Chronic Kidney Disease
Conditions
Keywords
Chronic Kidney Disease
Brief summary
The purpose of this clinical research study is to establish the dose of verinurad combined with allopurinol 300 mg once daily that will elicit the desired response; ie, reduction in urinary albumin to creatinine ratio (UACR) at 6 months.
Detailed description
Evidence shows independent associations between hyperuricaemia and the risk of hypertension, myocardial infarction, chronic kidney disease (CKD), type 2 diabetes, heart failure, and metabolic syndrome, including obesity Furthermore, gout, an inflammatory arthritis caused by deposition of monosodium urate crystals in joints, is associated with an increased risk of all-cause death, as well as cardiovascular (CV) death. Hyperuricaemia is a prerequisite for development of gout, thus linking high levels of sUA to gout and to poor outcomes. However, the causal relationship between hyperuricaemia / gout and the aforementioned diseases and outcomes remains to be proven. Uric acid transporter 1 (URAT1) is responsible for reabsorption of uric acid (UA in the proximal tubule. Inhibition of URAT1 results in increased urinary excretion of UA. Verinurad (RDEA3170) is a novel URAT1 inhibitor in Phase 2 development for chronic kidney disease and heart failure. Verinurad combined with the xanthine oxidase (XO)inhibitor (XOI) febuxostat or allopurinol has been shown to lower sUA in patients with recurrent gout in Phase 2 studies by up to 80%.. The primary objective of this study is to assess the effects of treatment with verinurad and allopurinol, allopurinol alone, and placebo on UACR at 6 months. In this study, change in UACR at 6 months of treatment is the primary endpoint for the efficacy evaluation of treatment with the combination of verinurad and allopurinol vs. placebo. A key secondary objective is evaluation of verinurad plus allopurinol on the reduction in UACR at 12 months. Further, standard safety parameters such as adverse event (AEs), serious adverse event (SAEs), and laboratory evaluations will be employed to assess the safety profile of the study drugs. Verinurad, allopurinol and oxypurinol plasma concentrations over time will also be measured. The study will recruit patients with Chronic Kidney Disease and Hyperuricaemia.
Interventions
DRUGVerinurad
Study treatments will be titrated in 3 steps for target low dose (3 mg), intermediate dose ( 7.5 mg) and High Dose (12 mg) Verinurad. As per Protocol Version 5.0, Patients from 3 mg dose will be switched to 24 mg at visit 9
DRUGAllopurinol
Study treatments will be titrated in 3 steps: Low dose (100 mg), intermediate (200 mg) and High Dose ( 300 mg) Allopurinol
Matching Capsule
Matching tablet
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
* The subject has given written informed consent prior to any mandatory study specific procedures, sampling, and analyses, and is able to understand and comply with all study procedures * Adult Patient ≥18 years of age with CKD for \>3 months. * Patients with background standard of care treatment for albuminuria and/or T2DM and treated according to locally recognised guidelines. Therapy optimised and stable for ≥4 weeks before study entry and including an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, unless justified. * If treated with a sodium-glucose transport protein (SGLT2) inhibitor, stable dose for ≥4 weeks before randomisation. * Meeting screening criteria for sUA and eGFR (Visit 2): sUA ≥6.0 mg/dL. ∙ eGFR ≥25 mL/min/1.73 m2 Chronic Kidney Disease Epidemiology Collaboration * UACR between 30 mg/g and 5000 mg/g. * Female patients: Negative pregnancy test for childbearing potential. 1 year post-menopausal, surgically sterile, or using an acceptable method of contraception during the study and 4 weeks after the last dose of study treatment.
Exclusion criteria
* Autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis or anti-neutrophil cytoplasmic antibody associated vasculitis (granulomatosis with polyangiitis \[Wegener's granulomatosis\], microscopic polyangiitis, or eosinophilic granulomatosis with polyangiitis \[Churg-Strauss syndrome\]). * History of renal transplantation * Known carrier of the Human Leukocyte Antigen-B \*58:01 allele. * Patients diagnosed with tumor lysis syndrome or Lesch-Nyhan syndrome * Patients who in the opinion of investigator are unable to perform the patients' tasks associated with the protocol or Presence of any condition which, places the patient at undue risk or potentially jeopardises the quality of the data to be generated * History of stroke, myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft in the past 6 months * Uncontrolled hypertension presenting with systolic blood pressure \>180 mm Hg and/or diastolic blood pressure \>100 mm Hg * Diagnosed with heart failure and New York Heart Association Functional Classification Class IV at the time of randomisation * QT interval corrected by the Fridericia formula \>470 msec; patients diagnosed with long QT syndrome; patients with a family history of long QT syndrome. * Subjects with severe hepatic impairment, as judged by the investigator, of Child-Pugh Class C (decompensated cirrhosis), or with major cirrhosis complications (eg, hepatorenal syndrome) * Receiving cytotoxic or immunosuppressive therapy or other immunotherapy for primary or secondary renal disease within 6 months prior to enrolment * Treated with any drug for hyperuricaemia in the 6 months preceding randomisation. * Dose of ACEi, ARBs, fenofibrate, guaifenesin, or SGLT2 inhibitors changed within 4 weeks of randomisation or further dose titration expected after randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Urinary Albumin to Creatinine Ratio (uACR) (mg/g) Change From Baseline at 6 Months (Visit 8), Repeated Measures Mixed Model (MMRM) | Baseline to 9 months (Visit 9); analysis at 6 months (Visit 8) | Analyses of change from baseline in uACR at 6 months (Visit 8) focused on: * High dose vs Placebo * High dose and Inter. dose combined vs Allopurinol alone * Inter. dose vs Placebo * Low dose vs Placebo * High dose vs Allopurinol * Inter. dose vs Allopurinol * Low dose vs Allopurinol * Allopurinol vs Placebo For High dose and Inter. dose combined the 2 categories merged forming 1 new temporary category. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serum Uric Acid (sUA) (mg/dL) Change From Baseline at 6 Months (Visit 8), Repeated Measures Mixed Model (MMRM) | Baseline to 9 months (Visit 9); analysis at 6 months (Visit 8) | Change from baseline in sUA at 6 months (Visit 8), there were 7 comparisons requested for each endpoint, namely: * High dose vs Placebo * Inter. dose vs Placebo * Low dose vs Placebo * High dose vs Allopurinol * Inter. dose vs Allopurinol * Low dose vs Allopurinol * Allopurinol vs Placebo. |
| Serum Uric Acid (sUA) Change From Baseline at 12 Months (Visit 10), Repeated Measures Mixed Model (MMRM) | Baseline to 12 months (Visit 10); analysis at 12 months (Visit 10) | Change from baseline in sUA at 12 months (Visit 10) for comparison of Switch dose protocol version 5.0 (PA5) versus double-capsule Placebo. |
| Estimated Glomerular Filtration Rate (eGFR) (mL/Min/1.73 m²) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM) | Baseline to 9 months (Visit 9); analysis at 6 months (Visit 8) | Change from baseline in eGFR at 6 months (Visit 8), there were 7 comparisons requested for this endpoint, namely: * High dose vs Placebo * Inter. dose vs Placebo * Low dose vs Placebo * High dose vs Allopurinol * Inter. dose vs Allopurinol * Low dose vs Allopurinol * Allopurinol vs Placebo. |
| Estimated Glomerular Filtration Rate (eGFR) (mL/Min/1.73 m²) Change From Baseline at 12 Months (Visit 10) | Change from baseline to 12 months (Visit 10) | Change from baseline in eGFR at 12 months (Visit 10) for the following treatments: * High Dose * Inter. Dose * Low Dose (a) * Switch Dose protocol version 5.0 (PA5) (b) * Allopurinol * Placebo 1. Subjects that switched from Verinurad 3 mg to Verinurad 24 mg at Visit 9 are not included in this group for Visit 10. 2. Contains all subjects randomized to the low dose group that later switched to Verinurad 24 mg plus Allopurinol 300 mg. |
