Clinical trial NCT04550234: A Study in Healthy Subjects to Assess Drug Availability of 4 Different Formulations of Verinurad and Allopurinol
Official title: A Randomised, Single Dose, 5-period, 5-treatment, Crossover Study to Assess the Relative Bioavailability of 4 Different Formulations of Verinurad and Allopurinol in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Chronic Kidney Disease
Keywords: 3-period
Crossover
URAT1 inhibitor
Xanthine oxidase inhibitor
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2020-09-16
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief 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.

Detailed description: The study comprises of:

* A Screening Period of maximum 28 days;
* Five treatment periods during which subjects will be resident from the morning of Day -2 until at least 72 hours after dosing in Treatment Period 5; discharged on the morning of Day 4 of Treatment Period 5; and
* A Follow-up Visit 7 to 14 days after the last dosing.

Each subject will receive 5 single dose treatments of verinurad and allopurinol or verinurad alone and subject will be involved in the study for 52 to 59 days.

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.

Primary outcomes:
measure: AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity in Fasted Condition
timeFrame: Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
measure: AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration in Fasted Condition
timeFrame: Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
measure: Cmax: Maximum Observed Plasma Drug Concentration in Fasted State
timeFrame: Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
Secondary outcomes:
measure: Cmax: Maximum Observed Plasma Drug Concentration
timeFrame: Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
measure: AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity
timeFrame: Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
measure: AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration
timeFrame: Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
measure: Tmax: Time to Reach Maximum Observed Plasma Concentration Following Drug Administration
timeFrame: Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
measure: Tlag: Time Delay Between Drug Administration and First Observed Concentration in Plasma
timeFrame: Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
measure: t½λz: Half-life Associated With Terminal Slope (λz) of Semi-logarithmic Concentration-time Curve
timeFrame: Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
measure: λz: Terminal Elimination Rate Constant
timeFrame: Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
measure: CL/F: Apparent Total Body Clearance of Drug Clearance of Drug From Plasma After Extravascular Administration
timeFrame: Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
measure: MRTinf: Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity
timeFrame: Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
measure: Vz/F: Apparent Volume of Distribution During Terminal Phase After Extravascular Administration
timeFrame: Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
measure: Vss/F: Apparent Volume of Distribution at Steady State Following Extravascular Administration
timeFrame: Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
measure: Emax, CB: Maximum Percentage Change From Baseline (CB)
timeFrame: Day -1, Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
measure: tEmax, CB: Time of Maximum Percentage CB Change From Baseline (CB)
timeFrame: Day -1, Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
measure: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events
timeFrame: From screening (Day -28 to -3) until follow-up visit (7 to 14 days post final dose) (approximately 52 to 59 days)
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Research Site
Study officials:
References: