Visual Abstract
Keywords: Albuminuria, Chronic Kidney Disease, Kidney Dysfunction, Randomized Controlled Trials
Abstract
Key Points
The SAPPHIRE trial was designed to assess albuminuria-lowering effects of the urate transporter 1 inhibitor verinurad combined with allopurinol in patients with CKD.
Verinurad 3, 7.5, and 12 mg in combination with allopurinol 300 mg did not reduce albuminuria during 34 weeks treatment compared with allopurinol alone or placebo.
Verinurad/allopurinol combination dose-dependently reduced serum urate concentrations compared with placebo.
Background
Hyperuricemia is associated with elevated risks of cardiovascular and chronic kidney disease (CKD). Since inhibition of urate transporter 1 has been suggested to be potentially nephroprotective, we performed a phase 2b study to assess albuminuria-lowering effects of the urate transporter 1 inhibitor verinurad combined with the xanthine oxidase inhibitor allopurinol in patients with CKD and hyperuricemia.
Methods
In this randomized placebo and active controlled trial, we enrolled participants with serum urate concentrations ≥6.0 mg/dl, eGFR ≥25 ml/min per 1.73 m2, and a urinary albumin-creatinine ratio (UACR) 30–5000 mg/g to one of five treatment arms: placebo, placebo+allopurinol 300 mg/day, verinurad 3 mg+allopurinol 300 mg/day, verinurad 7.5 mg+allopurinol 300 mg/day, or verinurad 12 mg+allopurinol 300 mg/day in a 1:1:1:1:1 ratio. The primary end point was the change in UACR from baseline to 34 weeks. Secondary end points were changes from baseline in UACR at week 60 and changes in serum urate and eGFR at weeks 34 and 60.
Results
Between August 2019 and November 2021, 861 adults with CKD (mean age 65 years, 33.0% female, mean eGFR 48 ml/min per 1.73 m2, median UACR 217 mg/g) were enrolled. At 34 weeks, the geometric mean percentage change in UACR from baseline did not differ among treatment groups (16.7%, 95% confidence interval [CI], −0.6 to 37.1 in the 3 mg group, 15.0% [95% CI, −1.85 to 34.6] in the 7.5 mg group, 14.0% [95% CI, −3.4 to 34.4] in the 12 mg group versus 9.9% [95% CI, −6.6 to 29.4] in the allopurinol group, and 37.3% [95% CI, 16.6 to 61.8] in the placebo group). UACR and eGFR change from baseline did not differ among treatment groups after 60 weeks. Verinurad/allopurinol combination dose-dependently reduced serum urate concentrations compared with placebo. The proportion of patients with adverse events and serious adverse events was balanced among treatment groups.
Conclusions
Verinurad in combination with allopurinol did not decrease UACR or eGFR decline, but further reduced serum urate compared with allopurinol alone or placebo.
Clinical Trial registry name and registration number:
SAPPHIRE Trial registration number, NCT03990363.
Introduction
Approximately 840 million people worldwide have CKD, which is associated with elevated risks of kidney failure, cardiovascular complications, and reduced quality of life.1 New therapies that slow CKD progression include sodium-glucose cotransporter 2 (SGLT2) inhibitors and the nonsteroidal mineralocorticoid receptor antagonist finerenone.2–4 Despite these advances in the pharmacotherapy, substantial residual risk for progressive kidney function loss persists in many people with CKD. The continued risk of progressive kidney function loss despite treatment with SGLT2 inhibitors or finerenone is associated with persistently elevated albuminuria.5,6 New therapies to reduce the risk factors of CKD progression, particularly in people with elevated albuminuria, are therefore needed.
Urate, the human end product of purine metabolism generated by xanthine oxidase, is renally expressed, including in podocytes.7 Elevated serum urate (hyperuricemia) is very common in people with CKD and is associated with hypertension, cardiovascular disease, and progression of CKD. On the basis of the epidemiologic associations between uric acid and kidney outcomes, urate has been considered a potential target to slow progressive GFR loss in people with CKD. However, xanthine oxidase inhibitor monotherapy with allopurinol or febuxostat has not exerted consistent nephroprotection in clinical trials.8–10
Verinurad, a selective inhibitor of the human urate-reabsorbing urate transporter URAT1, has potent uricosuric activity.11 In people with gout and/or asymptomatic hyperuricemia, verinurad significantly reduced serum urate in phase 2 dose-finding studies. When verinurad was combined with the xanthine oxidase inhibitor febuxostat or allopurinol, verinurad decreased serum urate levels by up to 80%.12–14
Post hoc analysis of the CITRINE study in 60 participants with type 2 diabetes and elevated albuminuria demonstrated that after 12 weeks of treatment, verinurad in combination with febuxostat compared with placebo reduced serum urate by 57% (95% confidence interval [CI], 48% to 64%) and albuminuria by 39% (90% CI, 4 to 62).12 Since treatment effects to reduce albuminuria by at least 25% have been associated with long-term kidney protection,15 this post hoc analysis suggested the potential of verinurad in combination with a xanthine oxidase inhibitor to reduce albuminuria and the risk of kidney failure. Because of the small sample size and uncertainty in CITRINE trial data, the Study of verinurAd and alloPurinol in Patients with cHronic kIdney disease and hyperuRicEmia (SAPPHIRE; NCT03990363) was designed to assess dose-response relationships between verinurad and urinary albumin-creatinine ratio (UACR) to inform the design of a clinical outcome trial. We here report the results of the SAPPHIRE trial.