| Urinary Albumin to Creatinine Ratio (uACR) (mg/g) Change From Baseline at 12 Months (Visit 10), Repeated Measures Mixed Model (MMRM) | Baseline to 12 months (Visit 10); analysis at 12 months (Visit 10) | Change from baseline in uACR at 12 months (Visit 10) for comparison of Switch dose protocol version 5.0 (PA5) versus double-capsule Placebo. The statistical model applied was an MMRM, which was basically the same as the one applied in the primary analysis but adjusted for a 12 month horizon and adapted to the double-capsule regimen from Visit 9 on. |
| S-creatinine (mg/dL) Change From Baseline at 12 Months (Visit 10) | Change from baseline to 12 months (Visit 10) | Change from baseline in S-creatinine at 12 months (Visit 10) for the following treatments: * High Dose * Inter. Dose * Low Dose (a) * Switch Dose protocol version 5.0 (PA5) (b) * Allopurinol * Placebo 1. Subjects that switched from Verinurad 3 mg to Verinurad 24 mg at Visit 9 are not included in this group for Visit 10. 2. Contains all subjects randomized to the low dose group that later switched to Verinurad 24 mg plus Allopurinol 300 mg. |
| P-cystatin C (mg/L) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM) | Baseline to 9 months (Visit 9); analysis at 6 months (Visit 8) | Change from baseline in P-cystatin C at 6 months (Visit 8), there were 7 comparisons requested for this endpoint, namely: * High dose vs Placebo * Inter. dose vs Placebo * Low dose vs Placebo * High dose vs Allopurinol * Inter. dose vs Allopurinol * Low dose vs Allopurinol * Allopurinol vs Placebo. |
| P-cystatin C (mg/L) Change From Baseline at 12 Months (Visit 10) | Change from baseline to 12 months (Visit 10) | Change from baseline in S-creatinine at 12 months (Visit 10) for the following treatments: * High Dose * Inter. Dose * Low Dose (a) * Switch Dose protocol version 5.0 (PA5) (b) * Allopurinol * Placebo 1. Subjects that switched from Verinurad 3 mg to Verinurad 24 mg at Visit 9 are not included in this group for Visit 10. 2. Contains all subjects randomized to the low dose group that later switched to Verinurad 24 mg plus Allopurinol 300 mg. |
| S-creatinine (mg/dL) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM) | Baseline to 9 months (Visit 9); analysis at 6 months (Visit 8) | Change from baseline in S-creatinine at 6 months (Visit 8), there were 7 comparisons requested for this endpoint, namely: * High dose vs Placebo * Inter. dose vs Placebo * Low dose vs Placebo * High dose vs Allopurinol * Inter. dose vs Allopurinol * Low dose vs Allopurinol * Allopurinol vs Placebo. |
Countries
Czechia, France, Hungary, Israel, Italy, Mexico, Poland, Romania, Slovakia, South Africa, Spain, United States
Participant flow
Recruitment details
Participants were enrolled if: * serum uric acid was greated than or equal to 6 mg/dL and * estimated glomerular filtration rate was greated than or equal to 25 mL/min/1.73 m2 and * urinary albumin to creatinine ratio was greated than or equal to 30 mg/g and less than or equal to 5000 mg/g
Participants by arm
| Arm | Count |
|---|---|
| High Dose Verinurad 12 mg plus allopurinol 300 mg | 172 |
| Inter. Dose Verinurad 7.5 mg plus allopurinol 300 mg | 172 |
| Low Dose Verinurad 3 mg plus allopurinol 300 mg.
As per Protocol Version 5.0, participants from 3 mg dose were switched to 24 mg at Visit 9. | 173 |
| Allopurinol Allopurinol alone (Allopurinol): 300 mg | 171 |
| Placebo Placebo only | 173 |
| Total | 861 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 3 | 2 | 2 | 0 |
| Overall Study | Death | 14 | 8 | 14 | 10 | 11 |
| Overall Study | Failure to meet randomization criteria | 0 | 1 | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 | 2 |
| Overall Study | Non-compliance with study drug | 2 | 1 | 2 | 0 | 0 |
| Overall Study | Not categorized | 5 | 5 | 3 | 2 | 2 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Site terminated by sponsor | 2 | 1 | 2 | 0 | 2 |
| Overall Study | Study terminated by sponsor | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 10 | 9 | 18 | 11 | 9 |
Baseline characteristics
