Overview

This trial has been completed.

Condition cystic fibrosis
Treatments azd5634 for inhalation, azd5634 for infusion, placebo
Phase phase 1
Sponsor AstraZeneca
Start date February 2016
End date October 2016
Trial size 78 participants
Trial identifier NCT02679729, D6600C00001

Summary

This is a Phase 1, first-in-human (FIH) single ascending dose study being conducted to better understand the safety, tolerability and pharmacokinetics of AZD5634 in healthy subjects

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification safety study
Intervention model parallel assignment
Masking single blind (investigator)
Primary purpose basic science
Arm
(Experimental)
Subjects will inhale single doses of AZD5634 or placebo under fasted conditions and will rinse his/her mouth with approximately 100 mL (up to 240 mL) of water which must be swallowed
azd5634 for inhalation
Solution, citrate buffer, saline nebulizer solution; strength 0.1 - 5 mg/g; administered by jet nebulizer
placebo
inactive substance
(Experimental)
Subjects will inhale single doses of AZD5634 or placebo under fasted conditions and will rinse his/her mouth with approximately 100 mL (up to 240 mL) of water which must be swallowed
azd5634 for inhalation
Solution, citrate buffer, saline nebulizer solution; strength 0.1 - 5 mg/g; administered by jet nebulizer
placebo
inactive substance
(Experimental)
Subjects will inhale single doses of AZD5634 or placebo under fasted conditions and will rinse his/her mouth with approximately 100 mL (up to 240 mL) of water which must be swallowed
azd5634 for inhalation
Solution, citrate buffer, saline nebulizer solution; strength 0.1 - 5 mg/g; administered by jet nebulizer
placebo
inactive substance
(Experimental)
Subjects will inhale single doses of AZD5634 or placebo under fasted conditions and will rinse his/her mouth with approximately 100 mL (up to 240 mL) of water which must be swallowed
azd5634 for inhalation
Solution, citrate buffer, saline nebulizer solution; strength 0.1 - 5 mg/g; administered by jet nebulizer
placebo
inactive substance
(Experimental)
Subjects will inhale single doses of AZD5634 or placebo under fasted conditions and will rinse his/her mouth with approximately 100 mL (up to 240 mL) of water which must be swallowed
azd5634 for inhalation
Solution, citrate buffer, saline nebulizer solution; strength 0.1 - 5 mg/g; administered by jet nebulizer
placebo
inactive substance
(Experimental)
Subjects will inhale single doses of AZD5634 or placebo under fasted conditions and will rinse his/her mouth with approximately 100 mL (up to 240 mL) of water which must be swallowed
azd5634 for inhalation
Solution, citrate buffer, saline nebulizer solution; strength 0.1 - 5 mg/g; administered by jet nebulizer
placebo
inactive substance
(Experimental)
Subjects will inhale single doses of AZD5634 or placebo under fasted conditions and will rinse his/her mouth with approximately 100 mL (up to 240 mL) of water which must be swallowed
azd5634 for inhalation
Solution, citrate buffer, saline nebulizer solution; strength 0.1 - 5 mg/g; administered by jet nebulizer
placebo
inactive substance
(Experimental)
Subjects will receive a single dose of IV AZD5634 and after a washout period of 14 days the same subjects will receive a single dose of inhaled AZD5634
azd5634 for infusion
Solution, citrate buffer, saline solution for infusion; strength 0.013 mg/mL

Primary Outcomes

Measure
Frequencies of adverse events
time frame: From screening to 2 months post final dose
Percentages of adverse events
time frame: From screening to 2 months post final dose
Supine heart rate
time frame: From screening up to 10 days postdose
Supine blood pressure
time frame: From screening up to 10 days postdose
Supine pulse oximetry
time frame: From screening to up to 10 days postdose
Supine respiratory rate
time frame: From screening up to 10 days postdose
Supine body temperature
time frame: From screening up to 10 days postdose
12-lead electrocardiogram
time frame: during study days 1 and 2
12-lead electrocardiogram (cardiac telemetry)
time frame: Part A: From day -1 to 24 hours postdose; Part B: From day -1 to 48 hours postdose
Safety electrocardiogram
time frame: From screening up to 10 days postdose
Chemistry evaluations
time frame: From screening to 2 months postdose
Hematology evaluations
time frame: From screening to 2 months postdose
Physical examination
time frame: From screening up to 10 days postdose
Spirometry
time frame: From screening to 2 months postdose
Urine collection
time frame: From 12 hours predose to 48 hours postdose
Urinalysis evaluations
time frame: From screening to 2 months postdose

Secondary Outcomes

Measure
Observed maximum plasma concentration, taken directly from the individual concentration-time curve (Cmax)
time frame: From predose to 48 hours postdose
Area under concentration-time curve from time zero extrapolated to infinity (AUC)
time frame: From predose to 48 hours postdose
Area under the plasma concentration-curve from time zero to time of last quantifiable concentration [AUC(0-t)]
time frame: From predose to 48 hours postdose
Absolute systemic bioavailability after inhalation (Part B only) (Finhalation,total)
time frame: From predose to 48 hours postdose
Amount of AZD5634 excreted into the urine from time t1 to t2 [Ae(t1-t2)]
time frame: From 12 hours predose to 48 hours postdose
Cumulative amount of AZD5634 excreted into the urine at the last sampling interval [Ae(0-last)]
time frame: From 12 hours predose to 48 hours postdose
Fraction of dose excreted unchanged into the urine from time zero to the last measured time point for AZD5634 estimated by dividing Ae(0-last) by dose [fe(0-last)]
time frame: From 12 hours predose to 48 hours postdose
Percentage of dose excreted unchanged into the urine from time zero to the last measured time point for AZD5634 estimated by dividing Ae(0-last) by dose [fe(0-last)%]
time frame: From 12 hours predose to 48 hours postdose
Renal clearance (CLr), estimated by dividing Ae(0-last) by AUC0-t
time frame: From 12 hours predose to 48 hours postdose
Cmax, divided by the dose administered (Cmax/Dose)
time frame: From predose to 48 hours postdose
Time to reach maximum concentration, taken directly from the individual concentration-time curve (tmax)
time frame: From predose to 48 hours postdose
Terminal rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve (λz)
time frame: From predose to 48 hours postdose
Terminal half-life (t1/2λz), estimated as (ln2)/λz
time frame: From predose to 48 hours postdose
AUC0-t, divided by the dose administered (AUC0-t/Dose)
time frame: From predose to 48 hours postdose
AUC, divided by the dose administered (AUC/Dose)
time frame: From predose to 48 hours postdose
Systemic clearance for AZD5634 estimated as dose divided by AUC (Part B IV dosing only) (CL)
time frame: From predose to 48 hours postdose
Apparent clearance for AZD5634 estimated as dose divided by AUC (Part A and Part B inhaled dosing only) (CL/F)
time frame: From predose to 48 hours postdose
Mean residence time (MRT)
time frame: From predose to 48 hours postdose
Mean Absorption Time, calculated as MRTinhaled - MRTIV (Part B only) (MAT)
time frame: From predose to 48 hours postdose
Volume of distribution for AZD5634 at steady state (IV administration), estimated by dividing the MRT by the systemic CL (Part B IV dosing only) (Vss)
time frame: From predose to 48 hours postdose
Volume of distribution for AZD5634 at terminal phase (IV administration), estimated by dividing the systemic CL by λz (Part B IV dosing only) (Vz)
time frame: From predose to 48 hours postdose
Apparent volume of distribution for AZD5634 at terminal phase (inhaled administration), estimated by dividing the CL/F by λz (Part A and Part B inhaled dosing only) (Vz/F)
time frame: From predose to 48 hours postdose
Fraction of dose excreted unchanged into the urine from time t1 to t2 [fe(t1-t2)]
time frame: From 12 hours predose to 48 hours postdose

Eligibility Criteria

Male or female participants from 18 years up to 50 years old.

