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

AstraZeneca

Status and phase: Completed; Phase 1

Conditions: Pulmonary/Respiratory Diseases

Treatments: Drug: AZD5634; Drug: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT02950805

D6600C00002

Details and patient eligibility

About

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

Full 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).

Enrollment: 9 patients

Sex: All

Ages: 18 to 60 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Quadruple Blind

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9 participants in 2 patient groups

Placebo + AZD5634

Experimental group

Description:

Subjects were administered single dose of placebo in period 1 and AZD5634 in period 2.

Treatment:

Drug: AZD5634

Drug: Placebo

AZD5634 + Placebo

Experimental group

Description:

Subjects were administered single dose of AZD5634 in period 1 and placebo in period 2.

Treatment:

Drug: AZD5634

Drug: Placebo