Methods
Trial Design
The SAPPHIRE trial was a randomized, double-blind, placebo-controlled, multicenter clinical trial. Details regarding the rationale, design, and baseline characteristics have been published previously.16 The trial was sponsored by AstraZeneca and conducted at 205 sites in 12 countries from August 28, 2019, through November 22, 2021. The trial protocol was approved by a central or local ethics committee at all study sites. The trial was registered at ClinicalTrials.gov (NCT03036150). All participants provided written informed consent before any study-specific procedure commenced.
Participants
Adults with CKD, eGFR ≥25 ml/min per 1.73 m2, and a UACR between 30 and 5000 mg/g and serum urate ≥6.0 mg/dl were eligible for participation. All participants were required to be receiving a stable dose of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) for at least 4 weeks before screening. Participants with documented ACE inhibitor or ARB intolerance were allowed to participate. Concurrent use of SGLT2 inhibitors was permitted. Key exclusion criteria included autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis, or antineutrophil cytoplasmic antibody-associated vasculitis. Participants carrying the Human Leukocyte Antigen-B *58:01 allele were also excluded. Treatment with any drug for hyperuricemia (including all xanthine oxidase inhibitors, URAT1 inhibitors, and urate oxidases) in the 6 months preceding randomization was another exclusion criterion. The full inclusion and exclusion criteria are listed in the Supplemental Material.
Trial Procedures
Participants were randomly assigned in a 1:1:1:1:1 ratio to one of five treatment arms: placebo, placebo+allopurinol 300 mg/day, verinurad 3 mg+allopurinol 300 mg/day, verinurad 7.5 mg+allopurinol 300 mg/day, or verinurad 12 mg+allopurinol 300 mg/day (hereafter referred to as verinurad 3 mg, verinurad 7.5 mg, or verinurad 12 mg). Study medication was uptitrated as displayed in Supplemental Table 1. Verinurad was administered in combination with allopurinol to reduce urate production and thereby decrease the risk for elevated urinary uric acid peak concentrations that could promote decreases in GFR. These doses were selected based on earlier phase 2 studies and a healthy volunteer study in Asia. Following an interim analysis when 90% of participants were enrolled in the trial, a protocol amendment was introduced that permitted a blinded dose increase to verinurad 24 mg+allopurinol 300 mg/day in approximately half of patients randomized to verinurad 3 mg+allopurinol 300 mg/day at 9 months postrandomization to assess the efficacy and safety of a higher verinurad dose. These participants were followed per protocol until the end-of-treatment visit at week 60. Participants who did not transition to the highest 24 mg verinurad dose continued treatment with verinurad 3 mg+allopurinol 300 mg/day.
Investigators used an interactive voice or web response system to determine treatment assignment. Participants and all study personnel (except the Independent Data Monitoring Committee) were masked to treatment allocation. Trial medication was packaged identically, with uniform tablet and capsule appearance, labeling, and administration schedule.
After randomization, an 8-week dose-titration phase was initiated with visits at 4 and 8 weeks to minimize the risk of gout flares and allopurinol hypersensitivity reactions. At 8 weeks, the target dose was initiated. In-person study visits were subsequently performed at 12, 20, 34, 47, and 60 weeks. At week 60, all patients discontinued randomized study medication and proceeded to a post-treatment 4-week wash-out period to assess off-study drug effects. At each follow-up visit, vital signs were recorded, blood and urine samples were sent for laboratory assessment, and information on potential study end points, adverse events, concomitant therapies, and study drug adherence were collected. If participants became pregnant; developed kidney stones; had confirmed AKI, skin reactions, or hypersensitivity to allopurinol; or experienced transaminase or bilirubin elevations, study medication had to be discontinued, but participants were to continue follow-up visits per protocol.
Investigators were encouraged to keep the dose of the ACE inhibitor, ARB, or SGLT2 inhibitors stable for each patient throughout the study. Management of BP, lipids, glucose, and use of other essential therapies were left to investigator discretion, in accordance with best clinical practice guidelines.
