Healthy Volunteers (Intended Indication: Chronic Kidney Disease)Phase 1NCT04256629

A Study to Assess the Effect of Verinurad on the Electric Activity of the Heart

A Phase 1 study testing Verinurad and Allopurinol in people with Healthy Volunteers (Intended Indication: Chronic Kidney Disease), run by AstraZeneca at 1 site in Germany.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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 Read more about this study

Who is it for?: Ages 18 to 50 yearsHealthy volunteers can take part
Conditions the study is for: Healthy Volunteers (Intended Indication: Chronic Kidney Disease)
What is being tested?: Verinurad and Allopurinol
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 24 participants
Where: 1 siteGermany
Study dates: 3 Mar 2020to 21 Aug 2020
Phase: Phase 1
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 50 years
All sexes
Healthy volunteers accepted
Adult

Who may be able to join

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 venipuncture.
Females must have a negative pregnancy test at Screening and on admission to the study centre must be:
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).
Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
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.

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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.

Who cannot join

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.
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.
Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of investigational medicinal product (IMP).
Subject has a positive test result for SARS-CoV-2 RT-PCR before randomisation.
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.
History of severe COVID-19 (hospitalization, extracorporeal membrane oxygenation, mechanically ventilated).

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Any clinically significant abnormalities in clinical chemistry, haematology, or urinalysis results, at Screening (Visit 1) as judged by the Investigator, including:
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:
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:
Prolonged QTcF >450 ms or shortened QTcF <340 ms or family history of long QT syndrome.
PR (PQ) interval shortening <120 ms (PR >110 ms but <120 ms is acceptable if there is no evidence of ventricular pre-excitation).
PR (PQ) interval prolongation (>220 ms) intermittent second (Wenckebach block while asleep is not exclusive) or third degree atrioventricular (AV) block, or AV dissociation.
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.

Trial locations and contacts

1 site in 1 country.

Germany1 site

Research Site
Berlin, 14050

Other trials in Germany

About this study

Official title: A Single-Centre, Randomised, Double-Blind, Placebo-Controlled, 3-Period, Cross-Over Phase I Study to Investigate the Effect on the QTcF Interval of a Single Dose of 2 Different Doses of Verinurad, Each in Combination With Allopurinol 300 mg, Compared With Placebo In Healthy Volunteers

Read the detailed description

This study will be conducted as a single-centre, randomised, placebo-controlled, double-blind, 3-period, crossover study to assess the effect on the QTcF interval of a single oral dose of verinurad 24 mg extended release (ER8) formulation (therapeutic exposure) or verinurad 40 mg immediate release (IR) formulation (supra-therapeutic exposure), each in combination with allopurinol 300 mg, compared to placebo in healthy subjects.

There are 3 study treatments:

Treatment A: Verinurad 24 mg ER8 formulation co-administered with 300 mg allopurinol
Treatment B: Verinurad 40 mg IR formulation co-administered with 300 mg allopurinol
Treatment C: Matched placebos for both verinurad and allopurinol

All subjects will receive a single dose of all 3 treatments (A, B, and C) in a cross-over design with wash-out periods of at least 7 days between each study dose administration.

Subjects will be randomised to the treatment sequence (ABC, BCA, CAB, etc.) using William's Latin square. The treatments will be administered in a double-blind manner after an overnight fast of at least 10 hours.

The study will comprise the following periods (visits):

Screening Period of maximum 28 days (Visit 1);
Three treatment periods of 3 days each, during which subjects will be resident at the study centre from the morning of the day before administration of the study dose until discharge 2 days after study dose administration (Visits 2 to 4);
Wash-out periods of at least 7 days between each study dose administration;
Final visit within 7 to 10 days after the last study dose administration (Visit 5).

Each subject will be involved in the study for approximately 53 days and have 5 study visits.

