Cystic Fibrosis
Conditions
Brief summary
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.
Interventions
DRUGRPL554
RPL554 suspension administered using a nebuliser
DRUGPlacebo
Placebo solution administered using a nebuliser
Sponsors
Cystic Fibrosis Trust
Verona Pharma plc
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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. -
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Maximum Plasma Concentration After Each Dose | Pre dose, 15 and 30 minutes and 1, 2, 4, 6, 8 and 24 hours post dose | Time to maximum concentration (Tmax) after a single dose of RPL554 |
| Half Life for Each Dose | Pre dose, 15 and 30 minutes and 1, 2, 4, 6, 8 and 24 hours post dose | Half life (t1/2) of RPL554 |
| AUC by Dose | Pre dose, 15 and 30 minutes and 1, 2, 4, 6, 8 and 24 hours post dose after each treatment | Area under the curve (AUC) |
| Maximum Plasma Concentration After Each Dose | Pre dose, 15 and 30 minutes and 1, 2, 4, 6, 8 and 24 hours post dose | Maximum plasma concentration (Cmax) after a single dose of RPL554 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC FEV1(0-8h) | pre dose and 15 and 30 minutes and 1, 2, 4, 6 and 8 hours post dose | Area under the curve for FEV1 over 8 hours measured using spirometry |
| FVC | Over 24 hours after treatment | Forced vital capacity (FVC) measured using spirometry |
| Breath Samples | 8 and 24 hours after treatment | Exhaled breath pH |
| Laboratory Safety Tests 1 | Screening and end of study | Biochemistry panel parameters |
| Laboratory Safety Tests 3 | Screening and end of study | Urinalysis measured by urine dipstick |
| Vital Signs 1 | Over 8 hours after treatment | Pulse rate after 5 minutes supine |
| Vital Signs 2 | Over 8 hours after treatment | Blood pressure after 5 minutes supine |
| ECG 1 | Over 8 hours after treatment | Heart rate |
| ECG 2 | Over 8 hours after treatment | QT interval |
| Laboratory Safety Tests 2 | Screening and end of study | Haematology panel parameters |
| Peak FEV1 for Each Treatment | Pre dose and 15 and 30 minutes and 1, 2 and 4 hours post dose after treatment | Maximum Forced expired volume in one second (FEV1) measured using spirometry |
| AUC FEV1(0-4h) | Pre dose and 15 and 30 minutes and 1, 2 and 4 hours post dose | Area under the curve for FEV1 over 4 hours measured using spirometry |
| AUC FEV1(0-6h) | Pre dose and 15 and 30 minutes and 1, 2, 4 and 6 hours post dose | Area under the curve FEV1 over 6 hours measured using spirometry |
Other
| Measure | Time frame | Description |
|---|---|---|
| Sputum Rheology | 8 and 12 hours after treatment | Rheological analysis for interleukin 8, tumour necrosis factor alpha and myeloperoxidase |
| Sputum Measurements | 8 and 12 hours after treatment | Levels of inflammatory mediators |
Countries
United Kingdom
Participant flow
Pre-assignment details
16 patients were screened; six patients failed screening. Patients had to discontinue long acting bronchodilators on the day prior to screening and short acting bronchodilators for 8 hours before all spirometry assessments
Participants by arm
| Arm | Count |
|---|---|
| Higher Dose RPL554/Lower Dose RPL554/Placebo Single dose of inhaled 6 mg RPL554 in Period 1, single dose of inhaled 1.5 mg RPL554 in Period 2, single inhaled dose of placebo in Period 3
RPL554: RPL554 suspension administered using a nebuliser Placebo: Placebo solution administered using a nebuliser | 1 |
| Lower Dose RPL554/Placebo/Higher Dose RPL554 Single dose of inhaled 1.5 mg RPL554 in Period 1, single dose of inhaled placebo RPL554 in Period 2, single dose of 6 mg RPL554 in Period 3
RPL554: RPL554 suspension administered using a nebuliser Placebo: Placebo solution administered using a nebuliser | 2 |
| Higher Dose RPL554/Placebo/Lower Dose RPL554 Single dose of inhaled 6 mg RPL554 in Period 1, single dose of inhaled placebo in Period 2, single dose of inhaled 1.5 mg RPL554 in Period 3
RPL554: RPL554 suspension administered using a nebuliser Placebo: Placebo solution administered using a nebuliser | 2 |
