A Study of RPL554 in Patients With Cystic Fibrosis

• 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 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 90 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 bronchodilators1 until the end of the treatment period, and short acting bronchodilators for 8 hours prior to administration of study treatment.
       9. Clinically stable CF in the 2 weeks prior to randomisation (Visit 2).

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 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 ≥10 mg/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, even on an occasional basis.
17. Pregnancy or lactation (female subjects only).
18. Any other reason that the Investigator considers makes the patient unsuitable to participate. -