Conditions: Healthy Volunteers (Intended Indication: Chronic Kidney Disease)
Being tested: Verinurad, Placebo, Allopurinol
Keywords: Randomised, Double-Blind, Placebo-Controlled, 3-Period Crossover, Verinurad, Allopurinol, Phase 1

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

VerinuradDrug
Also called verinurad ER 24 mg, verinurad IR 40 mg
Randomized subjects will receive oral dose of verinurad
PlaceboDrug
Also called verinurad matching placebo, allopurinol matching placebo
Randomized subjects will receive oral dose of placebo
AllopurinolDrug
Also called allopurinol 300 mg
Randomized subjects will receive oral dose of allpurinol (Treatment A and B)

Study groups in NCT04256629
Study group	Role	What they receive
Treatment ABC	Experimental	Subjects will receive a single dose of all 3 treatments (A, B, and C) in a crossover design with wash-out periods of at least 7 days between each study dose administration. Receives: Drug: Verinurad; Drug: Placebo; Drug: Allopurinol
Treatment BCA	Experimental	Subjects will receive a single dose of all 3 treatments (B, C, and A) in a crossover design with wash-out periods of at least 7 days between each study dose administration. Receives: Drug: Verinurad; Drug: Placebo; Drug: Allopurinol
Treatment CAB	Experimental	Subjects will receive a single dose of all 3 treatments (C, A, and B) in a crossover design with wash-out periods of at least 7 days between each study dose administration. Receives: Drug: Verinurad; Drug: Placebo; Drug: Allopurinol
Treatment ACB	Experimental	Subjects will receive a single dose of all 3 treatments (A, C, and B) in a crossover design with wash-out periods of at least 7 days between each study dose administration. Receives: Drug: Verinurad; Drug: Placebo; Drug: Allopurinol
Treatment BAC	Experimental	Subjects will receive a single dose of all 3 treatments (B, A, and C) in a crossover design with wash-out periods of at least 7 days between each study dose administration. Receives: Drug: Verinurad; Drug: Placebo; Drug: Allopurinol
Treatment CBA	Experimental	Subjects will receive a single dose of all 3 treatments (C, B and A) in a crossover design with wash-out periods of at least 7 days between each study dose administration. Receives: Drug: Verinurad; Drug: Placebo; Drug: Allopurinol

What is being measured

The primary outcome is the main question the study is designed to answer.

Model Predicted Baseline-corrected and Placebo-corrected QT Interval Corrected for Heart Rate (HR) Using Fridericia's Formula (QTcF)(ΔΔQTcF) (Derived From Concentration-QTcF Analysis) at Geometric Mean of Cmax of Verinurad
Assessment of the effect of a single dose of verinurad given as either a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of International Council for Harmonisation Guideline E14 and associated Questions and Answers [ICH E14 Q\&A]), both in combination with allopurinol 300 mg, on the QTcF interval compared to placebo using a concentration-QTcF analysis.
A linear mixed-effect concentration-QTcF model was used as the primary analysis. This is a result of the statistical model so it does not have values for every timepoint, it is just one set of numbers - summarizes data across all timepoints. No non-placebo-corrected QTcF data values were collected or could be obtained for each Arm/Group at Cmax of Verinurad.
Measured: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose

Secondary outcomes (24)