| Characteristic | Inter. Dose | High Dose | Low Dose | Allopurinol | Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 64.9 Years STANDARD_DEVIATION 11.2 | 65.3 Years STANDARD_DEVIATION 10 | 65.3 Years STANDARD_DEVIATION 11.2 | 65.1 Years STANDARD_DEVIATION 11 | 65.8 Years STANDARD_DEVIATION 10.4 | 65.3 Years STANDARD_DEVIATION 10.8 |
| Age, Customized <65 | 72 Participants | 72 Participants | 66 Participants | 76 Participants | 66 Participants | 352 Participants |
| Age, Customized >=65 | 100 Participants | 100 Participants | 107 Participants | 95 Participants | 107 Participants | 509 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 45 Participants | 42 Participants | 37 Participants | 40 Participants | 41 Participants | 205 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 127 Participants | 130 Participants | 136 Participants | 131 Participants | 132 Participants | 656 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 4 Participants | 4 Participants | 8 Participants | 5 Participants | 8 Participants | 29 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 4 Participants | 5 Participants | 4 Participants | 4 Participants | 20 Participants |
| Race (NIH/OMB) Black or African American | 24 Participants | 25 Participants | 24 Participants | 23 Participants | 20 Participants | 116 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 16 Participants | 16 Participants | 10 Participants | 20 Participants | 10 Participants | 72 Participants |
| Race (NIH/OMB) White | 125 Participants | 122 Participants | 126 Participants | 118 Participants | 131 Participants | 622 Participants |
| Region of Enrollment Czech Republic | 7 Participants | 6 Participants | 3 Participants | 7 Participants | 5 Participants | 28 Participants |
| Region of Enrollment France | 1 Participants | 2 Participants | 2 Participants | 0 Participants | 2 Participants | 7 Participants |
| Region of Enrollment Hungary | 25 Participants | 22 Participants | 19 Participants | 19 Participants | 22 Participants | 107 Participants |
| Region of Enrollment Israel | 17 Participants | 15 Participants | 19 Participants | 15 Participants | 13 Participants | 79 Participants |
| Region of Enrollment Italy | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 5 Participants |
| Region of Enrollment Mexico | 5 Participants | 6 Participants | 8 Participants | 7 Participants | 10 Participants | 36 Participants |
| Region of Enrollment Poland | 4 Participants | 1 Participants | 2 Participants | 3 Participants | 5 Participants | 15 Participants |
| Region of Enrollment Romania | 5 Participants | 2 Participants | 5 Participants | 3 Participants | 7 Participants | 22 Participants |
| Region of Enrollment Slovakia | 6 Participants | 8 Participants | 13 Participants | 5 Participants | 6 Participants | 38 Participants |
| Region of Enrollment South Africa | 21 Participants | 23 Participants | 20 Participants | 24 Participants | 23 Participants | 111 Participants |
| Region of Enrollment Spain | 12 Participants | 17 Participants | 14 Participants | 16 Participants | 17 Participants | 76 Participants |
| Region of Enrollment United States | 67 Participants | 70 Participants | 68 Participants | 71 Participants | 61 Participants | 337 Participants |
| Sex: Female, Male Female | 53 Participants | 69 Participants | 57 Participants | 55 Participants | 50 Participants | 284 Participants |
| Sex: Female, Male Male | 119 Participants | 103 Participants | 116 Participants | 116 Participants | 123 Participants | 577 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 14 / 172 | 8 / 172 | 13 / 172 | 1 / 37 | 10 / 171 | 11 / 173 |
| other Total, other adverse events | 32 / 172 | 32 / 172 | 28 / 172 | 1 / 37 | 39 / 171 | 49 / 173 |
| serious Total, serious adverse events | 36 / 172 | 39 / 172 | 40 / 172 | 4 / 37 | 42 / 171 | 35 / 173 |
Outcome results
Primary
Urinary Albumin to Creatinine Ratio (uACR) (mg/g) Change From Baseline at 6 Months (Visit 8), Repeated Measures Mixed Model (MMRM)
Analyses of change from baseline in uACR at 6 months (Visit 8) focused on: * High dose vs Placebo * High dose and Inter. dose combined vs Allopurinol alone * Inter. dose vs Placebo * Low dose vs Placebo * High dose vs Allopurinol * Inter. dose vs Allopurinol * Low dose vs Allopurinol * Allopurinol vs Placebo For High dose and Inter. dose combined the 2 categories merged forming 1 new temporary category.
