A Study in Healthy Subjects to Assess Drug Availability of 4 Different Formulations of Verinurad and Allopurinol
Condition: Chronic Kidney Disease
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic
Intervention: Verinurad prolonged release HPMC capsule; Allopurinol Tablet; Verinurad/Allopurinol FDC Capsule; Verinurad prolonged release gelatin Capsule
Intervention description: Randomized subjects will receive oral dose of verinurad HPMC capsule.; Randomized subjects will receive oral dose of allopurinol tablet.; Randomized subjects will receive oral dose of Verinurad/Allopurinol FDC capsule.; Randomized subjects will receive oral dose of Verinurad gelatin capsule.
Intervention MeSH terms: Allopurinol; Verinurad
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 25.0
Sex: All
Minimum age: 18 Years
Maximum age: 50 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: 3-period; Crossover; URAT1 inhibitor; Xanthine oxidase inhibitor

Summary:

      This study is a single centre, randomised, open-label, single-dose, 5-period, 5-treatment,
      crossover study in healthy male and female subjects. This study is intended to assess the
      relative bioavailability between the fixed dose combination (FDC, i.e. verinurad/allopurinol
      FDC capsule 12/300 mg) and free combination formulations of verinurad (i.e. verinurad
      prolonged release Hydroxypropyl methylcellulose [HPMC] capsule 12 mg) and allopurinol (i.e.
      allopurinol table 300 mg) in fasted and fed conditions. The study will also assess the
      relative bioavailability between a formulation only containing verinurad (i.e. verinurad
      prolonged release gelatin capsule 12 mg) and the FDC capsule.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Provision of signed and dated, written informed consent prior to any study specific
             procedures.

          -  Healthy male and female subjects aged 18 to 50 years (inclusive) with suitable veins
             for cannulation or repeated venepuncture.

          -  Have a body mass index between 18 and 30 kg/m^2 (inclusive) and weigh at least 50 kg
             and no more than 100 kg (inclusive).

          -  Females must have a negative pregnancy test at screening and on admission to the unit
             and must be:

               1. not pregnant or currently lactating or breastfeeding.

               2. of non-childbearing potential, confirmed at screening by fulfilling one of the
                  following criteria: (i) postmenopausal 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 postmenopausal range (FSH levels
                  > 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.

          -  Must be able to swallow multiple capsules and tablets.

        Exclusion Criteria:

          -  History of gout or any clinically significant disease which, in the opinion of the
             principal investigator (PI), may either put the volunteer at risk because of
             participation in the study, or influence the results or the volunteer's ability to
             participate in the study.

          -  Any clinically important illness, medical/surgical procedure or trauma within 4 weeks
             of the first administration of verinurad.

          -  History or presence of gastrointestinal, hepatic or renal disease, or any other
             condition known to interfere with absorption, distribution, metabolism, or excretion
             of drugs.

          -  Any clinically important abnormalities in clinical chemistry, haematology or
             urinalysis results as judged by the Investigator at screening and first admission,
             including:

               1. Alanine aminotransferase > 1.5 x upper limit of normal (ULN),

               2. Aspartate aminotransferase > 1.5 x ULN,

               3. Bilirubin (total) > 1.5 x ULN,

               4. Gamma glutamyl transpeptidase > 1.5 x ULN.

          -  Any clinically significant abnormal findings in vital signs at the Screening Visit
             and/or admission to the Clinical Unit, including, but not limited to, any of the
             following:

               1. Pulse (resting, supine) < 50 beats per minute (bpm) or > 90 bpm,

               2. Systolic blood pressure (BP) < 90 mmHg or > 140 mmHg and/or diastolic BP < 50
                  mmHg or > 90 mmHg sustained for > 10 minutes while resting in a supine position.

          -  Any clinically significant abnormalities on 12 lead electrocardiogram (ECG) at the
             Screening Visit, including, but not limited to any of the following:

               1. QTcF > 450 ms or < 340 ms or family history of long QT syndrome,

               2. Any significant arrhythmia

               3. Conduction abnormalities

               4. Clinically significant PR (PQ) interval prolongation (> 240 ms); intermittent
                  second or third degree AV block, or AV dissociation

               5. Complete bundle branch block and/or QRS duration > 120 ms.

          -  Any positive result at the Screening Visit for serum Hepatitis B surface antigen or
             Anti Hepatitis B core antibody, hepatitis virus C antibody, and human immunodeficiency
             virus antibody.

          -  Suspicion or known Gilbert's and/or Lesch Nyhan syndrome.

          -  Known or suspected history of alcohol or drug abuse or excessive intake of alcohol as
             judged by the PI.

          -  Has received another new chemical or biological entity within 30 days or at least 5
             half lives of the first administration of verinurad in this study.

          -  Subjects who have previously received verinurad.

          -  Plasma donation within 1 month of screening or any blood donation/loss of more than
             500 mL during the 3 months prior to the Screening Visit.

          -  Subjects who are pregnant, lactating or planning to become pregnant.

          -  Hypersensitivity to verinurad, allopurinol or any drug with a similar chemical
             structure/class to verinurad and/or allopurinol.

          -  Current smokers or those who have smoked or used nicotine products (including e
             cigarettes) within the 3 months prior to screening.

          -  Excessive intake of caffeine containing drinks or food as judged by the PI.

          -  Positive screen for drugs of abuse or cotinine (nicotine) at the Screening Visit or
             positive screen for alcohol, drugs of abuse and cotinine on each admission to the
             study centre.

          -  Use of drugs with enzyme inducing properties within 3 weeks prior to the first
             administration of verinurad.

          -  Use of any prescribed or non prescribed medication including antacids, analgesics,
             herbal remedies, megadose vitamins and minerals during the 2 weeks prior to the first
             administration of verinurad or longer if the medication has a long half life.

          -  Any AstraZeneca, Parexel or study site employee or their close relatives.

          -  Subjects who cannot communicate reliably with the PI and/or is not able to read, speak
             and understand the German language.

          -  Judgment by the PI 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.

          -  Vulnerable subjects, e.g., kept in detention, protected adults under guardianship,
             trusteeship, or committed to an institution by governmental or juridical order.

          -  Subjects with any special dietary restrictions such as subjects that are lactose
             intolerant or are vegetarians/vegans.

          -  Subject is a carrier of the HLA B*58:01 allele.

          -  Subject has a positive test result for severe acute respiratory syndrome corona virus
             (SARS-CoV-2) RT-PCR before randomisation.

          -  Subject has clinical signs and symptoms consistent with Coronavirus disease 2019
             (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.

          -  History of severe COVID-19 (hospitalisation, extracorporeal membrane oxygenation,
             mechanically ventilated).

          -  Subjects who are regularly exposed to COVID-19 as part of their daily life.

          -  Subjects who have had or are planning to have the COVID-19 vaccination within 4 weeks
             prior to screening or at any time during the study.