E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic obstructive pulmonary disease (COPD) |
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E.1.1.1 | Medical condition in easily understood language |
COPD (a smoking related disease of the airways resulting in difficulty breathing) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10010952 |
E.1.2 | Term | COPD |
E.1.2 | System Organ Class | 100000004855 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To investigate the bronchodilator (opening of the airways) effect on peak FEV1 (lung function) measured in first 4 hours after dosing and average FEV1 (lung function) over 12 hours of nebulised RPL554, dosed twice daily for 3 days (five total doses), as compared to placebo (dummy drug containing no active ingredient), when administered in addition to once daily tiotropium. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives: • To investigate the effect of twice daily nebulised doses of RPL554, as compared to placebo (dummy drug containing no active ingredient), when administered in addition to tiotropium on lung volumes • To assess the bronchodilator (opening of the airways) effect on peak FEV1 (lung volumes) (measured in first 4 hours after dosing) and average (measured as the area under the curve [AUC]) FEV1 over 12 hours of nebulised RPL554 after the first dose as compared to placebo, when administered in addition to tiotropium • To analyse plasma concentrations and assess the steady state pharmacokinetics (levels of study drug in the blood) of RPL554 when administered in addition to tiotropium • To assess the tolerability and safety of twice daily nebulised doses of RPL554 in addition to tiotropium • To assess the dose response of two different doses of RPL554 on peak, average (0 to 12 hours), and morning trough FEV1 on Day 3 when dosed in addition to tiotropium • To determine the |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 2 months 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 (as defined in Section 8.4) 4. If female: either be: a) 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 b) Of childbearing potential and agreeing to use a highly effective method of contraception (as defined in protocol section 8.4) 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 FEV1/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. |
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E.4 | Principal 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. 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Peak FEV1 (measured in first 4 hours after dosing) and AUC0-12h FEV1. These will be measured after dosing on Day 3.
The primary comparisons are RPL554 6mg + tiotropium vs RPL554 placebo + tiotropium, followed by RPL554 1.5 mg + tiotropium vs RPL554 placebo + tiotropium. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Treatment Period 1, 2 and 3 (Day 3): Pre-dose and post-dose at 5, 15 and 30 minutes and 1, 1.5, 2, 4, 6, 8 and 12 hours. |
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E.5.2 | Secondary end point(s) |
1. Determination of AUC0-4h FEV1 after morning dosing 2. Peak FEV1 (measured in first 4 hours after dosing) and AUC0-12h FEV1. These will be measured after dosing on Day 1. 3. Determination of onset of action (>10% increase in FEV1, from pre-first dose, censored at 120 minutes) on Day 1 4. RV, FRC and sGaw at 1.25 hours after dosing on Day 2 5. RPL554 steady state pharmacokinetics (AUC, Cmax, time to maximum concentration [tmax], half-life) Safety and tolerability: 6a. Continuous monitoring of adverse events 6b. Laboratory safety tests [haematology, biochemistry and urinalysis] 6c. 12-lead ECG (including QTcF and heart rate), supine vital signs [blood pressure and pulse rate] 6d. Peak (measured in first 4 hours after dosing) and AUC0-4h pulse rate for each treatment period. 6e. Holter monitor results Exploratory Endpoints: 7a. AUC0-24h FEV1 on Day 3 7b. Pre-dose FEV1 on Day 3 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Day 1 pre AM dose,5,15,30mins,1,1.5,2,4hrs post AM dose.Day 2 pre AM dose,15,30mins,1,2,3,4hrs post AM dose.Day 3 pre-dose,5,15,30mins,1,1.5,2,4hrs post dose 2. Day 1 pre AM dose,5,15,30mins,1,1.5,2,4,6,8,12hrs post AM dose 3. Day 1 pre AM dose,5,15,30mins,1,1.5,2hrs post AM dose 4. Day 2 pre AM dose,1.25hrs post AM dose 5. Day 3 pre-dose,5,30,45mins,1,1.5,2,4,8,12,15,24hrs post dose 6a. Throughout 6b. Screen,Day 4,EOS 6c. Screen,Day 1-3 pre AM dose,Day 1;30mins,1,2,4,6,8,12hrs post dose,Day 2;30mins,1,2,3,4,12hrs post dose,Day 3;30mins,1,2,4,6,8,24hrs post dose,EOS 6d. Day 1;30mins,1,2,4hrs post dose, Day 2;30mins,1,2,3,4hrs post dose,Day 3;30 mins,1,2,4hrs post dose 6e. Screen,Day 2-3 (24hrs) 7a. Day 3;pre-dose,5,15,30mins,1,1.5,2,4,6,8,12,15,24 hrs 7b. Day 3 pre-dose |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the study is defined as the date of the last end of study visit of the last patient in the study. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 9 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 9 |