A Study in Healthy Subjects to Assess Drug Availability of 4 Different Formulations of Verinurad and Allopurinol

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

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.

Study Overview

• Status: Completed
• Conditions: Chronic Kidney Disease
• Intervention / Treatment: Drug: Verinurad prolonged release HPMC capsule; Drug: Allopurinol Tablet; Drug: Verinurad/Allopurinol FDC Capsule; Drug: Verinurad prolonged release gelatin 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.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 14050
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment 1; Subjects will receive verinurad prolonged release HPMC capsule and allopurinol tablet in fasted state on Day 1.	Drug: Verinurad prolonged release HPMC capsule; Randomized subjects will receive oral dose of verinurad HPMC capsule.; Drug: Allopurinol Tablet; Randomized subjects will receive oral dose of allopurinol tablet.
Experimental: Treatment 2; Subjects will receive verinurad/allopurinol FDC capsule in fasted state on Day 1.	Drug: Verinurad/Allopurinol FDC Capsule; Randomized subjects will receive oral dose of Verinurad/Allopurinol FDC capsule.
Experimental: Treatment 3; Subjects will receive verinurad/allopurinol FDC capsule in fed state on Day 1.	Drug: Verinurad/Allopurinol FDC Capsule; Randomized subjects will receive oral dose of Verinurad/Allopurinol FDC capsule.
Experimental: Treatment 4; Subjects will receive verinurad prolonged release HPMC capsule and allopurinol tablet in fed state on Day 1.	Drug: Verinurad prolonged release HPMC capsule; Randomized subjects will receive oral dose of verinurad HPMC capsule.; Drug: Allopurinol Tablet; Randomized subjects will receive oral dose of allopurinol tablet.
Experimental: Treatment 5; Subjects will receive verinurad prolonged release gelatin capsule in fasted state on Day 1.	Drug: Verinurad prolonged release gelatin Capsule; Randomized subjects will receive oral dose of Verinurad gelatin capsule.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity in Fasted Condition	The AUCinf of verinurad, allopurinol and oxypurinol were assessed in fasted state as PK parameters	Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration in Fasted Condition	The AUClast of verinurad, allopurinol and oxypurinol were assessed in fasted condition as PK parameters	Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
Cmax: Maximum Observed Plasma Drug Concentration in Fasted State	The Cmax of verinurad, allopurinol and oxypurinol were assessed in fasted state as PK parameters	Day 1, Day 2, Day 3 and Day 4 of each Treatment Period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax: Maximum Observed Plasma Drug Concentration	The Cmax of verinurad, allopurinol and oxypurinol were assessed as PK parameters	Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity	The AUCinf of verinurad, allopurinol and oxypurinol were assessed as PK parameters	Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration	The AUClast of verinurad, allopurinol and oxypurinol were assessed as PK parameters	Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
Tmax: Time to Reach Maximum Observed Plasma Concentration Following Drug Administration	The tmax of verinurad, allopurinol and oxypurinol were assessed as PK parameters	Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
Tlag: Time Delay Between Drug Administration and First Observed Concentration in Plasma	The tlag of verinurad, allopurinol and oxypurinol were assessed as PK parameters	Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
t½λz: Half-life Associated With Terminal Slope (λz) of Semi-logarithmic Concentration-time Curve	The t½λz of verinurad, allopurinol and oxypurinol were assessed as PK parameters	Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
λz: Terminal Elimination Rate Constant	The λz of verinurad, allopurinol and oxypurinol were assessed as PK parameters	Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
CL/F: Apparent Total Body Clearance of Drug Clearance of Drug From Plasma After Extravascular Administration	The CL/F of verinurad and allopurinol were assessed as PK parameters	Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
MRTinf: Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity	The MRTinf of verinurad and allopurinol were assessed as PK parameters	Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
Vz/F: Apparent Volume of Distribution During Terminal Phase After Extravascular Administration	The Vz/F of verinurad and allopurinol were assessed as PK parameters	Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
Vss/F: Apparent Volume of Distribution at Steady State Following Extravascular Administration	The Vss/F of verinurad and allopurinol were assessed as PK parameters	Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
Emax, CB: Maximum Percentage Change From Baseline (CB)	The Emax, CB in serum uric acid (sUA) concentration (time-matched, Day -1) was assessed as PD parameter.	Day -1, Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
tEmax, CB: Time of Maximum Percentage CB Change From Baseline (CB)	The tEmax, CB in serum uric acid (sUA) concentration (time-matched, Day -1) was assessed as PD parameter.	Day -1, Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
Number of Subjects With Adverse Events (AEs) and Serious Adverse Events	The safety of single doses of verinurad and allopurinol were assessed	From screening (Day -28 to -3) until follow-up visit (7 to 14 days post final dose) (approximately 52 to 59 days)

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Parexel

Publications and helpful links

Helpful Links

• D5495C00014 CSR Synopsis
• D5495C00014 Protocol

Study record dates

Study Major Dates

• Study Start (Actual): April 13, 2021
• Primary Completion (Actual): July 15, 2021
• Study Completion (Actual): July 15, 2021

Study Registration Dates

• First Submitted: September 9, 2020
• First Submitted That Met QC Criteria: September 9, 2020
• First Posted (Actual): September 16, 2020

Study Record Updates

• Last Update Posted (Actual): May 10, 2023
• Last Update Submitted That Met QC Criteria: June 28, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: Crossover; URAT1 inhibitor; 3-period; Xanthine oxidase inhibitor
• Additional Relevant MeSH Terms: Urologic Diseases; Renal Insufficiency; Kidney Diseases; Renal Insufficiency, Chronic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites; Protective Agents; Antioxidants; Free Radical Scavengers; Gout Suppressants; Allopurinol; Verinurad
• Other Study ID Numbers: D5495C00014

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the requests portal. All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No