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The Effects of RPL554 in Addition to Tiotropium in COPD Patients

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ClinicalTrials.gov Identifier: NCT03028142
Recruitment Status : Completed
First Posted : January 23, 2017
Results First Posted : January 23, 2019
Last Update Posted : February 27, 2019
Sponsor:
Information provided by (Responsible Party):
Verona Pharma plc

Brief Summary:
This is a phase II, randomised, double blind, placebo controlled, complete block, three way crossover study to investigate treatment with nebulised RPL554 and tiotropium together in patients with moderate to severe chronic obstructive pulmonary disease (COPD). The purpose of this study is to assess the bronchodilator effect (opening of the airways) of RPL554 when used in combination with a long acting anti-muscarinic receptor antagonist (tiotropium) whilst dosing the RPL554 to steady state blood levels. It is planned to randomise up to 30 patients to have 24 evaluable patients at one study centre. In each treatment period, patients will receive an open label dose of tiotropium from a dry power inhaler (DPI) followed immediately by a double blind dose of either RPL554 6mg, 1.5mg or placebo (depending on treatment sequence) from a nebuliser in the morning on Day 1, Day 2 and Day 3. The dose of RPL554 or placebo will be repeated in the evening on Day 1 and Day 2; there will not be an evening dose on Day 3.

Condition or disease Intervention/treatment Phase
Chronic Obstructive Pulmonary Disease Moderate Drug: 1.5 mg RPL554 plus tiotropium Drug: 6 mg RPL554 plus tiotropium Drug: Placebo plus tiotropium Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Study Start Date : January 2017
Actual Primary Completion Date : August 2017
Actual Study Completion Date : August 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Lower Dose Nebulised Treatment
1.5 mg nebulised RPL554 twice daily plus 10 mcg tiotropium DPI once daily for 3 days
Drug: 1.5 mg RPL554 plus tiotropium
Experimental: Higher Dose Nebulised Treatment
6 mg nebulised RPL554 twice daily plus 10 mcg tiotropium DPI once daily for 3 days
Drug: 6 mg RPL554 plus tiotropium
Placebo Comparator: Placebo
Nebulised RPL554 matched placebo twice daily plus 10 mcg tiotropium DPI once daily for 3 days
Drug: Placebo plus tiotropium



Primary Outcome Measures :
  1. Peak Forced Expired Volume in 1 Second (FEV1) on the Third Day of Dosing [ Time Frame: Day 3 ]
    Peak forced expired volume in 1 second (FEV1) over 4 hours on the third day of dosing

  2. Average FEV1 Over 12 Hours on the Third Day of Dosing [ Time Frame: Day 3 ]
    Average FEV1 area under the curve (AUC) over 12 hours on the third day of dosing


Secondary Outcome Measures :
  1. Peak FEV1 on Day 1 [ Time Frame: Day 1 ]
    Peak FEV1 over 4 hours on Day 1

  2. Average FEV1 Over 12 Hours on Day 1 [ Time Frame: Day 1 ]
    Average FEV1 AUC over 12 hours on Day 1



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:

  1. Sign an informed consent document indicating they understand the purpose of and procedures required for the study and are willing to participate in the study.
  2. Male or female aged between 40 and 75 years inclusive, at the time of informed consent.
  3. If male: must agree to meet the following from the first dose up to 1 month after the last dose of study treatment:

    • Not donate sperm
    • Either: be sexually abstinent in accordance with a patient's usual and preferred lifestyle (but agree to abide by the contraception requirements below should their circumstances change) Or: use a condom with all sexual partners. If the partner is of childbearing potential the condom must be used with spermicide and a second highly effective form of contraception must also be used
  4. If female: either be:

    1. Of non-childbearing potential defined as being:

      • Either: post-menopausal (being spontaneously amenorrhoeic for at least 1 year with an appropriate clinical profile [e.g. age appropriate, history of vasomotor symptoms]
      • Or: permanently sterilised e.g. tubal occlusion, hysterectomy, bilateral oophorectomy, bilateral salpingectomy
    2. Of childbearing potential and agreeing to use a highly effective method of contraception until completion of the end of study visit.
  5. Have a 12-lead ECG recording at screening and randomisation (pre-dose in Treatment Period 1) showing the following:

    • Heart rate between 45 and 90 beats per minute (bpm)
    • QT interval corrected for heart rate using Fridericia's formula (QTcF) ≤450 msec for males and ≤470 ms for females
    • QRS interval ≤120 msec
    • No clinically significant abnormalities (as judged by the Investigator) including morphology (e.g. left bundle branch block, atrio-ventricular nodal dysfunction, ST segment abnormalities)
  6. Have a screening Holter report with a minimum of 18 hours recording that is able to be evaluated for rhythm analysis which shows no abnormality which indicates a significant impairment of patient safety or which may significantly impairs interpretation in the opinion of the Investigator including:

    • Significant arrhythmias including atrial flutter, atrial fibrillation, ventricular tachycardia
    • Any symptomatic arrhythmia (except isolated extra systoles)
    • Any sustained second or third degree heart block
  7. Capable of complying with all study restrictions and procedures including ability to use the study nebuliser and HandiHaler® DPI correctly.
  8. Body mass index (BMI) between 18 and 33 kg/m2 (inclusive) with a minimum weight of 45 kg.
  9. COPD diagnosis: Patients with a diagnosis of COPD as defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines (Celli and MacNee, 2004) with symptoms compatible with COPD for at least 1 year prior to screening.
  10. Post-bronchodilator (four puffs of salbutamol) spirometry at screening:

    • Post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio of ≤0.70
    • Post-bronchodilator FEV1 ≥40 % and ≤80% of predicted normal
    • Demonstrates ≥150 mL increase from pre-bronchodilator FEV1
  11. Clinically stable COPD in the 4 weeks prior to screening and randomisation (pre-dose in Treatment Period 1).
  12. A chest X-ray (post-anterior) at screening, or in the 12 months prior to screening showing no abnormalities, which are both clinically significant and unrelated to COPD.
  13. Meet the concomitant medication restrictions and be expected to do so for the rest of the study.
  14. Smoking history of ≥10 pack years.
  15. Capable of withdrawing from long acting bronchodilators for the duration of the study, and short acting bronchodilators for 8 hours prior to spirometry.

Exclusion Criteria:

  1. A history of life-threatening COPD exacerbation including Intensive Care Unit admission and/or requiring intubation.
  2. COPD exacerbation requiring oral steroids, or lower respiratory tract infection requiring antibiotics, in the 3 months prior to screening or randomisation (pre-dose in Treatment Period 1).
  3. A history of one or more hospitalisations for COPD in the 12 months prior to screening or randomisation (pre-dose in Treatment Period 1).
  4. Lactation (female patients only).
  5. Positive urine or serum pregnancy test at screening, or a positive urine pregnancy test prior to randomisation (female patients of childbearing potential only).
  6. Prior exposure to RPL554 or known hypersensitivity to RPL554 or its components.
  7. Intolerance or hypersensitivity to tiotropium.
  8. Evidence of cor pulmonale.
  9. Other respiratory disorders: Patients with a current diagnosis of asthma, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, interstitial lung diseases, sleep apnoea, known alpha-1 antitrypsin deficiency or other active pulmonary diseases.
  10. Previous lung resection or lung reduction surgery.
  11. Use of oral COPD medications (e.g. oral steroids, theophylline and romifulast) in the 3 months prior to screening or randomisation (pre-dose in Treatment Period 1).
  12. History of, or reason to believe, a patient has drug or alcohol abuse within the past 3 years.
  13. Inability to perform technically acceptable spirometry or whole body plethysmography (at screening or randomisation [pre dose in Treatment Period 1])
  14. Received an experimental drug within 30 days or five half lives, whichever is longer.
  15. Patients with a history of chronic uncontrolled disease including, but not limited to, endocrine, active hyperthyroidism, neurological, hepatic, gastrointestinal, renal, haematological, urological, immunological, or ophthalmic diseases that the Investigator believes are clinically significant.
  16. Documented cardiovascular disease: arrhythmias, angina, recent or suspected myocardial infarction, congestive heart failure, a history of unstable, or uncontrolled hypertension, or has been diagnosed with hypertension in the 3 months prior to screening or randomisation.
  17. Concurrent use of non-cardioselective oral beta-blockers.
  18. Has had major surgery, (requiring general anaesthesia) in the 6 weeks prior to screening or randomisation (pre-dose in Treatment Period 1), or will not have fully recovered from surgery, or planned surgery through the end of the study.
  19. A disclosed history or one known to the Investigator, of significant non compliance in previous investigational studies or with prescribed medications.
  20. Requires oxygen therapy, even on an occasional basis.
  21. Clinically significant prostatic hyperplasia (judged by the Investigator) or bladder-neck obstruction or with narrow-angle glaucoma.
  22. Any other reason that the Investigator considers makes the patient unsuitable to participate.
  Study Documents (Full-Text)

Documents provided by Verona Pharma plc:
Study Protocol  [PDF] April 26, 2017
Statistical Analysis Plan  [PDF] September 19, 2017

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Verona Pharma plc
ClinicalTrials.gov Identifier: NCT03028142    
Other Study ID Numbers: RPL554-CO-202
First Posted: January 23, 2017    Key Record Dates
Results First Posted: January 23, 2019
Last Update Posted: February 27, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Lung Diseases, Obstructive
Pulmonary Disease, Chronic Obstructive
Lung Diseases
Respiratory Tract Diseases
Tiotropium Bromide
Bronchodilator Agents
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