A Study to Assess the Effect of AZD5634 on Mucociliary Clearance, Safety, Tolerability and Pharmacokinetic Parameters in Patients With Cystic Fibrosis

Study Overview
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Brief Summary
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This study will assess the effect of inhaled AZD5634 on Mucociliary clearance (MCC) in patients with Cystic fibrosis (CF) after single-dose administration.

Detailed Description
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The primary pharmacodynamic endpoint will be the average whole lung particle clearance between 0 and 60 minutes after administration of aerosolized radiolabelled particles (colloids) at Visits 2 and 3 (%MCC 0-60, whole).

Official Title
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A Phase 1b Randomized Blinded Placebo-Controlled, Cross-Over Study to Assess the Effect of AZD5634 on Mucociliary Clearance as Well as Safety, Tolerability, and Pharmacokinetic Parameters Following Single Inhaled Dose Administration to Patients With Cystic Fibrosis.

Conditions
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Pulmonary/Respiratory Diseases

Intervention / Treatment
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* Drug: Placebo
* Drug: AZD5634


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated written informed consent prior to any study-specific procedures. Male or female patients aged 18-60 years old inclusive. Diagnosed of CF at Screening as evidenced in medical records by one of the following criteria: sweat chloride ≥ 60 mmol/L presence of 2 mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Chronic sinopulmonary disease or pancreatic insufficiency. FEV1measurement at Screening ≥ 40% of the predicted normal value of age, height, gender, and race. Stable CF regimen for at least 2 months before Screening. Body mass index (BMI) between 15-30 kg/m2 inclusive. 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. Ability of the patient to correctly perform the inhalation procedure after training during the Screening Visit. Exclusion Criteria: Had a pulmonary exacerbation requiring change in antibiotics and/or hospitalization within 28 days before the first dose of Investigational product. History of lung transplant or any other transplantation. Currently being treated with ivacaftor monotherapy at Screening or received ivacaftor monotherapy within 30 days before Screening. History of severe allergy/hypersensitivity or ongoing clinically significant allergy/hypersensitivity, as judged by the Investigator, to drugs in a similar class to AZD5634. History or presence of hepatic cirrhosis. Creatinine clearance <60 mL/min/m2 using the Cockroft-Gault Equation. Liver function test results >2x upper limit of normal (aspartate aminotransferase [AST], alanine aminotransferase [ALT], gamma-glutamyl transpeptidase [GGT], or bilirubin) 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. 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). Likely to require treatment during the study with drugs not permitted by the study protocol. Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results. Serum potassium levels are outside the normal range (3.5-5.1 mmol/L). Serum sodium levels <135 mmol/L. 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 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. QTc prolongation defined as QT interval corrected for heart rate using Fridericia's formula (QTcF) >450 ms. 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo + AZD5634<br>Subjects were administered single dose of placebo in period 1 and AZD5634 in period 2. | Drug: Placebo<br>* Subjects will receive a placebo in either period 1 or period 2 by inhalation.<br>Drug: AZD5634<br>* Subjects will receive a single tentative dose of 625 μg of AZD5634 in either period 1 or period 2 by inhalation.<br>|
| Experimental: AZD5634 + Placebo<br>Subjects were administered single dose of AZD5634 in period 1 and placebo in period 2. | Drug: Placebo<br>* Subjects will receive a placebo in either period 1 or period 2 by inhalation.<br>Drug: AZD5634<br>* Subjects will receive a single tentative dose of 625 μg of AZD5634 in either period 1 or period 2 by inhalation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of average whole lung particle clearance between 0 and 60 minutes after administration of aerosolized radiolabelled particles | Assessment of the average whole lung clearance between 0 and 60 minutes after administration of single inhaled dose of aerosolized radiolabelled particles (colloids) of AZD5634, (%MCC 0--60, whole) in subjects with cystic fibrosis (CF). | 0 to 60 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of average central clearance between 0 and 60 minutes after administration of aerosolized radiolabelled particles | Assessment and comparison of the average central clearance between 0 and 60 minutes after administration of single inhaled dose of aerosolized radiolabelled particles (colloids) of AZD5634, in subjects with CF. | 0 to 60 minutes | 