Primary and Secondary Study Outcomes
The primary efficacy end point was the change from baseline in UACR at week 34. Key secondary efficacy end points included change from baseline in UACR at 60 weeks and change in serum urate, creatinine, cystatin C, and eGFR at 34 and 60 weeks. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation.
Safety was assessed by collecting investigator-reported adverse events, vital signs, physical examinations, electrocardiograms, and clinical laboratory parameters. An independent adjudication committee assessed potential cardiovascular events using prespecified end point definitions.
Statistical Analysis
The analytical approach and power calculations have been previously published.16 In brief, a sample size of 145 participants in each randomized group provides 80% power to detect a 25% reduction in geometric mean UACR for the high dose of verinurad and allopurinol compared with placebo (treatment difference of approximately −0.29 on the natural log scale and assuming a SD of 1.0 on the natural log scale) at the two-sided alpha level of 0.1.
The primary efficacy analysis was conducted in the full analysis set defined as all randomized participants. The analysis of change in UACR from baseline to week 34 (i.e., 26 weeks of treatment at target dose) was based on the natural log-transformed UACR values using a mixed model for repeated measures (MMRM), with fixed categorical effects of treatment, week, diabetes status, moderately or severely elevated albuminuria, N terminal pro B-type natriuretic peptide < or ≥360 pg/ml, baseline SGLT2 inhibitor use, and treatment-by-week interaction. We added baseline log(UACR) and baseline log(UACR)-by-week interaction as continuous fixed covariates to the model. We computed estimates of the geometric mean percent change from baseline in UACR for each treatment group under the mixed model (with 95% CIs), as well as the geometric mean treatment ratio between the active treatment groups and the placebo/comparator group (with 95% CI and P value for a test of no treatment effect). As in previous dose finding studies in patients with CKD, we did not impute missing values, but we analyzed all available longitudinal ACR values under the assumption of missingness at random. The following three comparisons were tested sequentially at two-sided alpha=0.1: UACR at 6 months high-dose verinurad plus allopurinol versus placebo, 12 mg and 7.5 mg dose verinurad plus allopurinol versus allopurinol, and allopurinol alone versus placebo.
Secondary efficacy variables were analyzed using the same MMRM model as was used for the primary efficacy variable with the exception that baseline log UACR and the interaction between baseline log UACR and visit was replaced for baseline serum urate or eGFR and the interaction between baseline serum urate or eGFR with visit.
All safety analyses were conducted on the safety population defined as all randomized participants who took at least one dose of study medication. We summarized safety outcomes by treatment group based on the randomized treatment assignment. Adverse events of major cardiovascular events (acute myocardial infarction, hospitalization for unstable angina pectoris, heart failure hospitalization, urgent heart failure visit, stroke, and cardiovascular death) and clinically significant acute increases in serum creatinine values (as judged by the investigator) were adverse events of special interest in this study. Cardiovascular events were adjudicated by an independent clinical end point adjudication committee.
Analyses were performed with SAS version 9.4 (SAS Institute) and R version 4.10 (R Statistical Computing Vienna, Austria).
Results
Participants and Follow-Up
From August 2019 until November 2021, 1149 participants were screened, of whom 861 underwent randomization. A total of 37 participants randomized to verinurad 3 mg/day-allopurinol 300 mg/day were switched to verinurad 24 mg/day-allopurinol 300 mg/day 9 months after randomization (Figure 1). Overall, 703 (82%) completed the study. The most frequent reasons for not completing the study were death (N=57 [7%]) or participant decision (N=57 [7%]). Six hundred (70%) participants completed treatment. The most frequent reasons for discontinuation of the study treatment were adverse events (N=126 [15%]) or participant decision (N=90 [11%]). The mean adherence to study treatments, as assessed by pill count, was 95% (SD 15).
Figure 1.
Patient flow and disposition.
Baseline characteristics were well balanced among treatment groups (Table 1). The mean age was 65 years (SD 11), 284 (33%) participants were female, and 622 (72%) were White. The median UACR was 217 mg/g (25th, 75th percentile 72, 689), the mean eGFR was 48 ml/min per 1.73 m2 (SD 18), and the mean serum urate was 7.9 mg/dl (SD 1.6).
Table 1.