Time frame: Baseline to 9 months (Visit 9); analysis at 6 months (Visit 8)
Population: Full analysis set (evaluable participant included only)~In the primary endpoint the arms are presented as comparisons of treatment groups with either placebo or allopurinol alone.~Geometric mean ratio is presented between arms as a pre-specified analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| High Dose Versus Placebo | Urinary Albumin to Creatinine Ratio (uACR) (mg/g) Change From Baseline at 6 Months (Visit 8), Repeated Measures Mixed Model (MMRM) | 0.8300 mg/g |
| High Dose and Intermediate Dose Combined Versus Allopurinol | Urinary Albumin to Creatinine Ratio (uACR) (mg/g) Change From Baseline at 6 Months (Visit 8), Repeated Measures Mixed Model (MMRM) | 1.043 mg/g |
| Intermediate Dose Versus Placebo | Urinary Albumin to Creatinine Ratio (uACR) (mg/g) Change From Baseline at 6 Months (Visit 8), Repeated Measures Mixed Model (MMRM) | 0.8369 mg/g |
| Low Dose Versus Placebo | Urinary Albumin to Creatinine Ratio (uACR) (mg/g) Change From Baseline at 6 Months (Visit 8), Repeated Measures Mixed Model (MMRM) | 0.8499 mg/g |
| High Dose Versus Allopurinol | Urinary Albumin to Creatinine Ratio (uACR) (mg/g) Change From Baseline at 6 Months (Visit 8), Repeated Measures Mixed Model (MMRM) | 1.037 mg/g |
| Intermediate Dose Versus Allopurinol | Urinary Albumin to Creatinine Ratio (uACR) (mg/g) Change From Baseline at 6 Months (Visit 8), Repeated Measures Mixed Model (MMRM) | 1.046 mg/g |
| Low Dose Versus Allopurinol | Urinary Albumin to Creatinine Ratio (uACR) (mg/g) Change From Baseline at 6 Months (Visit 8), Repeated Measures Mixed Model (MMRM) | 1.062 mg/g |
| Allopurinol Versus Placebo | Urinary Albumin to Creatinine Ratio (uACR) (mg/g) Change From Baseline at 6 Months (Visit 8), Repeated Measures Mixed Model (MMRM) | 0.8001 mg/g |
p-value: 0.0648Repeated Measures Mixed Model
p-value: 0.6296Repeated Measures Mixed Model
p-value: 0.0263Repeated Measures Mixed Model
Secondary
Estimated Glomerular Filtration Rate (eGFR) (mL/Min/1.73 m²) Change From Baseline at 12 Months (Visit 10)
Change from baseline in eGFR at 12 months (Visit 10) for the following treatments: * High Dose * Inter. Dose * Low Dose (a) * Switch Dose protocol version 5.0 (PA5) (b) * Allopurinol * Placebo 1. Subjects that switched from Verinurad 3 mg to Verinurad 24 mg at Visit 9 are not included in this group for Visit 10. 2. Contains all subjects randomized to the low dose group that later switched to Verinurad 24 mg plus Allopurinol 300 mg.
Time frame: Change from baseline to 12 months (Visit 10)
Population: Full analysis set (evaluable participant included only)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| High Dose Versus Placebo | Estimated Glomerular Filtration Rate (eGFR) (mL/Min/1.73 m²) Change From Baseline at 12 Months (Visit 10) | 0.9809 mL/min/1.73 m² | Geometric Coefficient of Variation 20.09 |
| High Dose and Intermediate Dose Combined Versus Allopurinol | Estimated Glomerular Filtration Rate (eGFR) (mL/Min/1.73 m²) Change From Baseline at 12 Months (Visit 10) | 0.9454 mL/min/1.73 m² | Geometric Coefficient of Variation 21.24 |
| Intermediate Dose Versus Placebo | Estimated Glomerular Filtration Rate (eGFR) (mL/Min/1.73 m²) Change From Baseline at 12 Months (Visit 10) | 0.9613 mL/min/1.73 m² | Geometric Coefficient of Variation 17.59 |
| Low Dose Versus Placebo | Estimated Glomerular Filtration Rate (eGFR) (mL/Min/1.73 m²) Change From Baseline at 12 Months (Visit 10) | 1.101 mL/min/1.73 m² | Geometric Coefficient of Variation 27.23 |
| High Dose Versus Allopurinol | Estimated Glomerular Filtration Rate (eGFR) (mL/Min/1.73 m²) Change From Baseline at 12 Months (Visit 10) | 0.9593 mL/min/1.73 m² | Geometric Coefficient of Variation 23.36 |
| Intermediate Dose Versus Allopurinol | Estimated Glomerular Filtration Rate (eGFR) (mL/Min/1.73 m²) Change From Baseline at 12 Months (Visit 10) | 0.9469 mL/min/1.73 m² | Geometric Coefficient of Variation 23.33 |
Secondary
Estimated Glomerular Filtration Rate (eGFR) (mL/Min/1.73 m²) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM)
Change from baseline in eGFR at 6 months (Visit 8), there were 7 comparisons requested for this endpoint, namely: * High dose vs Placebo * Inter. dose vs Placebo * Low dose vs Placebo * High dose vs Allopurinol * Inter. dose vs Allopurinol * Low dose vs Allopurinol * Allopurinol vs Placebo.