Baseline-corrected Heart Rate (ΔHR)
Investigation of the effect of verinurad given either as a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of ICH E14 Q\&A), both in combination with allopurinol 300 mg, on heart rate (HR).
Measured: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 hour (h) post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose
Baseline-corrected and Placebo-adjusted Heart Rate (ΔΔHR)
Investigation of the effect of verinurad given either as a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of ICH E14 Q\&A), both in combination with allopurinol 300 mg, on HR.
Measured: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose
Baseline-corrected RR Interval (ΔRR Interval)
Investigation of the effect of verinurad given either as a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of ICH E14 Q\&A), both in combination with allopurinol 300 mg, on additional dECG variable (RR).
Measured: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose
Baseline-corrected and Placebo-adjusted RR Interval (ΔΔRR Interval)
Investigation of the effect of verinurad given either as a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of ICH E14 Q\&A), both in combination with allopurinol 300 mg, on additional dECG variable (RR).
Measured: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose
Baseline-corrected PR Interval (ΔPR Interval)
Investigation of the effect of verinurad given either as a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of ICH E14 Q\&A), both in combination with allopurinol 300 mg, on additional dECG variable (PR).
Measured: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose
Baseline-corrected and Placebo-adjusted PR Interval (ΔΔPR Interval)
Investigation of the effect of verinurad given either as a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of ICH E14 Q\&A), both in combination with allopurinol 300 mg, on additional dECG variable (PR).
Measured: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose
Baseline-corrected QRS Interval (ΔQRS Interval)
Investigation of the effect of verinurad given either as a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of ICH E14 Q\&A), both in combination with allopurinol 300 mg, on additional dECG variable (QRS).
Measured: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose
Baseline-corrected and Placebo-corrected QRS Interval (ΔΔQRS Interval)
Investigation of the effect of verinurad given either as a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of ICH E14 Q\&A), both in combination with allopurinol 300 mg, on additional dECG variable (QRS).
Measured: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose
Baseline-corrected QT Interval (ΔQT Interval)
Investigation of the effect of verinurad given either as a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of ICH E14 Q\&A), both in combination with allopurinol 300 mg, on additional dECG variable (QT).
Measured: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose
Baseline-corrected and Placebo-corrected QT Interval (ΔΔQT Interval)
Investigation of the effect of verinurad given either as a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of ICH E14 Q\&A), both in combination with allopurinol 300 mg, on additional dECG variable (QT).
Measured: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose
Baseline-corrected QTcF Interval (ΔQTcF Interval)
Investigation of the effect of verinurad given either as a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of ICH E14 Q\&A), both in combination with allopurinol 300 mg, on additional dECG variable (QTcF).
Measured: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose
Baseline-corrected and Placebo-corrected QTcF Interval (ΔΔQTcF Interval)
Investigation of the effect of verinurad given either as a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of ICH E14 Q\&A), both in combination with allopurinol 300 mg, on additional dECG variable (QTcF).
Measured: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose
Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC) for Verinurad, M1, M8, Allopurinol, and Oxypurinol
Assessment of the pharmacokinetic (PK) of verinurad and its metabolites (M1 and M8) and allopurinol and its metabolite (oxypurinol) in healthy participants.
Measured: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose
Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC[0-t]) for Verinurad, M1, M8, Allopurinol, and Oxypurinol
Assessment of the PK of verinurad and its metabolites (M1 and M8) and allopurinol and its metabolite (oxypurinol) in healthy participants.
Measured: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose
Maximum Observed Plasma Concentration (Cmax) for Verinurad, M1, M8, Allopurinol, and Oxypurinol
Assessment of the PK of verinurad and its metabolites (M1 and M8) and allopurinol and its metabolite (oxypurinol) in healthy participants.
Measured: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose
Time to Reach Maximum Plasma Concentration (Tmax) for Verinurad, M1, M8, Allopurinol, and Oxypurinol
Assessment of the PK of verinurad and its metabolites (M1 and M8) and allopurinol and its metabolite (oxypurinol) in healthy participants.
Measured: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose
Time Delay Between Drug Administration and the First Observed Concentration in Plasma (Tlag) for Verinurad, M1, M8, Allopurinol, and Oxypurinol
Assessment of the PK of verinurad and its metabolites (M1 and M8) and allopurinol and its metabolite (oxypurinol) in healthy participants.
Measured: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose
Terminal Half-life (t½λz) for Verinurad, M1, M8, Allopurinol, and Oxypurinol
Assessment of the PK of verinurad and its metabolites (M1 and M8) and allopurinol and its metabolite (oxypurinol) in healthy participants.
Measured: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose
Time of Last Quantifiable Plasma Concentration (Tlast) for Verinurad, M1, M8, Allopurinol, and Oxypurinol
Assessment of the PK of verinurad and its metabolites (M1 and M8) and allopurinol and its metabolite (oxypurinol) in healthy participants.
Measured: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose
Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (Parent Drug Only) (CL/F) for Verinurad and Allopurinol
Assessment of the PK of verinurad and allopurinol in healthy participants.
Measured: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose
Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Parent Drug Only) (Vz/F) for Verinurad and Allopurinol
Assessment of the PK of verinurad and allopurinol in healthy participants.
Measured: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose
Apparent Volume of Distribution at Steady State Following Extravascular Administration (Parent Drug Only) (Vss/F) for Verinurad and Allopurinol
Assessment of the PK of verinurad and allopurinol in healthy participants.
Measured: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose
Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity (MRT) for Verinurad and Oxypurinol
Assessment of the PK of verinurad and allopurinol in healthy participants.
Measured: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose
Number of Participants With Adverse Events (AEs)
Examination of the safety and tolerability of verinurad and allopurinol.
Measured: From Screening (Day -28 to Day -2) until the Follow-up visit (7 to 10 Days After the Last Dose)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

