥10 pack years.
  • Capable of withdrawing long acting bronchodilators until the end of the treatment period, and short acting bronchodilators for 8 hours prior to administration of study medication.

Exclusion Criteria:

  • A history of life-threatening COPD including Intensive Care Unit admission and requiring intubation.
  • COPD exacerbation requiring oral steroids in the previous 3 months
  • A history of one or more hospitalizations for COPD in the previous 6 months
  • Lower respiratory tract infection treated with antibiotics in the previous 3 months
  • Evidence of cor pulmonale or clinically significant pulmonary hypertension.
  • Patients with a current diagnosis of asthma, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, interstitial lung diseases, sleep apnea, known alpha-1 antitrypsin deficiency or other active pulmonary diseases.
  • Previous lung resection or lung reduction surgery.
  • Oral therapies for COPD (e.g. oral steroids, theophylline, and roflumilast) in the previous 3 months and throughout the study.
  • Pulmonary rehabilitation, unless such treatment has been stable from 4 weeks prior to Visit 1) and remains stable during the trial.
  • A history of, or reason to believe a subject has, drug or alcohol abuse in the previous 3 years.
  • Received an experimental drug within 30 days or five half-lives of the first dose
  • Prior exposure to RPL554.
  • Women who are pregnant or breast-feeding.
  • Patients with a history of current uncontrolled disease that the Investigator believes are clinically significant.
  • myocardial infarction in the previous 6 month; congestive heart failure, a history of unstable or uncontrolled hypertension, or has been diagnosed with hypertension in last 3 months.
  • Use of oral beta blockers.
  • Major surgery (requiring general anesthesia) in the previous 6 weeks, lack of full recovery from surgery at screening, or planned surgery through the end of the study.
  • History of malignancy of any organ system within 5 years, with the exception of localized skin cancers (basal or squamous cell).
  • Clinically significant abnormal values for safety laboratory tests
  • Significant non-compliance in previous investigational studies or with prescribed medications.
  • Requirement for oxygen therapy, even on an occasional basis.
  • Known hypersensitivity to RPL554 or its excipients/components.
  • Abnormal clinically significant 12 lead Holter findings,
  • Any other reason that the Investigator considers makes the subject 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): NCT03443414


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Sponsors and Collaborators
Verona Pharma plc

Responsible Party: Verona Pharma plc
ClinicalTrials.gov Identifier: NCT03443414     History of Changes
Other Study ID Numbers: RPL554-CO-203
First Posted: February 23, 2018    Key Record Dates
Last Update Posted: May 8, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Verona Pharma plc:
COPD, bronchodilation, FEV1

Additional relevant MeSH terms:
Pulmonary Disease, Chronic Obstructive
Lung Diseases, Obstructive
Lung Diseases
Respiratory Tract Diseases