| Lower Dose RPL554/Higher Dose RPL554/Placebo Single dose of inhaled 1.5 mg RPL554 in Period 1, single dose of inhaled 6 mg RPL554 in Period 2, single inhaled dose of placebo in Period 3
RPL554: RPL554 suspension administered using a nebuliser Placebo: Placebo solution administered using a nebuliser | 2 |
| Placebo/Higher Dose RPL554/Lower Dose RPL554 Single dose of inhaled placebo in Period 1, single dose of inhaled 6 mg RPL554 in Period 2, single dose of inhaled 1.5 mg RPL554 in Period 3
RPL554: RPL554 suspension administered using a nebuliser Placebo: Placebo solution administered using a nebuliser | 1 |
| Placebo/Lower Dose RPL554/Higher Dose RPL554 Single dose of inhaled placebo in Period 1, single dose of inhaled 1.5 mg RPL554 in Period 2, single dose of inhaled 6 mg RPL554 in Period 3
RPL554: RPL554 suspension administered using a nebuliser Placebo: Placebo solution administered using a nebuliser | 2 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Lower Dose RPL554/Placebo/Higher Dose RPL554 | Higher Dose RPL554/Placebo/Lower Dose RPL554 | Lower Dose RPL554/Higher Dose RPL554/Placebo | Higher Dose RPL554/Lower Dose RPL554/Placebo | Placebo/Higher Dose RPL554/Lower Dose RPL554 | Placebo/Lower Dose RPL554/Higher Dose RPL554 | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 2 Participants | 2 Participants | 1 Participants | 1 Participants | 2 Participants | 10 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 2 Participants | 2 Participants | 1 Participants | 1 Participants | 2 Participants | 10 Participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 6 / 9 | 6 / 10 | 3 / 10 |
| serious Total, serious adverse events | 0 / 9 | 1 / 10 | 0 / 10 |
Outcome results
Primary
AUC by Dose
Area under the curve (AUC)
Time frame: Pre dose, 15 and 30 minutes and 1, 2, 4, 6, 8 and 24 hours post dose after each treatment
Population: All randomised patients with blood sampling performed after at least one dose of RPL554 and with data sufficient to calculate pharmacokinetic parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose RPL554 | AUC by Dose | 7699 pg*h/mL | Standard Deviation 2965.7 |
| Lower Dose RPL554 | AUC by Dose | 2342 pg*h/mL | Standard Deviation 1029.9 |
Primary
Half Life for Each Dose
Half life (t1/2) of RPL554
Time frame: Pre dose, 15 and 30 minutes and 1, 2, 4, 6, 8 and 24 hours post dose
Population: All randomised patients with blood sampling performed after at least one dose of RPL554 and with data sufficient to calculate pharmacokinetic parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose RPL554 | Half Life for Each Dose | 10.14 Hours | Standard Deviation 3.1 |
| Lower Dose RPL554 | Half Life for Each Dose | 7.52 Hours | Standard Deviation 3.3 |
Primary
Maximum Plasma Concentration After Each Dose
Maximum plasma concentration (Cmax) after a single dose of RPL554
Time frame: Pre dose, 15 and 30 minutes and 1, 2, 4, 6, 8 and 24 hours post dose
Population: All randomised patients with blood sampling performed after at least one dose of RPL554 and with data sufficient to calculate pharmacokinetic parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose RPL554 | Maximum Plasma Concentration After Each Dose | 828.3 pg/mL | Standard Deviation 256.1 |
| Lower Dose RPL554 | Maximum Plasma Concentration After Each Dose | 270.1 pg/mL | Standard Deviation 91.9 |
Primary
Time to Maximum Plasma Concentration After Each Dose
Time to maximum concentration (Tmax) after a single dose of RPL554
Time frame: Pre dose, 15 and 30 minutes and 1, 2, 4, 6, 8 and 24 hours post dose
Population: All randomised patients with blood sampling performed after at least one dose of RPL554 and with data sufficient to calculate pharmacokinetic parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose RPL554 | Time to Maximum Plasma Concentration After Each Dose | 1.53 hours | Standard Deviation 0.66 |
| Lower Dose RPL554 | Time to Maximum Plasma Concentration After Each Dose | 1.33 hours | Standard Deviation 0.62 |
Secondary
AUC FEV1(0-4h)
Area under the curve for FEV1 over 4 hours measured using spirometry
