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Key inclusion & exclusion criteria
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Inclusion Criteria:
1. Provision of signed and dated written informed consent prior to any study-specific
procedures.
2. Male or female patients aged 18-60 years old inclusive.
3. Diagnosed of CF at Screening as evidenced in medical records by one of the following
criteria:
1. sweat chloride = 60 mmol/L
2. presence of 2 mutations in the Cystic Fibrosis Transmembrane Conductance
Regulator (CFTR) gene.
4. Chronic sinopulmonary disease or pancreatic insufficiency.
5. FEV1measurement at Screening = 40% of the predicted normal value of age, height,
gender, and race.
6. Stable CF regimen for at least 2 months before Screening.
7. Body mass index (BMI) between 15-30 kg/m2 inclusive.
8. Female patients are not pregnant and do not plan to become pregnant during the study,
are not lactating, or are of non-childbearing potential. Females of childbearing
potential must provide a negative serum pregnancy test and have a date of last
menstruation consistent with non-pregnancy, negative urine pregnancy tests at each
visit, and must be using at least one highly effective method of contraception.
9. Ability of the patient to correctly perform the inhalation procedure after training
during the Screening Visit.
Exclusion Criteria:
1. Had a pulmonary exacerbation requiring change in antibiotics and/or hospitalization
within 28 days before the first dose of Investigational product.
2. History of lung transplant or any other transplantation.
3. Currently being treated with ivacaftor monotherapy at Screening or received ivacaftor
monotherapy within 30 days before Screening.
4. History of severe allergy/hypersensitivity or ongoing clinically significant
allergy/hypersensitivity, as judged by the Investigator, to drugs in a similar class
to AZD5634.
5. History or presence of hepatic cirrhosis.
6. Creatinine clearance <60 mL/min/m2 using the Cockroft-Gault Equation.
7. Liver function test results >2x upper limit of normal (aspartate aminotransferase
[AST], alanine aminotransferase [ALT], gamma-glutamyl transpeptidase [GGT], or
bilirubin)
8. History of any clinically significant disease or disorder which, in the opinion of the
Investigator, may either put the patient at risk because of participation in the
study, or influence the results or the patient's ability to participate in the study.
9. Received treatment with the following medications within the 3 weeks before Screening:
strong or moderate Cytochrome P450 (CYP) 3A inhibitors, as classified by the Food and
Drug Administration (FDA).
10. Likely to require treatment during the study with drugs not permitted by the study
protocol.
11. Any clinically significant abnormalities in clinical chemistry, hematology, or
urinalysis results.
12. Serum potassium levels are outside the normal range (3.5-5.1 mmol/L).
13. Serum sodium levels <135 mmol/L.
14. Abnormal vital signs, after 5 minutes rest, at Screening or Visit 2 (seated or supine;
position should be consistent for a given patient at both visits), defined as any of
the following:
- Systolic blood pressure (B.P) < 90 or = 150 mmHg
- Diastolic B.P < 45 or = 90 mmHg
- Pulse rate < 45 or >110 beats/minute
15. Any clinically significant abnormalities in rhythm, conduction, or morphology of the
resting ECG and any clinically significant abnormalities in the 12-lead ECG, as
considered by the Investigator, that may interfere with the interpretation of
corrected ECG interval measured from the onset of the QRS complex to the offset of the
T wave (QTc) interval changes.
16. QTc prolongation defined as QT interval corrected for heart rate using Fridericia's
formula (QTcF) >450 ms.
17. ECG interval measured from the onset of the P wave to the onset of the QRS complex
(PR/PQ) interval prolongation (>240 ms), intermittent second or third degree
atrioventricular (AV) block, or AV dissociation.
18. Persistent or intermittent complete bundle branch block (BBB) with ECG interval
measured from the onset of the QRS complex to the J point (QRS) >120 ms or evidence of
pre-excitation.
