| 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 |
| COPD (a smoking related disease of the airways resulting in difficulty breathing) |
|
| 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 | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010952 |
| E.1.2 | Term | COPD |
| E.1.2 | System Organ Class | 100000004855 |
|
| 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 lung function over 8 hours of single nebulised doses of RPL554, as compared to placebo (dummy drug containing no active ingredient), when administered in addition to standard care bronchodilators (salbutamol, ipratropium) or placebo. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
- To investigate the bronchodilator (opening of the airways) effect on lung function over 4, 6 and 12 hours of single nebulised doses of RPL554, as compared to placebo (dummy drug containing no active ingredient), when administered in addition to standard care bronchodilators (salbutamol, ipratropium) or placebo.
- To investigate the effect of single nebulised doses of RPL554 on lung volumes, as compared to placebo, when administered in addition to standard care bronchodilators (salbutamol, ipratropium) or placebo.
- To perform an assessment of the pharmacokinetics (levels of study drug in the blood) of RPL554 when administered in combination with standard care bronchodilators compared to RPL554 alone.
- To assess the tolerability and safety of single nebulised doses of RPL554 in combination with standard care bronchodilators (salbutamol, ipratropium) compared with salbutamol, ipratropium or RPL554 alone.
Exploratory Objectives:
- To compare the amount of |
|
| 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 70 years inclusive, at the time of informed consent.
3.If male: must be willing, able and 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 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 defined as being:
Either: postmenopausal (being spontaneously amenorrhoeic for at least 1 year with an appropriate clinical profile [e.g. age appropriate, history of vasomotor symptoms]. However, if indicated, this should be confirmed by follicle stimulating hormone levels consistent with postmenopausal status [according to local laboratory ranges]) Or: Permanently sterilised e.g. tubal occlusion, hysterectomy, bilateral oophorectomy, bilateral salpingectomy.
4.Have a 12-lead ECG recording at screening (Visit 1) and Visit 2 pre-dose 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
•QRS interval ≤120 msec
•PR interval ≤220 msec
•No clinically significant abnormality including morphology (e.g. left bundle branch block, atrio-ventricular nodal dysfunction, ST segment abnormalities)
5.Capable of complying with all study restrictions and procedures including ability to use the study nebuliser correctly.
6.Body mass index (BMI) between 18 and 33 kg/m2 (inclusive) with a minimum weight of 45 kg.
7.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 (Visit 1).
8.Post-bronchodilator (two puffs of salbutamol followed by two puffs of ipratropium) spirometry at screening (Visit 1):
The following must be confirmed at 1 hour post-dose for inclusion:
•Post-bronchodilator FEV1/FVC ratio of ≤0.70
•Post-bronchodilator FEV1 ≥40 % and ≤80% of predicted normal
The following must be confirmed at either 30 minutes or 1 hour post-dose for inclusion:
•Demonstrates ≥150 mL increase from pre-bronchodilator FEV1
9.Clinically stable COPD in the 4 weeks prior to screening (Visit 1) and randomisation (Visit 2).
10.A chest X-ray (post-anterior [PA]) at screening, or in the 12 months prior to screening showing no abnormalities, which are both clinically significant and unrelated to COPD.
11.Meet the concomitant medication restrictions and be expected to do so for the rest of the study.
12.Smoking history of ≥10 pack years.
13.Capable of withdrawing from long acting bronchodilators, as defined in Section 5.9, until the end of the treatment period , and short acting bronchodilators for 8 hours prior to administration of study treatment. |
|
| E.4 | Principal exclusion criteria |
1.A history of life-threatening COPD including Intensive Care Unit admission and/or requiring intubation.
2.COPD exacerbation requiring oral steroids in the 3 months prior to screening (Visit 1) or prior to randomisation (Visit 2).
3.A history of one or more hospitalisations for COPD in the 12 months prior to screening (Visit 1).
4.Respiratory tract infection (both upper and lower) treated with antibiotics within 12 weeks of screening (Visit 1) or prior to randomisation (Visit 2).
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.Oral therapies for COPD (e.g. oral steroids, theophylline, and roflumilast) in the 3 months prior to screening (Visit 1) and throughout the study.
9.History of, or reason to believe a subject has, drug or alcohol abuse within the past 3 years.
10.Received an experimental drug within 3 months or five half-lives, whichever is longer.
11.Prior exposure to RPL554
12.Patients with a history of chronic uncontrolled disease including, but not limited to, cardiovascular (including arrhythmias), endocrine, active hyperthyroidism, neurological, hepatic, gastrointestinal, renal, haematological, urological, immunological, or ophthalmic diseases that the Investigator believes are clinically significant.
13.Documented cardiovascular disease: angina, recent or suspected myocardial infarction, congestive heart failure, a history of unstable, or uncontrolled hypertension, or has been diagnosed with hypertension in the last 3 months.
14.Has had major surgery, (requiring general anaesthesia) in the 6 weeks prior to screening (Visit 1), or will not have fully recovered from surgery, or planned surgery through the end of the study.
15.History of malignancy of any organ system within 5 years with the exception of localised skin cancers (basal or squamous cell)
16.Clinically significant abnormal values for safety laboratory tests (haematology, biochemistry or urinalysis) at screening (Visit 1), as determined by the Investigator.
17.A disclosed history, or one known to the Investigator, of significant non-compliance in previous investigational studies or with prescribed medications.
18.Requires oxygen therapy, even on an occasional basis.
19.Inability to adequately perform whole body plethysmography.
20.Any other reason that the Investigator considers makes the subject unsuitable to participate.
21.Patients with known hypersensitivity to atropine or its derivatives, or to ipratropium bromide or its excipients.
22.Patients with known hypersensitivity to salbutamol or its excipients.
23.Patients with known hypersensitivity to RPL554 or its excipients/components. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Peak and AUC FEV1 over 8 hours.
The primary comparisons are RPL554 + salbutamol versus placebo + salbutamol and RPL554 + ipratropium versus placebo + ipratropium. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Treatment visits (Visits 2-7): Pre-dose (2 assessments), 5, 15, 30 mins, 1, 2, 4, 6 & 8 hours post-dose. |
|
| E.5.2 | Secondary end point(s) |
(1) AUC FEV1 over 4, 6 and 12 hours
(2) Determination of onset of action
(3) Determination of duration of action
(4) TGV (FRC), RV, RV/TLC, sGaw at 1 and 4 hours after dosing
(5) RPL554 pharmacokinetics (AUC, Cmax, tmax,)
(6) Safety and tolerability:
(6.1)- Continuous monitoring of adverse events
(6.2)- Laboratory safety tests [haematology, biochemistry and urinalysis]
(6.3)- 12-lead ECG (including QTcF and heart rate), supine vital signs [blood pressure and pulse rate] over 12 hours |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
(1) (Visits 2-7) Pre-dose(2 assessments), 5, 15, 30 mins, 1, 2, 4, 6, 8, 12 hours post-dose.
(2) (Visits 2-7) Post-dose
(3) (Visits 2-7) Post-dose
(4) (Visits 2-7) Pre-dose, 1 & 4 hours post-dose.
(5) (Visits 2-7) Pre-dose, 15, 30 mins, 1, 2, 4, 6, 8 & 12 hours post-dose.
(6.1) - Screening to follow-up (EOS)
(6.2) - Screening & End of study.
(6.3) - (Visits 2-7) Pre-dose, 1, 2,4 & 12 hours post-dose. |
|
| 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 | 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 | 6 |
| 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
|
| The end of the study is defined as the date of the last end of study visit of the last patient in the study. |
|
| 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 | 15 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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