Time frame: Pre dose and 15 and 30 minutes and 1, 2 and 4 hours post dose
Population: All randomized patients with sufficient data collected after intake of study treatment to compute the pharmacodynamic parameters on at least two study visits.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose RPL554 | AUC FEV1(0-4h) | 2.313 Liters | Standard Deviation 0.73 |
| Lower Dose RPL554 | AUC FEV1(0-4h) | 2.194 Liters | Standard Deviation 0.72 |
| Placebo | AUC FEV1(0-4h) | 2.133 Liters | Standard Deviation 0.73 |
p-value: 0.004395% CI: [1.026, 1.12]ANCOVA
p-value: 0.010995% CI: [1.014, 1.096]ANCOVA
p-value: 0.430695% CI: [0.942, 1.027]ANCOVA
Secondary
AUC FEV1(0-6h)
Area under the curve FEV1 over 6 hours measured using spirometry
Time frame: Pre dose and 15 and 30 minutes and 1, 2, 4 and 6 hours post dose
Population: all randomized patients with sufficient data collected after intake of study treatment to compute the pharmacodynamic parameters on at least two study visits.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose RPL554 | AUC FEV1(0-6h) | 2.304 Liters | Standard Deviation 0.74 |
| Lower Dose RPL554 | AUC FEV1(0-6h) | 2.188 Liters | Standard Deviation 0.73 |
| Placebo | AUC FEV1(0-6h) | 2.133 Liters | Standard Deviation 0.73 |
p-value: 0.006495% CI: [1.021, 1.11]ANCOVA
p-value: 0.014995% CI: [1.011, 1.089]ANCOVA
p-value: 0.46695% CI: [0.945, 1.027]ANCOVA
Secondary
AUC FEV1(0-8h)
Area under the curve for FEV1 over 8 hours measured using spirometry
Time frame: pre dose and 15 and 30 minutes and 1, 2, 4, 6 and 8 hours post dose
Population: All randomised patients with sufficient data collected after intake of study treatment to compute the pharmacodynamic parameters on at least two study visits.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose RPL554 | AUC FEV1(0-8h) | 2.287 Liters | Standard Deviation 0.75 |
| Lower Dose RPL554 | AUC FEV1(0-8h) | 2.185 Liters | Standard Deviation 0.74 |
| Placebo | AUC FEV1(0-8h) | 2.130 Liters | Standard Deviation 0.74 |
p-value: 0.009395% CI: [1.017, 1.107]ANCOVA
p-value: 0.033395% CI: [1.004, 1.082]ANCOVA
p-value: 0.369395% CI: [0.941, 1.024]ANCOVA
Secondary
Breath Samples
Exhaled breath pH
Time frame: 8 and 24 hours after treatment
Secondary
ECG 1
Heart rate
Time frame: Over 8 hours after treatment
Secondary
ECG 2
QT interval
Time frame: Over 8 hours after treatment
Secondary
FVC
Forced vital capacity (FVC) measured using spirometry
Time frame: Over 24 hours after treatment
Secondary
Laboratory Safety Tests 1
Biochemistry panel parameters
Time frame: Screening and end of study
Secondary
Laboratory Safety Tests 2
Haematology panel parameters
Time frame: Screening and end of study
Secondary
Laboratory Safety Tests 3
Urinalysis measured by urine dipstick
Time frame: Screening and end of study
Secondary
Peak FEV1 for Each Treatment
Maximum Forced expired volume in one second (FEV1) measured using spirometry
Time frame: Pre dose and 15 and 30 minutes and 1, 2 and 4 hours post dose after treatment
Population: All randomized patients with sufficient data collected after intake of study treatment to compute the pharmacodynamic parameters on at least two study visits.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Higher Dose RPL554 | Peak FEV1 for Each Treatment | 2.384 Liters | Standard Deviation 0.73 |
| Lower Dose RPL554 | Peak FEV1 for Each Treatment | 2.247 Liters | Standard Deviation 0.72 |
| Placebo | Peak FEV1 for Each Treatment | 2.256 Liters | Standard Deviation 0.71 |
p-value: 0.019695% CI: [1.007, 1.07]ANCOVA
p-value: 0.080295% CI: [0.997, 1.052]ANCOVA
p-value: 0.348795% CI: [0.957, 1.017]ANCOVA
Secondary
Vital Signs 1
Pulse rate after 5 minutes supine
Time frame: Over 8 hours after treatment
Secondary
Vital Signs 2
Blood pressure after 5 minutes supine
Time frame: Over 8 hours after treatment
Other Pre-specified
Sputum Measurements
Levels of inflammatory mediators
Time frame: 8 and 12 hours after treatment
Other Pre-specified
Sputum Rheology
Rheological analysis for interleukin 8, tumour necrosis factor alpha and myeloperoxidase
Time frame: 8 and 12 hours after treatment