Clinical trial NCT02679729: To Assess the Safety, Tolerability and Pharmacokinetics of AZD5634 Following Inhaled and Intravenous (IV)Dose Administration
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Cystic Fibrosis
Keywords: inhaled dose
intravenous dose
healthy subjects
safety
tolerability
pharmacokinetics
AZD5634
jet nebulizer
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2016-02-10
Enrollment: 63
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief 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

Detailed 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

Eligibility criteria: 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.

Primary outcomes:
measure: Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B).
timeFrame: Screening (serious adverse event, SAE), Day -1 (SAE), Spontaneous plus Predose, 3,12,24, and 48 h postdose (Days 1 to 3), Follow-up 7-10 days postdose, 2 months post final dose.
Secondary outcomes:
measure: Observed Maximum Plasma Concentration, Taken Directly From the Individual Concentration-time Curve (Cmax)- For Part A and Part B
timeFrame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
measure: Area Under Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC) for Part A and Part B
timeFrame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
measure: Area Under the Plasma Concentration-curve From Time Zero to Time of Last Quantifiable Concentration [AUC(0-t)] for Part A and Part B
timeFrame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
measure: Absolute Systemic Bioavailability After Inhalation (Part B Only) (Finhalation,Total)
timeFrame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
measure: Renal Clearance (CLR), Estimated by Dividing Ae(0-last) by AUC0-t - For Part A and Part B
timeFrame: -12-0, 0-6, 6-12, 12-24, 24-48 h (Days 1 to 3)
measure: Cmax, Divided by the Dose Aministered (Cmax/Dose) - For Part A and Part B
timeFrame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
measure: Terminal Half-life (t1/2λz), Estimated as (ln2)/λz - For Part A and Part B
timeFrame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
measure: AUC0-t, Divided by the Dose Administered (AUC0-t/Dose) - For Part A and Part B
timeFrame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
measure: AUC, Divided by the Dose Administered (AUC/Dose) - For Part A and Part B
timeFrame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
measure: Systemic Clearance for AZD5634 Estimated as Dose Divided by AUC (Part B IV Dosing Only) (CL)
timeFrame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
measure: Apparent Clearance for AZD5634 Estimated as Dose Divided by AUC (Part A and Part B Inhaled Dosing Only) (CL/F)
timeFrame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
measure: Mean Residence Time (MRT) - For Part A and Part B
timeFrame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
measure: Mean Absorption Time, Calculated as MRTinhaled - MRTIV (Part B Only) (MAT)
timeFrame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
measure: 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)
timeFrame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
measure: Volume of Distribution for AZD5634 at Terminal Phase (IV Administration), Estimated by Dividing the Systemic CL by λz (Part B IV Dosing Only) (Vz)
timeFrame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
measure: 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)
timeFrame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
Other outcomes:
Locations:
city: Glendale
country: United States
facility: Research Site
state: California
city: Baltimore
country: United States
facility: Research Site
state: Maryland
Study officials:
affiliation: PAREXEL Early Phase Clinical Unit Baltimore
name: Ronald Goldwater, MDCM, M.Sc, CPI
role: PRINCIPAL_INVESTIGATOR
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.