E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cystic Fibrosis (CF) |
Zystische Fibrose |
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E.1.1.1 | Medical condition in easily understood language |
Cystic Fibrosis (Genetic disorder that affects mostly the lungs but also the pancreas, liver, kidneys, and intestine.) |
Zystische Fibrose (Erbliche Erkrankung, die hauptsächlich die Lunge betrifft, aber auch die Bauchspeicheldrüse, Leber, Nieren und den Darm.) |
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E.1.1.2 | Therapeutic area | Body processes [G] - Genetic Phenomena [G05] |
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 | 10011762 |
E.1.2 | Term | Cystic fibrosis |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To investigate pharmacokinetics of single nebulised doses of RPL554 in patients with Cystic Fibrosis. |
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E.2.2 | Secondary objectives of the trial |
- To investigate the bronchodilator effect on peak forced expiratory volume in 1 second after single nebulised doses of RPL554 as compared to placebo. - To investigate the bronchodilator effect on area under the curve forced expiratory volume in 1 second over 4, 6 and 8 hours of single nebulised doses of RPL554, as compared to placebo. - To assess the tolerability and safety of single nebulised doses of RPL554 in patients with Cystic Fibrosis. Exploratory Objective: - To examine the anti-inflammatory effects of single nebulised doses of RPL554 in patients with Cystic Fibrosis. |
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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 ≥18 years at the time of informed consent. Females of childbearing potential must have been using a consistent and reliable form of contraception (see protocol appendix 1) from the last menses before the first study treatment administration, and must commit to continue to do so during the study and for 3 months after the last dose of study treatment. 3. Have a 12-lead ECG recording at screening (Visit 1) and Visit 2 pre-dose showing the following: - Heart rate between 45 and 100 beats per minute - QT interval corrected for heart rate using Fridericia’s formula (QTcF) interval ≤450 msec - QRS interval ≤120 msec - PR Interval ≤220 msec - No clinically significant abnormality including morphology (e.g. left bundle branch block, atrioventricular nodal dysfunction, ST segment abnormalities) 4. Capable of complying with all study restrictions and procedures including ability to use the study nebuliser correctly. 5. Body mass index (BMI) between 18 and 30 kg/m2 (inclusive) with a minimum weight of 40 kg. 6. Patients with a genetic diagnosis of CF. 7. Spirometry at screening demonstrating an FEV1 ≥40% and ≤80% of predicted normal. 8. Capable of withdrawing from long acting bronchodilators for 48 hours prior to study visits, and short acting bronchodilators for 8 hours prior to study visits. 9. Clinically stable CF in the 2 weeks prior to randomisation (Visit 2). |
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E.4 | Principal exclusion criteria |
1. History of cirrhotic liver disease or portal hypertension. 2. CF exacerbation requiring hospitalisation in the month prior to screening (Visit 1) or prior to randomisation (Visit 2). 3. Use of oral or intravenous antibiotics (in additional to usual maintenance therapy) in the 2 weeks prior to screening (Visit 1) or randomisation (Visit 2). 4. Other non-CF related respiratory disorders: Patients with a current diagnosis of active tuberculosis, lung cancer, sarcoidosis, sleep apnoea, known alpha-1 antitrypsin deficiency or other active pulmonary diseases. 5. Previous lung resection or lung transplant. 6. History of, or reason to believe a patient has, drug or alcohol abuse within the past 3 years. 7. Received an experimental drug within 3 months or five half-lives, whichever is longer. 8. Patients with a history of chronic uncontrolled disease, unless CF related, 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. 9. 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 last 3 months. 10. 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. 11. Infection with nontuberculous mycobacteria, methicillin-resistant Staphylococcus aureus (MRSA), or Burkholderia species. 12. Use of immune-suppression; long term use of prednisolone >10mg/day. 13. History of malignancy of any organ system within 5 years with the exception of localised skin cancers (basal or squamous cell). 14. Clinically significant abnormal values for safety laboratory tests (haematology, biochemistry or urinalysis) at screening (Visit 1), as determined by the Investigator. 15. A disclosed history or one known to the Investigator, of significant non-compliance in previous investigational studies or with prescribed medications. 16. Requires oxygen therapy on a regular basis. 17. Pregnancy or lactation (female subjects only). 18. 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) |
RPL554 pharmacokinetic parameters (AUC, Cmax, tmax, t1/2). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Treatment Visits (Visits 2 - 4): Pre-dose and up to 24 hours post-dose. |
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E.5.2 | Secondary end point(s) |
1. Peak and AUC FEV1 over 4, 6 and 8 hours 2. Determination of onset of action 3. Determination of duration of action 4. Safety and tolerability: a) Continuous monitoring of adverse events b) Laboratory safety tests [haematology, biochemistry and urinalysis] c) 12-lead ECG (including QTcF and heart rate), supine vital signs [blood pressure and pulse rate] over 8 hours |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Treatment Visits (Visits 2 - 4): Pre-dose, and 15, 30 min, 1, 2, 4, 6, 8 and 24 hours post-dose. 2. Treatment Visits (Visits 2 - 4): Pre-dose, and 15, 30 min, 1, 2, 4, 6, 8 and 24 hours post-dose. 3. Treatment Visits (Visits 2 - 4): Pre-dose, and 15, 30 min, 1, 2, 4, 6, 8 and 24 hours post-dose. 4. a) Screening to End of study. b) Screening and End of study. c) ECG at pre-dose, 1, 2, 4 and 8 hours post- dose. Supine vital signs at pre-dose, 30 min, 1, 2, 4, 6 and 8 hours post-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) | 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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
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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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 | 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 | 5 |
E.8.9.2 | In all countries concerned by the trial days | 30 |