Age minimum:
18 Years
Age maximum:
60 Years
Gender:
All
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Secondary Outcome(s)
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Area under the plasma concentration-time curve from time zero to 6 hours post-dose (AUC 0-6)
[Time Frame: Pre-dose and up to 6 hours post-dose]
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Percentage of average peripheral cough clearance between 60 minutes and 90 minutes after administration of aerosolized radiolabelled particles
[Time Frame: 60 minutes to 90 minutes]
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Apparent volume of distribution at terminal phase (Vz/F)
[Time Frame: Pre-dose and up to 6 hours post-dose]
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Cumulative percentage of dose excreted unchanged in urine from time zero to 6 hours (fe(0-6)%)
[Time Frame: Pre-dose and up to 6 hours post-dose]
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Percentage of average central clearance between 0 and 60 minutes after administration of aerosolized radiolabelled particles
[Time Frame: 0 to 60 minutes]
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Area under the concentration-time curve from time zero extrapolated to infinity (AUC)
[Time Frame: Pre-dose and up to 6 hours post-dose]
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Percentage of average whole lung cough clearance between 60 minutes and 90 minutes after administration of aerosolized radiolabelled particles
[Time Frame: 60 minutes to 90 minutes]
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Safety of subjects by evaluating fractional excretion of potassium (FEK)
[Time Frame: Pre-dose and at 0-6 hours post-dose]
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Safety of subjects by evaluating the respiratory rate.
[Time Frame: From screening (=28 days) up to 14-21 days post dosing]
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Apparent clearance (CL/F)
[Time Frame: Pre-dose and up to 6 hours post-dose]
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Percentage of average peripheral clearance between 0 and 60 minutes after administration of aerosolized radiolabelled particles
[Time Frame: 0 to 60 minutes]
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Safety of subjects by evaluating urine sodium/potassium (Na/K) ratio
[Time Frame: Pre-dose and at 0-6 hours post-dose]
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Terminal elimination half-life (t1/2,?z)
[Time Frame: Pre-dose and up to 6 hours post-dose]
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Percentage of average tracheobronchial cough clearance between 60 minutes and 90 minutes after administration of aerosolized radiolabelled particles
[Time Frame: 60 minutes to 90 minutes]
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Cumulative amount of AZD5634 excreted in urine from time zero to 6 hours (Ae 0-6)
[Time Frame: Pre-dose and up to 6 hours post-dose]
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Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUC 0-last)
[Time Frame: Pre-dose and up to 6 hours post-dose]
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Observed last quantifiable concentration (C last)
[Time Frame: Pre-dose and up to 6 hours post-dose]
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Safety of subjects by evaluating the clinical laboratory test results for biochemistry
[Time Frame: From screening (=28 days) until 14-21 days post dosing]
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Maximum observed plasma concentration (Cmax)
[Time Frame: Pre-dose and up to 6 hours post-dose]
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Percentage of average central cough clearance between 60 minutes and 90 minutes after administration of aerosolized radiolabelled particles
[Time Frame: 60 minutes to 90 minutes]
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Percentage of average tracheobronchial clearance between 0 and 60 minutes after administration of aerosolized radiolabelled particles
[Time Frame: 0 to 60 minutes]
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Renal clearance, estimated by dividing Ae(0-t) (CLR)
[Time Frame: Pre-dose and up to 6 hours post-dose]
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Safety of subjects by evaluating spirometry results
[Time Frame: From screening (=28 days) up to 14-21 days post dosing]
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Safety of subjects by evaluating the ECG results
[Time Frame: Pre-dose and up to 6 hours post-dose]
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Safety of subjects by evaluating the incidence of adverse events (AEs)
[Time Frame: From screening (=28 days) up to 14-21 days post dosing]
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Percentage of particle clearance at 6-hour
[Time Frame: 6 hours]
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Safety of subjects by evaluating the pulse oximetry
[Time Frame: From screening (=28 days) up to 14-21 days post dosing]
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Safety of subjects by evaluating the pulse rate.
[Time Frame: From screening (=28 days) up to 14-21 days post dosing]
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Time of last quantifiable concentration (t last)
[Time Frame: Pre-dose and up to 6 hours post-dose]
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Safety of subjects by evaluating the systolic and diastolic blood pressure
[Time Frame: From screening (=28 days) up to 14-21 days post dosing]
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Time to reach maximum plasma concentration (t max)
[Time Frame: Pre-dose and up to 6 hours post-dose]
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Safety of subjects by evaluating the clinical laboratory test results for hematology
[Time Frame: From screening (=28 days) until 14-21 days post dosing]
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Safety of subjects by evaluating the clinical laboratory test results for urinalysis
[Time Frame: From screening (=28 days) until 14-21 days post dosing]
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Safety of subjects by the physical examination
[Time Frame: From screening (=28 days) up to 14-21 days post dosing]
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Terminal elimination rate constant (?z)
[Time Frame: Pre-dose and up to 6 hours post-dose]
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