Clinical trial NCT02950805: A Study to Assess the Effect of AZD5634 on Mucociliary Clearance, Safety, Tolerability and Pharmacokinetic Parameters in Patients With Cystic Fibrosis
Official title: 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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Pulmonary/Respiratory Diseases
Keywords: AZD5634
Mucociliary Clearance
Safety
Tolerability
Pharmacokinetic
Cystic Fibrosis
Cross-Over Study
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2016-11-01
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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: 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).

Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of average whole lung particle clearance between 0 and 60 minutes after administration of aerosolized radiolabelled particles
timeFrame: 0 to 60 minutes
Secondary outcomes:
measure: Percentage of average central clearance between 0 and 60 minutes after administration of aerosolized radiolabelled particles
timeFrame: 0 to 60 minutes
measure: Percentage of average peripheral clearance between 0 and 60 minutes after administration of aerosolized radiolabelled particles
timeFrame: 0 to 60 minutes
measure: Percentage of average tracheobronchial clearance between 0 and 60 minutes after administration of aerosolized radiolabelled particles
timeFrame: 0 to 60 minutes
measure: Percentage of particle clearance at 6-hour
timeFrame: 6 hours
measure: Percentage of average whole lung cough clearance between 60 minutes and 90 minutes after administration of aerosolized radiolabelled particles
timeFrame: 60 minutes to 90 minutes
measure: Percentage of average central cough clearance between 60 minutes and 90 minutes after administration of aerosolized radiolabelled particles
timeFrame: 60 minutes to 90 minutes
measure: Percentage of average peripheral cough clearance between 60 minutes and 90 minutes after administration of aerosolized radiolabelled particles
timeFrame: 60 minutes to 90 minutes
measure: Percentage of average tracheobronchial cough clearance between 60 minutes and 90 minutes after administration of aerosolized radiolabelled particles
timeFrame: 60 minutes to 90 minutes
measure: Maximum observed plasma concentration (Cmax)
timeFrame: Pre-dose and up to 6 hours post-dose
measure: Area under the concentration-time curve from time zero extrapolated to infinity (AUC)
timeFrame: Pre-dose and up to 6 hours post-dose
measure: Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUC 0-last)
timeFrame: Pre-dose and up to 6 hours post-dose
measure: Area under the plasma concentration-time curve from time zero to 6 hours post-dose (AUC 0-6)
timeFrame: Pre-dose and up to 6 hours post-dose
measure: Observed last quantifiable concentration (C last)
timeFrame: Pre-dose and up to 6 hours post-dose
measure: Time of last quantifiable concentration (t last)
timeFrame: Pre-dose and up to 6 hours post-dose
measure: Time to reach maximum plasma concentration (t max)
timeFrame: Pre-dose and up to 6 hours post-dose
measure: Terminal elimination rate constant (λz)
timeFrame: Pre-dose and up to 6 hours post-dose
measure: Terminal elimination half-life (t1/2,λz)
timeFrame: Pre-dose and up to 6 hours post-dose
measure: Apparent clearance (CL/F)
timeFrame: Pre-dose and up to 6 hours post-dose
measure: Apparent volume of distribution at terminal phase (Vz/F)
timeFrame: Pre-dose and up to 6 hours post-dose
measure: Cumulative amount of AZD5634 excreted in urine from time zero to 6 hours (Ae 0-6)
timeFrame: Pre-dose and up to 6 hours post-dose
measure: Cumulative percentage of dose excreted unchanged in urine from time zero to 6 hours (fe(0-6)%)
timeFrame: Pre-dose and up to 6 hours post-dose
measure: Renal clearance, estimated by dividing Ae(0-t) (CLR)
timeFrame: Pre-dose and up to 6 hours post-dose
measure: Safety of subjects by evaluating the incidence of adverse events (AEs)
timeFrame: From screening (≤28 days) up to 14-21 days post dosing
measure: Safety of subjects by evaluating the systolic and diastolic blood pressure
timeFrame: From screening (≤28 days) up to 14-21 days post dosing
measure: Safety of subjects by evaluating the pulse rate.
timeFrame: From screening (≤28 days) up to 14-21 days post dosing
measure: Safety of subjects by evaluating spirometry results
timeFrame: From screening (≤28 days) up to 14-21 days post dosing
measure: Safety of subjects by evaluating the ECG results
timeFrame: Pre-dose and up to 6 hours post-dose
measure: Safety of subjects by the physical examination
timeFrame: From screening (≤28 days) up to 14-21 days post dosing
measure: Safety of subjects by evaluating the respiratory rate.
timeFrame: From screening (≤28 days) up to 14-21 days post dosing
measure: Safety of subjects by evaluating fractional excretion of potassium (FEK)
timeFrame: Pre-dose and at 0-6 hours post-dose
measure: Safety of subjects by evaluating urine sodium/potassium (Na/K) ratio
timeFrame: Pre-dose and at 0-6 hours post-dose
measure: Safety of subjects by evaluating the pulse oximetry
timeFrame: From screening (≤28 days) up to 14-21 days post dosing
measure: Safety of subjects by evaluating the clinical laboratory test results for biochemistry
timeFrame: From screening (≤28 days) until 14-21 days post dosing
measure: Safety of subjects by evaluating the clinical laboratory test results for urinalysis
timeFrame: From screening (≤28 days) until 14-21 days post dosing
measure: Safety of subjects by evaluating the clinical laboratory test results for hematology
timeFrame: From screening (≤28 days) until 14-21 days post dosing
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Research Site
state: Alabama
city: Baltimore
country: United States
facility: Research Site
state: Maryland
city: Chapel Hill
country: United States
facility: Research Site
state: North Carolina
Study officials:
References:
citation: Kristensson C, Astrand A, Donaldson S, Goldwater R, Abdulai R, Patel N, Gardiner P, Tehler U, Mercier AK, Olsson M, Ersdal E, Maenpaa J, Bramer T, Malmgren A, Bennett W, Keen C. AZD5634, an inhaled ENaC inhibitor, in healthy subjects and patients with cystic fibrosis. J Cyst Fibros. 2022 Jul;21(4):684-690. doi: 10.1016/j.jcf.2022.02.010. Epub 2022 Feb 26.