3 Mar 202021 Aug 2020

First posted5 Feb 2020
Study start3 Mar 2020
Primary completion21 Aug 2020
Study completion21 Aug 2020

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for Healthy Volunteers (Intended Indication: Chronic Kidney Disease)Studies of the same condition, open and under way.
More trials run by AstraZenecaThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: Triple blind
Who is masked: Participant, Investigator, Outcomes assessor
Enrolment: 24 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT04256629
Sponsor's protocol ID: D5495C00012
Status last verified: Nov 2021
First submitted: 3 Feb 2020
Last updated: 31 Jan 2022
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: No
Individual data sharing: Yes: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request 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.

Publications

Parkinson J, Dota C, Kallgren C, Gottfridsson C, Bjursell M, Perl S, Kӧrnicke T, Rekic D, Johansson S. Verinurad does not prolong QTc interval: a thorough QT study using concentration-QTc modelling. Br J Clin Pharmacol. 2023 Jun;89(6):1747-1755. doi: 10.1111/bcp.15637. Epub 2023 Jan 2.
PubMed 36504291

Study at a glance

From the registry record, last updated by the sponsor on 31 Jan 2022. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Single-Centre, Randomised, Double-Blind, Placebo-Controlled, 3-Period, Cross-Over Phase I Study to Investigate the Effect on the QTcF Interval of a Single Dose of 2 Different Doses of Verinurad, Each in Combination With Allopurinol 300 mg, Compared With Placebo In Healthy Volunteers
ClinicalTrials.gov ID: NCT04256629
Acronym / sponsor ID: D5495C00012
Conditions: Healthy Volunteers (Intended Indication: Chronic Kidney Disease)
Keywords: Randomised, Double-Blind, Placebo-Controlled, 3-Period Crossover, Verinurad, Allopurinol, Phase 1
Phase: Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 24 participants (actual)
Lead sponsor: AstraZenecaIndustry (pharma, biotech, devices)
Collaborators: Parexel
Study start: 3 Mar 2020 (actual)
Primary completion: 21 Aug 2020 (actual)
Study completion: 21 Aug 2020 (actual)
First posted: 5 Feb 2020 (actual)
Results: Posted 31 Jan 2022

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

There are 3 study treatments:

Treatment A: Verinurad 24 mg ER8 formulation co-administered with 300 mg allopurinol
Treatment B: Verinurad 40 mg IR formulation co-administered with 300 mg allopurinol
Treatment C: Matched placebos for both verinurad and allopurinol

All subjects will receive a single dose of all 3 treatments (A, B, and C) in a cross-over design with wash-out periods of at least 7 days between each study dose administration.

The study will comprise the following periods (visits):

Screening Period of maximum 28 days (Visit 1);
Three treatment periods of 3 days each, during which subjects will be resident at the study centre from the morning of the day before administration of the study dose until discharge 2 days after study dose administration (Visits 2 to 4);
Wash-out periods of at least 7 days between each study dose administration;
Final visit within 7 to 10 days after the last study dose administration (Visit 5).

Each subject will be involved in the study for approximately 53 days and have 5 study visits.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: Triple blind (participant, investigator, outcomes assessor)
Number of arms: 6

Arm	Type	Receives
Treatment ABC	Experimental	Drug: Verinurad, Drug: Placebo, Drug: AllopurinolSubjects will receive a single dose of all 3 treatments (A, B, and C) in a crossover design with wash-out periods of at least 7 days between each study dose administration.
Treatment BCA	Experimental	Drug: Verinurad, Drug: Placebo, Drug: AllopurinolSubjects will receive a single dose of all 3 treatments (B, C, and A) in a crossover design with wash-out periods of at least 7 days between each study dose administration.
Treatment CAB	Experimental	Drug: Verinurad, Drug: Placebo, Drug: AllopurinolSubjects will receive a single dose of all 3 treatments (C, A, and B) in a crossover design with wash-out periods of at least 7 days between each study dose administration.
Treatment ACB	Experimental	Drug: Verinurad, Drug: Placebo, Drug: AllopurinolSubjects will receive a single dose of all 3 treatments (A, C, and B) in a crossover design with wash-out periods of at least 7 days between each study dose administration.
Treatment BAC	Experimental	Drug: Verinurad, Drug: Placebo, Drug: AllopurinolSubjects will receive a single dose of all 3 treatments (B, A, and C) in a crossover design with wash-out periods of at least 7 days between each study dose administration.
Treatment CBA	Experimental	Drug: Verinurad, Drug: Placebo, Drug: AllopurinolSubjects will receive a single dose of all 3 treatments (C, B and A) in a crossover design with wash-out periods of at least 7 days between each study dose administration.

