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

Chronic Kidney Disease Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04550234
• Other study ID #: D5495C00014
• Status: Completed
• Phase: Phase 1
• Start date: April 13, 2021
• Est. completion date: July 15, 2021

Study information

• Verified date: June 2022
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 25
• Est. completion date: July 15, 2021
• Est. primary completion date: July 15, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 50 Years

Eligibility

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.

Related Conditions & MeSH terms

• Chronic Kidney Disease
• Kidney Diseases
• Renal Insufficiency, Chronic

Intervention

Drug:
• Verinurad prolonged release HPMC capsule
Randomized subjects will receive oral dose of verinurad HPMC capsule.
• Allopurinol Tablet
Randomized subjects will receive oral dose of allopurinol tablet.
• Verinurad/Allopurinol FDC Capsule
Randomized subjects will receive oral dose of Verinurad/Allopurinol FDC capsule.
• Verinurad prolonged release gelatin Capsule
Randomized subjects will receive oral dose of Verinurad gelatin capsule.

Locations

Country	Name	City	State
Germany	Research Site	Berlin

Sponsors (2)

Lead Sponsor	Collaborator
AstraZeneca	Parexel

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	t½?z: Half-life Associated With Terminal Slope (?z) of Semi-logarithmic Concentration-time Curve	The t½?z of verinurad, allopurinol and oxypurinol were assessed as PK parameters	Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
Secondary	?z: Terminal Elimination Rate Constant	The ?z of verinurad, allopurinol and oxypurinol were assessed as PK parameters	Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)

External Links

•   D5495C00014 CSR Synopsis
•   D5495C00014 Protocol