Inclusion Criteria: 1. Provision of signed and dated, written informed consent prior to any study specific procedures. 2. Healthy male and/or female subjects aged 18 - 50 years with suitable veins for cannulation or repeated venipuncture. 3. Females must have a negative pregnancy test at screening and on admission to the unit, must not be lactating and must be of non-childbearing potential, confirmed at screening by fulfilling 1 of the following criteria: - Post-menopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle-stimulating hormone (FSH) levels in the post-menopausal range. - Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy, but not tubal ligation. 4. Have a body mass index (BMI) between 18 and 30 kg/m2, inclusive, and weigh at least 50 kg and no more than 100 kg, inclusive. 5. Have a FEV1 (Forced expiratory volume in 1 second in liters) ≥ 80% of the predicted value at screening. 6. Provision of signed, written and dated informed consent for optional genetic/biomarker research. Exclusion Criteria: 1. History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study. 2. History or presence of gastrointestinal (GI), hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs. 3. Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the administration of investigational medicinal product (IMP). 4. Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, as judged by the investigator. 5. Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV). 6. Abnormal vital signs, after 10 minutes supine rest, at screening and check-in, defined as any of the following: - Systolic blood pressure (SBP) < 90mmHg (millimeter of mercury) or ≥ 140 mmHg - Diastolic blood pressure (DBP) < 50mmHg or ≥ 90 mmHg - Heart Rate < 45 or > 85 beats per minute (bpm) 7. Any clinically significant abnormalities in rhythm, conduction or morphology of the resting electrocardiogram (ECG) and any clinically significant abnormalities in the 12-lead ECG, as considered by the investigator that may interfere with the interpretation of QTc (QT [ECG interval measured from the onset of the QRS complex to the end of the T wave] interval corrected for heart rate) interval changes, including abnormal ST-T-wave morphology, particularly in the protocol defined primary lead or left ventricular hypertrophy, at screening. 8. PR (PQ [ECG interval measured from the onset of the P wave to the onset of the QRS complex]) interval prolongation (> 240 ms) intermittent second (Wenckebach block while asleep is not exclusive) or third degree atrioventricular (AV) block, or AV dissociation, at screening. 9. Persistent or intermittent complete bundle branch block (BBB), incomplete bundle branch block (IBBB), or intraventricular conduction delay (IVCD) with QRS > 110 ms. Subjects with QRS (ECG interval measured from the onset of the QRS complex to the J point) > 110 ms but < 115 ms are acceptable if there is no evidence of, for example, ventricular hypertrophy or pre-excitation, at screening. 10. Serum/plasma potassium levels are outside the normal range and lower than 3.5 to 5.1 mEq/L (milliequivalents per liter) at screening and prior to dosing. 11. Has active lung disease/asthma that requires treatment. 12. Known or suspected history of drug abuse, as judged by the investigator. 13. Current smokers or those who have smoked or used nicotine products within the previous 3 months. 14. History of alcohol abuse or excessive intake of alcohol, as judged by the investigator. 15. Positive screen for drugs of abuse, cotinine (nicotine), or alcohol at screening or admission to the unit. 16. History of severe allergy/hypersensitivity or ongoing clinically significant allergy/hypersensitivity, as judged by the investigator or history of hypersensitivity to drugs with a similar chemical structure or class to AZD5634. 17. Excessive intake of caffeine containing drinks or food (e.g., coffee, tea, chocolate), as judged by the investigator. 18. Use of drugs with enzyme inducing properties such as St John's Wort within 3 weeks prior to the administration of IMP. 19. Use of any prescribed or non-prescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the 2 weeks prior to the administration of IMP or longer if the medication has a long half-life. 20. Plasma donation within 1 month of screening or any blood donation/blood loss > 500 mL during the 3 months prior to screening. 21. Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of the administration of IMP in this study. The period of exclusion is 3 months after the final dose from a previous study. Note: Subjects consented and screened, but not randomized in this study or a previous phase I study, are not excluded. 22. Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order. 23. Involvement of any Astra Zeneca, PAREXEL or study site employee or their close relatives. 24. Judgment by the investigator that the subject should not participate in the study if they have any ongoing or recent (i.e., during the screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions and requirements. 25. Subjects who are vegans or have medical dietary restrictions. 26. Subjects who cannot communicate reliably with the investigator. In addition, any of the following is regarded as a criterion for exclusion from the genetic research: 27. Previous bone marrow transplant. 28. Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection.

Additional Information

Official title A Phase I, Randomized, Single-Blind, Placebo-Controlled Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD5634 Following Single-Ascending Inhaled Doses (Part A) and After Single Inhaled and Intravenous Doses (Part B) in Healthy Subjects
Principal investigator Ronald Goldwater, MDCM, M.Sc, CPI
Description This study is a Phase I, FIH, randomized, single-blinded (study center staff remain blinded during the dosing phase of the study), placebo-controlled, single ascending dose, sequential dose group study in healthy male subjects and/or female subjects of non-childbearing potential at a single study center to assess AZD5634 following inhaled and intravenous dose administration
Trial information was received from ClinicalTrials.gov and was last updated in November 2016.
Information provided to ClinicalTrials.gov by AstraZeneca.