Who may qualify

Ages: 18 to 50 years
Sex: All
Healthy volunteers: Accepted
Age groups: Adult

Key inclusion criteria (9 listed)

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 venipuncture.
Females must have a negative pregnancy test at Screening and on admission to the study centre must be:
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).
Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.

Key exclusion criteria (29 listed)

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.
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.
Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of investigational medicinal product (IMP).
Subject has a positive test result for SARS-CoV-2 RT-PCR before randomisation.
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.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
VerinuradAlso: verinurad ER 24 mg, verinurad IR 40 mgRandomized subjects will receive oral dose of verinurad	Drug	Treatment ABC, Treatment ACB, Treatment BAC, Treatment BCA, Treatment CAB, Treatment CBA
PlaceboAlso: verinurad matching placebo, allopurinol matching placeboRandomized subjects will receive oral dose of placebo	Drug	Treatment ABC, Treatment ACB, Treatment BAC, Treatment BCA, Treatment CAB, Treatment CBA
AllopurinolAlso: allopurinol 300 mgRandomized subjects will receive oral dose of allpurinol (Treatment A and B)	Drug	Treatment ABC, Treatment ACB, Treatment BAC, Treatment BCA, Treatment CAB, Treatment CBA

Primary outcome

Model Predicted Baseline-corrected and Placebo-corrected QT Interval Corrected for Heart Rate (HR) Using Fridericia's Formula (QTcF)(ΔΔQTcF) (Derived From Concentration-QTcF Analysis) at Geometric Mean of Cmax of Verinurad
Time frame: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose
Assessment of the effect of a single dose of verinurad given as either a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of International Council for Harmonisation Guideline E14 and associated Questions and Answers [ICH E14 Q\&A]), both in combination with allopurinol 300 mg, on the QTcF interval compared to placebo using a concentration-QTcF analysis. A linear mixed-effect concentration-QTcF model was used as the primary analysis. This is a result of the statistical model so it does not have values for every timepoint, it is just one set of numbers - summarizes data across all timepoints. No non-placebo-corrected QTcF data values were collected or could be obtained for each Arm/Group at Cmax of Verinurad.

24 secondary outcomes

Baseline-corrected Heart Rate (ΔHR)
Time frame: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 hour (h) post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose
Baseline-corrected and Placebo-adjusted Heart Rate (ΔΔHR)
Time frame: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose
Baseline-corrected RR Interval (ΔRR Interval)
Time frame: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose
Baseline-corrected and Placebo-adjusted RR Interval (ΔΔRR Interval)
Time frame: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose
Baseline-corrected PR Interval (ΔPR Interval)
Time frame: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose
Baseline-corrected and Placebo-adjusted PR Interval (ΔΔPR Interval)
Time frame: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose
Baseline-corrected QRS Interval (ΔQRS Interval)
Time frame: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose
Baseline-corrected and Placebo-corrected QRS Interval (ΔΔQRS Interval)
Time frame: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose
Baseline-corrected QT Interval (ΔQT Interval)
Time frame: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose
Baseline-corrected and Placebo-corrected QT Interval (ΔΔQT Interval)
Time frame: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose
Baseline-corrected QTcF Interval (ΔQTcF Interval)
Time frame: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose
Baseline-corrected and Placebo-corrected QTcF Interval (ΔΔQTcF Interval)
Time frame: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose
Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC) for Verinurad, M1, M8, Allopurinol, and Oxypurinol
Time frame: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose
Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC[0-t]) for Verinurad, M1, M8, Allopurinol, and Oxypurinol
Time frame: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose
Maximum Observed Plasma Concentration (Cmax) for Verinurad, M1, M8, Allopurinol, and Oxypurinol
Time frame: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose
Time to Reach Maximum Plasma Concentration (Tmax) for Verinurad, M1, M8, Allopurinol, and Oxypurinol
Time frame: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose
Time Delay Between Drug Administration and the First Observed Concentration in Plasma (Tlag) for Verinurad, M1, M8, Allopurinol, and Oxypurinol
Time frame: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose
Terminal Half-life (t½λz) for Verinurad, M1, M8, Allopurinol, and Oxypurinol
Time frame: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose
Time of Last Quantifiable Plasma Concentration (Tlast) for Verinurad, M1, M8, Allopurinol, and Oxypurinol
Time frame: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose
Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (Parent Drug Only) (CL/F) for Verinurad and Allopurinol
Time frame: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose
Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Parent Drug Only) (Vz/F) for Verinurad and Allopurinol
Time frame: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose
Apparent Volume of Distribution at Steady State Following Extravascular Administration (Parent Drug Only) (Vss/F) for Verinurad and Allopurinol
Time frame: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose
Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity (MRT) for Verinurad and Oxypurinol
Time frame: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose
Number of Participants With Adverse Events (AEs)
Time frame: From Screening (Day -28 to Day -2) until the Follow-up visit (7 to 10 Days After the Last Dose)