Time frame: Baseline to 9 months (Visit 9); analysis at 6 months (Visit 8)
Population: Full analysis set (evaluable participant included only)~In this secondary endpoint the arms are presented as comparisons of treatment groups with either placebo or allopurinol alone.~Geometric mean ratio is presented between arms as a pre-specified analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| High Dose Versus Placebo | Estimated Glomerular Filtration Rate (eGFR) (mL/Min/1.73 m²) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM) | 1.009 mL/min/1.73 m² |
| High Dose and Intermediate Dose Combined Versus Allopurinol | Estimated Glomerular Filtration Rate (eGFR) (mL/Min/1.73 m²) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM) | 0.9730 mL/min/1.73 m² |
| Intermediate Dose Versus Placebo | Estimated Glomerular Filtration Rate (eGFR) (mL/Min/1.73 m²) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM) | 1.010 mL/min/1.73 m² |
| Low Dose Versus Placebo | Estimated Glomerular Filtration Rate (eGFR) (mL/Min/1.73 m²) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM) | 1.023 mL/min/1.73 m² |
| High Dose Versus Allopurinol | Estimated Glomerular Filtration Rate (eGFR) (mL/Min/1.73 m²) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM) | 0.9859 mL/min/1.73 m² |
| Intermediate Dose Versus Allopurinol | Estimated Glomerular Filtration Rate (eGFR) (mL/Min/1.73 m²) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM) | 1.024 mL/min/1.73 m² |
| Low Dose Versus Allopurinol | Estimated Glomerular Filtration Rate (eGFR) (mL/Min/1.73 m²) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM) | 0.9868 mL/min/1.73 m² |
Secondary
P-cystatin C (mg/L) Change From Baseline at 12 Months (Visit 10)
Change from baseline in S-creatinine at 12 months (Visit 10) for the following treatments: * High Dose * Inter. Dose * Low Dose (a) * Switch Dose protocol version 5.0 (PA5) (b) * Allopurinol * Placebo 1. Subjects that switched from Verinurad 3 mg to Verinurad 24 mg at Visit 9 are not included in this group for Visit 10. 2. Contains all subjects randomized to the low dose group that later switched to Verinurad 24 mg plus Allopurinol 300 mg.
Time frame: Change from baseline to 12 months (Visit 10)
Population: Full analysis set (evaluable participant included only)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| High Dose Versus Placebo | P-cystatin C (mg/L) Change From Baseline at 12 Months (Visit 10) | 1.070 mg/L | Geometric Coefficient of Variation 17.98 |
| High Dose and Intermediate Dose Combined Versus Allopurinol | P-cystatin C (mg/L) Change From Baseline at 12 Months (Visit 10) | 1.079 mg/L | Geometric Coefficient of Variation 15.63 |
| Intermediate Dose Versus Placebo | P-cystatin C (mg/L) Change From Baseline at 12 Months (Visit 10) | 1.065 mg/L | Geometric Coefficient of Variation 16.51 |
| Low Dose Versus Placebo | P-cystatin C (mg/L) Change From Baseline at 12 Months (Visit 10) | 1.018 mg/L | Geometric Coefficient of Variation 13.68 |
| High Dose Versus Allopurinol | P-cystatin C (mg/L) Change From Baseline at 12 Months (Visit 10) | 1.083 mg/L | Geometric Coefficient of Variation 23.13 |
| Intermediate Dose Versus Allopurinol | P-cystatin C (mg/L) Change From Baseline at 12 Months (Visit 10) | 1.048 mg/L | Geometric Coefficient of Variation 14.89 |
Secondary
P-cystatin C (mg/L) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM)
Change from baseline in P-cystatin C at 6 months (Visit 8), there were 7 comparisons requested for this endpoint, namely: * High dose vs Placebo * Inter. dose vs Placebo * Low dose vs Placebo * High dose vs Allopurinol * Inter. dose vs Allopurinol * Low dose vs Allopurinol * Allopurinol vs Placebo.
