| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Obstructive Pulmonary Disease (COPD) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Obstructive Pulmonary Disease (COPD) |
|
| 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 | PT |
| E.1.2 | Classification code | 10009033 |
| E.1.2 | Term | Chronic obstructive pulmonary disease |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| 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 effect on peak forced expired volume in 1 second (FEV1) (measured in the first 4 hours after dosing) of nebulised RPL554 dosed twice daily for 3 days, as compared to placebo, when administered in addition to once daily tiotropium/olodaterol. The peak FEV1 is measured after the morning dose on Day 3.) |
|
| E.2.2 | Secondary objectives of the trial |
Secondary
assess bronchodilator effect peak FEV1 & average FEV1 over 12h nebulised RPL554 vs placebo + tiotropium/olodaterol after 1st dose
investigate
effect of 2xday doses RPL554 vs placebo + tiotropium/olodaterol on morning trough FEV1 on Day4
effect of 2xday doses RPL554 vs placebo + tiotropium/olodaterol on average FEV1 over 4 & 12hrs after Day3 morning dose
assess bronchodilator effect on peak FEV1 within 4h after RPL554 evening dose on Day3
analyse plasma concentrations & assess pharmacokinetics RPL554 + tiotropium/olodaterol
assess tolerability & safety of 2xday doses RPL554 + tiotropium/olodaterol
determine onset action RPL554 after 1st dose + tiotropium/olodaterol
investigate effects RPL554 on specific airway conductance & lung volumes + tiotropium/olodaterol
Exploratory
assess dose response RPL554 peak & average Day3 & morning trough FEV1 Day4 + tiotropium/olodaterol
examine effect RPL554 on average FEV1 over 24h after 3 days dosing + tiotropium/olodaterol |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Male or female aged between 40 and 80 years inclusive, at the time of informed consent.
Must agree to meet the following from the first dose up to 1 month after the last dose of study medication:
If male
• 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 reliable form of contraception must also be used (e.g. diaphragm/cap with spermicide, established hormonal contraception, intra-uterine device)
If female: be of non-childbearing potential or use a highly effective form of contraception as defined in Section 14.1.
4. Have a 12-lead ECG recording at Screening and pre-dose in Treatment Period 1 showing the following:
• Heart rate between 45 and 90 beats per minute
• QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≤450 msec for males, and ≤ 470 msec for females
• QRS interval ≤120 msec
• No clinically significant abnormality including morphology (e.g. left bundle branch block, atrio-ventricular nodal dysfunction, ST segment abnormalities consistent with ischemia)
5. Have a 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, 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
6. Capable of complying with all study restrictions and procedures including ability to use the study nebuliser and Respimat® correctly.
7. Body mass index (BMI) between 18 and 36 kg/m2 (inclusive) with a minimum weight of 45 kg.
8. 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.
9. Post-bronchodilator (two puffs of salbutamol/albuterol followed by two puffs of ipratropium) spirometry at Screening:
• Post-bronchodilator FEV1/FVC ratio of ≤0.70
• Post-bronchodilator FEV1 ≥30 % and ≤70% of predicted normal
• Demonstrates ≥150 mL increase from pre-bronchodilator FEV1
10. Clinically stable COPD in the 4 weeks prior to Screening and Randomisation (pre-dose in Treatment Period 1).
11. A chest X-ray (posterior-anterior) at Screening, or in the 12 months prior to Screening 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. |
|
| E.4 | Principal exclusion criteria |
. 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 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. Intolerance or hypersensitivity to tiotropium, olodaterol, atropine, ipratropium, or RPL554.
5. Evidence of cor pulmonale or clinically significant pulmonary hypertension.
6. 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.
7. Previous lung resection or lung reduction surgery.
8. Use of oral COPD medications, except mucolytics, in the 3 months prior to Screening or Randomisation.
9. Pulmonary rehabilitation, unless such treatment has been stable from 4 weeks prior to Screening and remains stable during the study.
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 (at Screening or pre-dose in Treatment Period 1).
12. Received an experimental drug within 30 days or five half-lives, whichever is longer.
13. Patients with uncontrolled disease including, but not limited to, endocrine, active hyperthyroidism, neurological, hepatic, gastrointestinal, renal, haematological, urological, immunological, psychiatric, or ophthalmic diseases that the Investigator believes are clinically significant. This includes any hepatic disease, or an alanine aminotransferase or aspartate aminotransferase>2 x 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 3 months prior to Screening or Randomisation.
15. Use of non-selective oral β-blockers.
16. 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.
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 (haematology, biochemistry, virology or urinalysis) at Screening, as determined by the Investigator.
22. Any other reason that the Investigator considers makes the patient unsuitable to participate. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is peak FEV1 (measured in first 4 hours after morning dosing). This will be measured after dosing on Day 3.
The primary comparisons are RPL554 6mg + tiotropium/olodaterol vs RPL554 placebo + tiotropium/olodaterol, followed by RPL554 1.5 mg + tiotropium/olodaterol vs RPL554 placebo + tiotropium/olodaterol.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints
• Change from baseline in trough FEV1 on Day 4 (mean of -1 and 0 time prior to dosing)
• Determination of AUC0-4h FEV1 after morning dosing on Day 3
• Peak FEV1 (measured in first 4 hours after dosing) and AUC0-12h FEV1. These will be measured after dosing on Day 1
• Change from baseline in AUC0-12h FEV1 measured on Day 3
• Change from pre-evening dose FEV1 on Day 3 (peak over 4 hours)
• Determination of onset of action (>10% increase in FEV1, from pre-first dose, censored at 120 minutes) on Day 1
• RV, FRC and sGaw at 1.25 hours on Day 1 and 1.25, 8.25 and 12.25 hours after dosing on Day 3
• RPL554 steady state pharmacokinetics (AUC, Cmax, time to maximum concentration [tmax])
• Safety and tolerability:
− Continuous monitoring of adverse events
− Laboratory safety tests [haematology, biochemistry and urinalysis]
− 12-lead ECG (including QTcF and heart rate), supine vital signs [blood pressure and pulse rate]
− Peak (measured in first 4 hours after dosing) and AUC0-4h pulse rate for each treatment period.
− Holter monitor results
Exploratory Endpoints
• AUC0-24h FEV1 on Day 3
• Change from baseline in Likert dyspnoea scale |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Baseline through to Day 4
Day 1 |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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) | No |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| 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 | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United Kingdom |
| United States |
|
| 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
|
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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