Results and safety

Results posted to the registry on 31 Jan 2022, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Treatment Sequence ABC	4	4
Treatment Sequence BCA	4	3
Treatment Sequence CAB	4	4
Treatment Sequence ACB	4	4
Treatment Sequence BAC	4	4
Treatment Sequence CBA	4	3

Primary outcome: Model Predicted Baseline-corrected and Placebo-corrected QT Interval Corrected for Heart Rate (HR) Using Fridericia's Formula (QTcF)(ΔΔQTcF) (Derived From Concentration-QTcF Analysis) at Geometric Mean of Cmax of Verinurad

Time frame: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose. Geometric mean (90% Confidence Interval). Unit: msec

Measure	Treatment A n = 24	Treatment B n = 24
Value	-2.8 (-4.7 to -0.9)	-0.3 (-3.1 to 2.5)

Population analysed: In the Primary Outcome we present the predicted value of ΔΔQTcF based on a statistical model created for the study. The results may be presented for the active arms only, since the placebo arm did not receive Verinurad and thus have no Cmax. Placebo-corrected and baseline adjusted QTcF, ∆∆QTcF with 90% confidence interval at the verinurad maximum concentration of interest is presented as the primary result from the analysis.

24 secondary outcomes are reported in the full results.

Adverse events

Time frame: From Screening (Day -28 to Day -2) until the Follow-up visit (7 to 10 Days After the Last Dose). Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Treatment A	0 of 22 (0%)	8 of 22 (36.4%)	0 of 22
Treatment B	0 of 24 (0%)	4 of 24 (16.7%)	0 of 24
Treatment C	0 of 23 (0%)	5 of 23 (21.7%)	0 of 23

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 31 Jan 2022.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 36504291Parkinson J, Dota C, Kallgren C, Gottfridsson C, Bjursell M, Perl S, Kӧrnicke T, Rekic D, Johansson S. Verinurad does not prolong QTc interval: a thorough QT study using concentration-QTc modelling. Br J Clin Pharmacol. 2023 Jun;89(6):1747-1755. doi: 10.1111/bcp.15637. Epub 2023 Jan 2.
Protocol and Statistical Analysis Plan (SAP)Link provided by the sponsor.
CSR SynopsisLink provided by the sponsor.
Individual participant dataSharing planned: Yes. Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request 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.

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Thomas Kӧrnicke, MD principal investigator

PAREXEL Early Phase Clinical Unit Berlin

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Verinurad and Allopurinol in people with Healthy Volunteers (Intended Indication: Chronic Kidney Disease), run by AstraZeneca at 1 site in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 31 Jan 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 31 Jan 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Model Predicted Baseline-corrected and Placebo-corrected QT Interval Corrected for Heart Rate (HR) Using Fridericia's Formula (QTcF)(ΔΔQTcF) (Derived From Concentration-QTcF Analysis) at Geometric Mean of Cmax of Verinurad (time frame: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04256629, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Jan 2022.