A Study of RPL554 in Patients With Cystic Fibrosis

A Phase IIa, Randomised, Double Blind, Placebo Controlled, Three Way Crossover Study to Assess the Pharmacokinetics of RPL554 Administered to Adult Patients With Cystic Fibrosis.

This study evaluates two doses of RPL554 and placebo in adult patients with cystic fibrosis. All patients receive all three treatments in a randomised sequence.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: RPL554; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Cambridge, United Kingdom, CB23 3RE
    • Papworth Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 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. -

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Higher Dose RPL554; Single dose of inhaled 6 mg RPL554	Drug: RPL554; RPL554 suspension administered using a nebuliser
Experimental: Lower dose RPL554; Single dose of inhaled 1.5 mg RPL554	Drug: RPL554; RPL554 suspension administered using a nebuliser
Placebo Comparator: Placebo; Inhaled placebo dose	Drug: Placebo; Placebo solution administered using a nebuliser

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC by Dose	Area under the curve (AUC)	Pre dose, 15 and 30 minutes and 1, 2, 4, 6, 8 and 24 hours post dose after each treatment
Maximum Plasma Concentration After Each Dose	Maximum plasma concentration (Cmax) after a single dose of RPL554	Pre dose, 15 and 30 minutes and 1, 2, 4, 6, 8 and 24 hours post dose
Time to Maximum Plasma Concentration After Each Dose	Time to maximum concentration (Tmax) after a single dose of RPL554	Pre dose, 15 and 30 minutes and 1, 2, 4, 6, 8 and 24 hours post dose
Half Life for Each Dose	Half life (t1/2) of RPL554	Pre dose, 15 and 30 minutes and 1, 2, 4, 6, 8 and 24 hours post dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak FEV1 for Each Treatment	Maximum Forced expired volume in one second (FEV1) measured using spirometry	Pre dose and 15 and 30 minutes and 1, 2 and 4 hours post dose after treatment
AUC FEV1(0-4h)	Area under the curve for FEV1 over 4 hours measured using spirometry	Pre dose and 15 and 30 minutes and 1, 2 and 4 hours post dose
AUC FEV1(0-6h)	Area under the curve FEV1 over 6 hours measured using spirometry	Pre dose and 15 and 30 minutes and 1, 2, 4 and 6 hours post dose
AUC FEV1(0-8h)	Area under the curve for FEV1 over 8 hours measured using spirometry	pre dose and 15 and 30 minutes and 1, 2, 4, 6 and 8 hours post dose
FVC	Forced vital capacity (FVC) measured using spirometry	Over 24 hours after treatment
Breath Samples	Exhaled breath pH	8 and 24 hours after treatment
Laboratory Safety Tests 1	Biochemistry panel parameters	Screening and end of study
Laboratory Safety Tests 2	Haematology panel parameters	Screening and end of study
Laboratory Safety Tests 3	Urinalysis measured by urine dipstick	Screening and end of study
Vital Signs 1	Pulse rate after 5 minutes supine	Over 8 hours after treatment
Vital Signs 2	Blood pressure after 5 minutes supine	Over 8 hours after treatment
ECG 1	Heart rate	Over 8 hours after treatment
ECG 2	QT interval	Over 8 hours after treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sputum Rheology	Rheological analysis for interleukin 8, tumour necrosis factor alpha and myeloperoxidase	8 and 12 hours after treatment
Sputum Measurements	Levels of inflammatory mediators	8 and 12 hours after treatment

Collaborators and Investigators

• Sponsor: Verona Pharma plc
• Collaborators: Cystic Fibrosis Trust
• Investigators: Principal Investigator: Andres Floto, Cambridge Centre for Medical Research, Papworth Hospital

Study record dates

Study Major Dates

• Study Start (Actual): February 8, 2017
• Primary Completion (Actual): November 3, 2017
• Study Completion (Actual): November 3, 2017

Study Registration Dates

• First Submitted: September 21, 2016
• First Submitted That Met QC Criteria: September 27, 2016
• First Posted (Estimated): September 30, 2016

Study Record Updates

• Last Update Posted (Actual): May 21, 2024
• Last Update Submitted That Met QC Criteria: April 22, 2024
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis
• Other Study ID Numbers: RPL554-010-2015; 2015-004263-36 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No