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

NCT04256629 | Completed Phase 1 Results

• 1 other identifier: D5495C00012
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief 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

Conditions

Healthy Volunteers (Intended Indication: Chronic Kidney Disease)

Keywords

Randomised; Double-Blind; Placebo-Controlled; 3-Period Crossover; Verinurad; Allopurinol; Phase 1

Outcome Measures

Primary Outcomes (1)

• 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.

  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)

  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)

  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)

  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)

  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)

  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

Study Arms (6)

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.

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.

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.

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.

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.

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.

Drug: Verinurad; Drug: Placebo; Drug: Allopurinol

Interventions

Verinurad DRUG

Randomized subjects will receive oral dose of verinurad

Also known as: verinurad ER 24 mg, verinurad IR 40 mg

Treatment ABC; Treatment ACB; Treatment BAC; Treatment BCA; Treatment CAB; Treatment CBA

Placebo DRUG

Randomized subjects will receive oral dose of placebo

Also known as: verinurad matching placebo, allopurinol matching placebo

Treatment ABC; Treatment ACB; Treatment BAC; Treatment BCA; Treatment CAB; Treatment CBA

Allopurinol DRUG

Randomized subjects will receive oral dose of allpurinol (Treatment A and B)

Also known as: allopurinol 300 mg

Treatment ABC; Treatment ACB; Treatment BAC; Treatment BCA; Treatment CAB; Treatment CBA

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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:
• (1) 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).
• (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 and 3 months after the Follow-up Visit.
• \. 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.
• \. 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.
• \. Must be able to swallow multiple capsules/tablets.

You may not qualify if:

• 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).
• Any clinically significant abnormalities in clinical chemistry, haematology, or urinalysis results, at Screening (Visit 1) as judged by the Investigator, including:
• (1) 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:
• (1) 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.
• \. Any positive result on Screening for serum hepatitis B surface antigen OR anti-HBc antibody, hepatitis C antibody, and human immunodeficiency virus (HIV) antibody.
• \. 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.

Sponsors & Collaborators

• AstraZeneca: lead
• Parexel: collaborator

Study Sites (1)

Research Site

Berlin, 14050, Germany

Location

Related Publications (1)

• 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.

  PMID: 36504291 DERIVED

Related Links

• Protocol and Statistical Analysis Plan (SAP)
• CSR Synopsis

MeSH Terms

Interventions

verinurad; Allopurinol

Intervention Hierarchy (Ancestors)

Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Global Clinical Lead
• Organization: AstraZeneca Clinical Study Information Center

information.center@astrazeneca.com

1-877-240-9479

Study Officials

• Thomas Kӧrnicke, MD

  PAREXEL Early Phase Clinical Unit Berlin

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: This study is double-blind with regards to treatment (verinurad and allopurinol or the matching placebos) at each dose level. Placebo will be matched with verinurad and allopurinol for appearance and amount. Subjects randomized to placebo will receive the same volume of oral suspension as subjects on active drug.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 3, 2020
• First Posted: February 5, 2020
• Study Start: March 3, 2020
• Primary Completion: August 21, 2020
• Study Completion: August 21, 2020
• Last Updated: January 31, 2022
• Results First Posted: January 31, 2022

Record last verified: 2021-11

Data Sharing

• IPD Sharing: Will share
• 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 refer to our disclosure commitment at: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• 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

Locations

DE (1)