| Percentage of average peripheral clearance between 0 and 60 minutes after administration of aerosolized radiolabelled particles | Assessment and comparison of the average peripheral clearance between 0 and 60 minutes after administration of single inhaled dose of aerosolized radiolabelled particles (colloids) of AZD5634 in subjects with CF. | 0 to 60 minutes | 
| Percentage of average tracheobronchial clearance between 0 and 60 minutes after administration of aerosolized radiolabelled particles | Assessment and comparison of the average tracheobronchial clearance between 0 and 60 minutes after administration of single inhaled dose of aerosolized radiolabelled particles (colloids) of AZD5634 in subjects with CF. | 0 to 60 minutes | 
| Percentage of particle clearance at 6-hour | Assessment and comparison the 6-hour clearance after administration of aerosolized radiolabelled particles (colloids) of AZD5634 in subjects with CF. | 6 hours | 
| Percentage of average whole lung cough clearance between 60 minutes and 90 minutes after administration of aerosolized radiolabelled particles | Assessment of the average whole lung cough clearance between 60 minutes and 90 minutes after administration of single inhaled dose of aerosolized radiolabelled particles (colloids) of AZD5634 in subjects with CF. | 60 minutes to 90 minutes | 
| Percentage of average central cough clearance between 60 minutes and 90 minutes after administration of aerosolized radiolabelled particles | Assessment and comparison of the average central cough clearance between 60 minutes and 90 minutes after administration of single inhaled dose of aerosolized radiolabelled particles (colloids) of AZD5634 in subjects with CF. | 60 minutes to 90 minutes | 
| Percentage of average peripheral cough clearance between 60 minutes and 90 minutes after administration of aerosolized radiolabelled particles | Assessment and comparison of the average peripheral cough clearance between 60 minutes and 90 minutes after administration of single inhaled dose of aerosolized radiolabelled particles (colloids) of AZD5634 in subjects with CF. | 60 minutes to 90 minutes | 
| Percentage of average tracheobronchial cough clearance between 60 minutes and 90 minutes after administration of aerosolized radiolabelled particles | Assessment and comparison of the average tracheobronchial cough clearance between 60 minutes and 90 minutes after administration of single inhaled dose of aerosolized radiolabelled particles (colloids) of AZD5634 in subjects with CF. | 60 minutes to 90 minutes | 
| Maximum observed plasma concentration (Cmax) | Assessment of Cmax in subjects with CF after the administration of single inhaled dose of AZD5634. | Pre-dose and up to 6 hours post-dose | 
| Area under the concentration-time curve from time zero extrapolated to infinity (AUC) | Assessment of AUC in subjects with CF after the administration of single inhaled dose of AZD5634. | Pre-dose and up to 6 hours post-dose | 
| Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUC 0-last) | Assessment of AUC 0-last in subjects with CF after the administration of single inhaled dose of AZD5634. | Pre-dose and up to 6 hours post-dose | 
| Area under the plasma concentration-time curve from time zero to 6 hours post-dose (AUC 0-6) | Assessment of AUC 0-6 in subjects with CF after the administration of single inhaled dose of AZD5634. | Pre-dose and up to 6 hours post-dose | 
| Observed last quantifiable concentration (C last) | Assessment of C last in subjects with CF after the administration of single inhaled dose of AZD5634. | Pre-dose and up to 6 hours post-dose | 
| Time of last quantifiable concentration (t last) | Assessment of t last in subjects with CF after the administration of single inhaled dose of AZD5634. | Pre-dose and up to 6 hours post-dose | 
| Time to reach maximum plasma concentration (t max) | Assessment of t max in subjects with CF after the administration of single inhaled dose of AZD5634. | Pre-dose and up to 6 hours post-dose | 
| Terminal elimination rate constant (λz) | Assessment of λz in subjects with CF after the administration of single inhaled dose of AZD5634. | Pre-dose and up to 6 hours post-dose | 
| Terminal elimination half-life (t1/2,λz) | Assessment of t1/2,λz in subjects with CF after the administration of single inhaled dose of AZD5634. | Pre-dose and up to 6 hours post-dose | 
| Apparent clearance (CL/F) | Assessment of CL/F in subjects with CF after the administration of single inhaled dose of AZD5634. | Pre-dose and up to 6 hours post-dose | 
