Study to assess the effects of inhaled RPL554 in adults with cystic fibrosis.

Phase 1

Conditions: Cystic Fibrosis (CF)
MedDRA version: 20.0Level: PTClassification code 10011762Term: Cystic fibrosisSystem Organ Class: 10010331 - Congenital, familial and genetic disorders
Therapeutic area: Body processes [G] - Genetic Phenomena [G05]

Registration Number: EUCTR2015-004263-36-DE

Lead Sponsor: Verona Pharma plc

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 10

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).
Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 10
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range 0

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.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To investigate pharmacokinetics of single nebulised doses of RPL554 in patients with Cystic Fibrosis.;Secondary Objective: - To investigate the bronchodilator effect on peak forced expiratory volume in 1 second after single nebulised doses of RPL554 as compared to placebo.<br>- 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.<br>- To assess the tolerability and safety of single nebulised doses of RPL554 in patients with Cystic Fibrosis.<br>Exploratory Objective:<br>- To examine the anti-inflammatory effects of single nebulised doses of RPL554 in patients with Cystic Fibrosis.;Primary end point(s): RPL554 pharmacokinetic parameters (AUC, Cmax, tmax, t1/2).;Timepoint(s) of evaluation of this end point: Treatment Visits (Visits 2 - 4): Pre-dose and up to 24 hours post-dose.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): 1. Peak and AUC FEV1 over 4, 6 and 8 hours<br>2. Determination of onset of action<br>3. Determination of duration of action<br>4. Safety and tolerability:<br> a) Continuous monitoring of adverse events<br> b) Laboratory safety tests [haematology, biochemistry and urinalysis]<br> c) 12-lead ECG (including QTcF and heart rate), supine vital signs [blood pressure and pulse rate] over 8 hours;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.<br>2. Treatment Visits (Visits 2 - 4): Pre-dose, and 15, 30 min, 1, 2, 4, 6, 8 and 24 hours post-dose.<br>3. Treatment Visits (Visits 2 - 4): Pre-dose, and 15, 30 min, 1, 2, 4, 6, 8 and 24 hours post-dose.<br>4. a) Screening to End of study.<br> b) Screening and End of study.<br> 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.