A Study to Assess the Effect of Verinurad on the Electric Activity of the Heart
Condition: Healthy Volunteers (Intended Indication: Chronic Kidney Disease)
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic
Intervention: Verinurad; Placebo; Allopurinol
Intervention description: Randomized subjects will receive oral dose of verinurad; Randomized subjects will receive oral dose of placebo; Randomized subjects will receive oral dose of allpurinol (Treatment A and B)
Intervention MeSH terms: Allopurinol; Verinurad
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking description: This study is double-blind with regards to treatment (verinurad and allopurinol or the matching placebos) at each dose level. Placebo will be matched with verinurad and allopurinol for appearance and amount. Subjects randomized to placebo will receive the same volume of oral suspension as subjects on active drug.
Enrollment: 24.0
Sex: All
Minimum age: 18 Years
Maximum age: 50 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Randomised; Double-Blind; Placebo-Controlled; 3-Period Crossover; Verinurad; Allopurinol; Phase 1

Summary:

      This study will be conducted to investigate the safety of verinurad in healthy volunteers in
      combination with allopurinol 300 mg, compared with placebo in particular its effect on
      electrocardiogram (ECG), with focus on the QT/QTc interval
    

Eligibility criteria:

        Inclusion Criteria:

          1. Provision of signed and dated, written informed consent prior to any study-specific
             procedures.

          2. Healthy male and female subjects aged 18 to 50 years (inclusive) with suitable veins
             for cannulation or repeated venipuncture.

          3. Females must have a negative pregnancy test at Screening and on admission to the study
             centre must be:

        (1) Not pregnant or currently lactating or breast-feeding. (2) Of non-childbearing
        potential confirmed at the Screening Visit by fulfilling one of the following criteria: (i)
        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 (FSH >40 IU/mL).

        (ii) Documentation of irreversible surgical sterilization by hysterectomy, bilateral
        oophorectomy or bilateral salpingectomy but not tubal ligation.

        (3) OR, if of childbearing potential, must be willing to use an acceptable method of
        contraception to avoid pregnancy for the entire study period and 3 months after the
        Follow-up Visit.

        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. Serum uric acid (sUA) <300 μmol/L at Screening (Visit 1) and sUA <330 μmol/L on Day -1
        in every treatment period (Visit 2 to 4). Note: Since sUA levels might vary on a daily
        basis, subjects with sUA ≥330 μmol/L on Day -1 will be retested. Treatment on Day 1 will
        only be administered when the sUA level on Day -1 is <330 μmol/L upon retesting. Subjects
        with sUA ≥330 μmol/L despite retesting, may conduct the treatment period at a later date
        when they have sUA <330 μmol/L.

        6. Must be able to swallow multiple capsules/tablets.

        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 first administration of investigational medicinal product (IMP).

          4. Subject has a positive test result for SARS-CoV-2 RT-PCR before randomisation.

          5. Subject has clinical signs and symptoms consistent with COVID-19, eg, fever, dry
             cough, dyspnoea, sore throat, fatigue or confirmed infection by appropriate laboratory
             test within the last 4 weeks prior to screening or on admission.

          6. History of severe COVID-19 (hospitalization, extracorporeal membrane oxygenation,
             mechanically ventilated).

          7. Any clinically significant abnormalities in clinical chemistry, haematology, or
             urinalysis results, at Screening (Visit 1) as judged by the Investigator, including:

        (1) Alanine aminotransferase (ALT) >1.5 × upper limit of normal (ULN) (2) Aspartate
        aminotransferase (AST) >1.5 × ULN (3) Bilirubin (total) >1.5 × ULN (4) Gamma glutamyl
        transpeptidase (GGT) >1.5 × ULN 8. Any clinically significant abnormal findings in vital
        signs at Screening as judged by the Investigator, including:

        (1) Systolic blood pressure <90 mmHg or >140 mmHg (2) Diastolic blood pressure <50 mmHg or
        >90 mmHg (3) Heart rate <50 or >90 bpm 9. Carrier of the HLA-B*58:01 allele. 10. Any
        clinically important abnormalities in rhythm, conduction or morphology of the 12 lead
        safety ECG and any clinically important abnormalities in the 12-lead safety ECG as
        considered by the Investigator that may interfere with the interpretation of QT interval
        corrected for heart rate using Fridericia's formula (QTcF), including abnormal ST T wave
        morphology, particularly in the Clinical Study Protocol (CSP)-defined primary lead for dECG
        analysis or left ventricular hypertrophy:

          1. Prolonged QTcF >450 ms or shortened QTcF <340 ms or family history of long QT
             syndrome.

          2. PR (PQ) interval shortening <120 ms (PR >110 ms but <120 ms is acceptable if there is
             no evidence of ventricular pre-excitation).

          3. PR (PQ) interval prolongation (>220 ms) intermittent second (Wenckebach block while
             asleep is not exclusive) or third degree atrioventricular (AV) block, or AV
             dissociation.

          4. Persistent or intermittent complete bundle branch block, incomplete bundle branch
             block, or intraventricular conduction delay with QRS >110 ms. Subjects with QRS >110
             ms but <115 ms are acceptable if there is no evidence of ventricular hypertrophy or
             pre-excitation.

        11. Any positive result on Screening for serum hepatitis B surface antigen OR anti-HBc
        antibody, hepatitis C antibody, and human immunodeficiency virus (HIV) antibody.

        12. Suspected or known Gilbert's syndrome. 13. Current smokers or those who have smoked or
        used nicotine products (including e cigarettes) within the 3 months prior to Screening.

        14. Known or suspected history of alcohol abuse or excessive intake of alcohol as judged by
        the Investigator. Excessive intake of alcohol defined as the regular consumption of more
        than 24 g of alcohol per day for men or 12 g per day for women.

        15. Positive screen for drugs of abuse, cotinine (nicotine) or alcohol at the Screening
        Visit or on each admission to the study centre.

        16. Excessive intake of caffeine-containing drinks or food (eg, coffee, tea, chocolate) as
        judged by the Investigator. Excessive intake of caffeine defined as the regular consumption
        of more than 600 mg of caffeine per day (eg, >5 cups of coffee) or would likely be unable
        to refrain from the use of caffeine-containing beverages during confinement at the study
        site.

        17. Previous hypersensitivity reaction to allopurinol or any URAT1 inhibitor. 18. Subjects
        who are pregnant, breast-feeding or planning to become pregnant (pregnancy is to be avoided
        for the entire study period and 3 months after the Follow up Visit).

        19. Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks
        prior to the first administration of IMP.

        20. Use of any prescribed or non-prescribed medication including antacids, analgesics
        (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to
        600 × the recommended daily dose) and minerals during the 2 weeks prior to the first
        administration of IMP or within 5 half-lives (whichever is longer). Hormone replacement
        therapy is allowed for females.

        21. Plasma donation within 1 month of Screening or any blood donation/blood loss >500 mL
        during the 3 months prior to Screening.

        22. Has received another new chemical or biological entity (defined as a compound which has
        not been approved for marketing in the US) within 30 days or within 5 half lives (whichever
        is longer) of the first administration of IMP in this study.

        Note: Subjects consented and screened, but not randomised in this study or a previous Phase
        I study, are not excluded.

        23. Involvement of any AstraZeneca, Parexel or study site employee or their close
        relatives.

        24. Subjects who have previously received verinurad. 25. Subjects who cannot communicate
        reliably with the Investigator and/or are not able to read, speak and understand the German
        language.

        26. Judgment by the Investigator that the subject should not participate in the study if
        there are any ongoing or recent (ie, during the Screening Period) minor medical complaints
        that may interfere with the interpretation of the study data or are considered unlikely to
        comply with study procedures, restrictions and requirements.

        27. Subjects who are vegans or have medical dietary restrictions. 28. Vulnerable subjects,
        eg, kept in detention, protected adults under guardianship, trusteeship, or committed to an
        institution by governmental or juridical order.

        29. Subjects who are regularly exposed to COVID-19 (eg, health care professionals working
        in COVID-19 wards or at emergency departments) as part of their daily life.