Time frame: Baseline to 9 months (Visit 9); analysis at 6 months (Visit 8)
Population: Full analysis set (evaluable participant included only)~In this secondary endpoint the arms are presented as comparisons of treatment groups with either placebo or allopurinol alone.~Geometric mean ratio is presented between arms as a pre-specified analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| High Dose Versus Placebo | P-cystatin C (mg/L) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM) | 1.009 Geometric Mean Ratio |
| High Dose and Intermediate Dose Combined Versus Allopurinol | P-cystatin C (mg/L) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM) | 1.038 Geometric Mean Ratio |
| Intermediate Dose Versus Placebo | P-cystatin C (mg/L) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM) | 1.018 Geometric Mean Ratio |
| Low Dose Versus Placebo | P-cystatin C (mg/L) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM) | 0.9849 Geometric Mean Ratio |
| High Dose Versus Allopurinol | P-cystatin C (mg/L) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM) | 1.014 Geometric Mean Ratio |
| Intermediate Dose Versus Allopurinol | P-cystatin C (mg/L) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM) | 0.9946 Geometric Mean Ratio |
| Low Dose Versus Allopurinol | P-cystatin C (mg/L) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM) | 1.024 Geometric Mean Ratio |
Secondary
S-creatinine (mg/dL) Change From Baseline at 12 Months (Visit 10)
Change from baseline in S-creatinine at 12 months (Visit 10) for the following treatments: * High Dose * Inter. Dose * Low Dose (a) * Switch Dose protocol version 5.0 (PA5) (b) * Allopurinol * Placebo 1. Subjects that switched from Verinurad 3 mg to Verinurad 24 mg at Visit 9 are not included in this group for Visit 10. 2. Contains all subjects randomized to the low dose group that later switched to Verinurad 24 mg plus Allopurinol 300 mg.
Time frame: Change from baseline to 12 months (Visit 10)
Population: Full analysis set (evaluable participant included only)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| High Dose Versus Placebo | S-creatinine (mg/dL) Change From Baseline at 12 Months (Visit 10) | 1.011 mg/dL | Geometric Coefficient of Variation 18.57 |
| High Dose and Intermediate Dose Combined Versus Allopurinol | S-creatinine (mg/dL) Change From Baseline at 12 Months (Visit 10) | 1.038 mg/dL | Geometric Coefficient of Variation 18.37 |
| Intermediate Dose Versus Placebo | S-creatinine (mg/dL) Change From Baseline at 12 Months (Visit 10) | 1.026 mg/dL | Geometric Coefficient of Variation 17.15 |
| Low Dose Versus Placebo | S-creatinine (mg/dL) Change From Baseline at 12 Months (Visit 10) | 0.9078 mg/dL | Geometric Coefficient of Variation 17.66 |
| High Dose Versus Allopurinol | S-creatinine (mg/dL) Change From Baseline at 12 Months (Visit 10) | 1.028 mg/dL | Geometric Coefficient of Variation 24.44 |
| Intermediate Dose Versus Allopurinol | S-creatinine (mg/dL) Change From Baseline at 12 Months (Visit 10) | 1.043 mg/dL | Geometric Coefficient of Variation 20.91 |
Secondary
S-creatinine (mg/dL) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM)
Change from baseline in S-creatinine at 6 months (Visit 8), there were 7 comparisons requested for this endpoint, namely: * High dose vs Placebo * Inter. dose vs Placebo * Low dose vs Placebo * High dose vs Allopurinol * Inter. dose vs Allopurinol * Low dose vs Allopurinol * Allopurinol vs Placebo.
Time frame: Baseline to 9 months (Visit 9); analysis at 6 months (Visit 8)
Population: Full analysis set (evaluable participant included only)~In this secondary endpoint the arms are presented as comparisons of treatment groups with either placebo or allopurinol alone.~Geometric mean ratio is presented between arms as a pre-specified analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| High Dose Versus Placebo | S-creatinine (mg/dL) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM) | 0.9888 Geometric Mean Ratio |
| High Dose and Intermediate Dose Combined Versus Allopurinol | S-creatinine (mg/dL) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM) | 1.023 Geometric Mean Ratio |
| Intermediate Dose Versus Placebo | S-creatinine (mg/dL) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM) | 0.9901 Geometric Mean Ratio |
| Low Dose Versus Placebo | S-creatinine (mg/dL) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM) | 0.9801 Geometric Mean Ratio |
| High Dose Versus Allopurinol | S-creatinine (mg/dL) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM) | 1.014 Geometric Mean Ratio |
| Intermediate Dose Versus Allopurinol | S-creatinine (mg/dL) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM) | 0.9814 Geometric Mean Ratio |
| Low Dose Versus Allopurinol | S-creatinine (mg/dL) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM) | 1.009 Geometric Mean Ratio |
Secondary
Serum Uric Acid (sUA) Change From Baseline at 12 Months (Visit 10), Repeated Measures Mixed Model (MMRM)
Change from baseline in sUA at 12 months (Visit 10) for comparison of Switch dose protocol version 5.0 (PA5) versus double-capsule Placebo.
