To Assess the Safety, Tolerability and Pharmacokinetics of AZD5634 Following Inhaled and Intravenous (IV)Dose Administration
Condition: Cystic Fibrosis
MeSH terms: Cystic Fibrosis
Intervention: AZD5634 for inhalation; AZD5634 for infusion; Placebo
Intervention description: Solution, citrate buffer, saline nebulizer solution; strength 0.1 - 5 mg/g; administered by jet nebulizer; Solution, citrate buffer, saline solution for infusion; strength 0.013 mg/mL; inactive substance
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Investigator)
Enrollment: 63.0
Sex: All
Minimum age: 18 Years
Maximum age: 50 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: inhaled dose; intravenous dose; healthy subjects; safety; tolerability; pharmacokinetics; AZD5634; jet nebulizer

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
    

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.