| Apparent volume of distribution at terminal phase (Vz/F) | Assessment of Vz/F in subjects with CF after the administration of single inhaled dose of AZD5634. | Pre-dose and up to 6 hours post-dose | 
| Cumulative amount of AZD5634 excreted in urine from time zero to 6 hours (Ae 0-6) | Assessment of Ae 0-6 in subjects with CF after the administration of single inhaled dose of AZD5634. | Pre-dose and up to 6 hours post-dose | 
| Cumulative percentage of dose excreted unchanged in urine from time zero to 6 hours (fe(0-6)%) | Assessment of fe(0-6)% in subjects with CF after the administration of single inhaled dose of AZD5634. | Pre-dose and up to 6 hours post-dose | 
| Renal clearance, estimated by dividing Ae(0-t) (CLR) | Assessment of CLR in subjects with CF after the administration of single inhaled dose of AZD5634. CLR is defined as renal clearance, estimated by dividing Ae(0-t) cumulative amount of AZD5634 excreted in urine from time zero up to time t) by AUC 0-t (area under the plasma concentration-time curve from time zero to time t), where t represents a matching time point for plasma and urine sampling. | Pre-dose and up to 6 hours post-dose | 
| Safety of subjects by evaluating the incidence of adverse events (AEs) | Assessment of the safety in terms of the incidences of the AEs after the administration of single inhaled dose of AZD5634 in subjects with CF. | From screening (≤28 days) up to 14-21 days post dosing | 
| Safety of subjects by evaluating the systolic and diastolic blood pressure | Assessment of the safety in terms of systolic and diastolic blood pressure after the administration of single inhaled dose of AZD5634 in subjects with CF. | From screening (≤28 days) up to 14-21 days post dosing | 
| Safety of subjects by evaluating the pulse rate. | Assessment of the safety in terms of pulse rate after the administration of single inhaled dose of AZD5634 in subjects with CF. | From screening (≤28 days) up to 14-21 days post dosing | 
| Safety of subjects by evaluating spirometry results | Assessment of the safety by evaluating the spirometry results after administration of the of single inhaled dose of AZD5634 in subjects with CF. | From screening (≤28 days) up to 14-21 days post dosing | 
| Safety of subjects by evaluating the ECG results | Assessment of the safety by evaluating the ECG results after administration of the of single inhaled dose of AZD5634 in subjects with CF. | Pre-dose and up to 6 hours post-dose | 
| Safety of subjects by the physical examination | Assessment of the safety by physical examination after administration of the of single inhaled dose of AZD5634 in subjects with CF. | From screening (≤28 days) up to 14-21 days post dosing | 
| Safety of subjects by evaluating the respiratory rate. | Assessment of the safety in terms of respiratory rate after the administration of single inhaled dose of AZD5634 in subjects with CF. | From screening (≤28 days) up to 14-21 days post dosing | 
| Safety of subjects by evaluating fractional excretion of potassium (FEK) | Assessment of FEK after the administration of single inhaled dose of AZD5634 in subjects with CF. | Pre-dose and at 0-6 hours post-dose | 
| Safety of subjects by evaluating urine sodium/potassium (Na/K) ratio | Assessment of ratio of Na/K after the administration of single inhaled dose of AZD5634 in subjects with CF. | Pre-dose and at 0-6 hours post-dose | 
| Safety of subjects by evaluating the pulse oximetry | Assessment of the safety in terms of pulse rate after the administration of single inhaled dose of AZD5634 in subjects with CF. | From screening (≤28 days) up to 14-21 days post dosing | 
| Safety of subjects by evaluating the clinical laboratory test results for biochemistry | Assessment of the clinical laboratory test results in terms of biochemistry after the administration of single inhaled dose of AZD5634 in subjects with CF. | From screening (≤28 days) until 14-21 days post dosing | 
| Safety of subjects by evaluating the clinical laboratory test results for urinalysis | Assessment of the clinical laboratory test results in terms of urinalysis after the administration of single inhaled dose of AZD5634 in subjects with CF. | From screening (≤28 days) until 14-21 days post dosing | 
| Safety of subjects by evaluating the clinical laboratory test results for hematology | Assessment of the clinical laboratory test results in terms of hematology after the administration of single inhaled dose of AZD5634 in subjects with CF. | From screening (≤28 days) until 14-21 days post dosing | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AZD5634, Mucociliary Clearance, Safety, Tolerability, Pharmacokinetic, Cystic Fibrosis, Cross-Over Study