Time frame: Baseline to 12 months (Visit 10); analysis at 12 months (Visit 10)
Population: Full analysis set (evaluable participant included only)~In this secondary endpoint the arm presented provides a comparison between the Switch Dose group and double-capsule placebo at Visit 10. This is a pre-specified analysis between the Switch Dose group and double-capsule placebo at Visit 10.~Geometric mean ratio is presented between arms as a pre-specified analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| High Dose Versus Placebo | Serum Uric Acid (sUA) Change From Baseline at 12 Months (Visit 10), Repeated Measures Mixed Model (MMRM) | 0.5540 mg/dL |
Secondary
Serum Uric Acid (sUA) (mg/dL) Change From Baseline at 6 Months (Visit 8), Repeated Measures Mixed Model (MMRM)
Change from baseline in sUA at 6 months (Visit 8), there were 7 comparisons requested for each endpoint, namely: * High dose vs Placebo * Inter. dose vs Placebo * Low dose vs Placebo * High dose vs Allopurinol * Inter. dose vs Allopurinol * Low dose vs Allopurinol * Allopurinol vs Placebo.
Time frame: Baseline to 9 months (Visit 9); analysis at 6 months (Visit 8)
Population: Full analysis set (evaluable participant included only)~In this secondary endpoint the arms are presented as comparisons of treatment groups with either placebo or allopurinol alone.~Geometric mean ratio is presented between arms as a pre-specified analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| High Dose Versus Placebo | Serum Uric Acid (sUA) (mg/dL) Change From Baseline at 6 Months (Visit 8), Repeated Measures Mixed Model (MMRM) | 0.5098 mg/dL |
| High Dose and Intermediate Dose Combined Versus Allopurinol | Serum Uric Acid (sUA) (mg/dL) Change From Baseline at 6 Months (Visit 8), Repeated Measures Mixed Model (MMRM) | 0.5810 mg/dL |
| Intermediate Dose Versus Placebo | Serum Uric Acid (sUA) (mg/dL) Change From Baseline at 6 Months (Visit 8), Repeated Measures Mixed Model (MMRM) | 0.6096 mg/dL |
| Low Dose Versus Placebo | Serum Uric Acid (sUA) (mg/dL) Change From Baseline at 6 Months (Visit 8), Repeated Measures Mixed Model (MMRM) | 0.8184 mg/dL |
| High Dose Versus Allopurinol | Serum Uric Acid (sUA) (mg/dL) Change From Baseline at 6 Months (Visit 8), Repeated Measures Mixed Model (MMRM) | 0.9327 mg/dL |
| Intermediate Dose Versus Allopurinol | Serum Uric Acid (sUA) (mg/dL) Change From Baseline at 6 Months (Visit 8), Repeated Measures Mixed Model (MMRM) | 0.9786 mg/dL |
| Low Dose Versus Allopurinol | Serum Uric Acid (sUA) (mg/dL) Change From Baseline at 6 Months (Visit 8), Repeated Measures Mixed Model (MMRM) | 0.6229 mg/dL |
Secondary
Urinary Albumin to Creatinine Ratio (uACR) (mg/g) Change From Baseline at 12 Months (Visit 10), Repeated Measures Mixed Model (MMRM)
Change from baseline in uACR at 12 months (Visit 10) for comparison of Switch dose protocol version 5.0 (PA5) versus double-capsule Placebo. The statistical model applied was an MMRM, which was basically the same as the one applied in the primary analysis but adjusted for a 12 month horizon and adapted to the double-capsule regimen from Visit 9 on.
Time frame: Baseline to 12 months (Visit 10); analysis at 12 months (Visit 10)
Population: Full analysis set (evaluable participant included only)~In this secondary endpoint the arm presented provides a comparison between the Switch Dose group and double-capsule placebo at Visit 10. This is a pre-specified analysis between the Switch Dose group and double-capsule placebo at Visit 10.~Geometric mean ratio is presented between arms as a pre-specified analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| High Dose Versus Placebo | Urinary Albumin to Creatinine Ratio (uACR) (mg/g) Change From Baseline at 12 Months (Visit 10), Repeated Measures Mixed Model (MMRM) | 1.016 mg/g |