Demographic and clinical characteristics of the participants at baseline
| Characteristic | Verinurad 12 mg (n=172) |
Verinurad 7.5 mg (n=172) |
Verinurad 3 mg (n=173)a |
Verinurad 24 mg/day (n=37)b |
Allopurinol 300 mg/day (n=171) |
Placebo (n=173) |
|---|---|---|---|---|---|---|
| Age, yr, mean (SD) | 65 (10) | 65 (11) | 65 (11) | 64 (13) | 65 (11) | 66 (10) |
| Female sex, n (%) | 69 (40) | 53 (31) | 57 (33) | 11 (30) | 55 (32) | 50 (29) |
| Race, n (%) | ||||||
| Asian | 4 (2) | 3 (2) | 5 (3) | 2 (5) | 4 (2) | 4 (2) |
| Black or African American | 25 (15) | 24 (14) | 24 (14) | 3 (8) | 23 (14) | 20 (12) |
| Other | 20 (12) | 20 (12) | 17 (10) | 0 (0) | 26 (15) | 18 (10) |
| White | 122 (71) | 125 (73) | 126 (73) | 32 (87) | 118 (69) | 131 (76) |
| Weight, kg, mean (SD) | 92 (21) | 91 (18) | 93 (21) | 93 (23) | 89 (20) | 89 (19) |
| BMI, kg/m2, mean (SD) | 33 (7) | 32 (6) | 33 (6) | 32 (6) | 32 (7) | 31 (6) |
| BP, mm Hg, mean (SD) | ||||||
| Systolic | 136 (18) | 139 (16) | 136 (14) | 137 (13) | 136 (17) | 135 (18) |
| Diastolic | 75 (10) | 77 (10) | 75 (10) | 78 (11) | 74 (11) | 75 (10) |
| eGFR, ml/min per 1.73 m2, n (%) | ||||||
| ≥90 | 7 (4) | 4 (2) | 4 (2) | 1 (3) | 10 (6) | 5 (3) |
| 75 to <90 | 10 (6) | 11 (6) | 10 (6) | 2 (5) | 13 (8) | 8 (5) |
| 60 to <75 | 19 (11) | 35 (20) | 15 (9) | 2 (5) | 9 (5) | 19 (11) |
| 45 to <60 | 44 (26) | 43 (25) | 45 (26) | 10 (27) | 51 (30) | 46 (27) |
| 30 to <45 | 73 (42) | 61 (36) | 81 (47) | 17 (46) | 64 (37) | 74 (43) |
| <30 | 19 (11) | 18 (11) | 18 (10) | 5 (14) | 24 (14) | 21 (12) |
| Serum urate, mg/dl, mean (SD) | 7.8 (1.5) | 7.9 (1.5) | 8.2 (1.6) | 7.9 (1.4) | 8.0 (1.7) | 7.7 (1.4) |
| Hemoglobin, g/dl, mean (SD)c | 13.1 (1.9) | 13.4 (1.6) | 13.0 (1.9) | 13.4 (1.9) | 13.1 (1.7) | 13.2 (1.7) |
| Serum potassium, mEq/L, mean (SD)c | 4.7 (0.5) | 4.6 (0.5) | 4.7 (0.6) | 4.8 (0.6) | 4.7 (0.5) | 4.7 (0.6) |
| UACR, mg/g, median (25–75th percentile) | 248 (70–817) | 203 (83–617) | 174 (58–563) | 146 (55–548) | 221 (80–655) | 251 (74–729) |
| Type 2 diabetes, n (%) | 149 (87) | 137 (80) | 144 (83) | 26 (70) | 133 (78) | 144 (83) |
| History of gout, n (%) | 39 (23) | 33 (19) | 28 (16) | 7 (19) | 23 (14) | 33 (19) |
| Prior medication, n (%) c | ||||||
| ACE inhibitor/ARB | 158 (92) | 151 (88) | 152 (88) | 32 (87) | 150 (88) | 158 (91) |
| SGLT2i | 18 (11) | 23 (13) | 19 (11) | 6 (16) | 12 (7) | 11 (6) |
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BMI, body mass index; SGLT2i, sodium-glucose cotransporter-2 inhibitor; UACR, urinary albumin-creatinine ratio.
Contains all participants randomized to the low-dose group, including those who later switched to verinurad 24 mg+allopurinol 300 mg.
Contains all participants randomized to the low-dose group who later switched to verinurad 24 mg+allopurinol 300 mg.
Safety analysis set.
Primary Outcome
Figure 2 shows the albuminuria changes over time. In the placebo group, the geometric mean percent change from baseline in UACR remained stable over time except at weeks 34 and 47 (26 and 39 weeks post-titration), at which point, the geometric mean UACR level modestly increased from baseline (Figure 2A; at week 34: 37.3% [95% CI, 16.6 to 61.8]). Similarly, UACR remained stable in all verinurad groups, regardless of dose (Figure 2A). At week 34, the geometric mean percentage change in UACR from baseline was 16.7% (95% CI, −0.6 to 37.1) in the 3 mg group, 15.0% (95% CI, −1.85 to 34.6) in the 7.5 mg group, and 14.0% (95% CI, −3.4 to 34.4) in the 12 mg group (Figure 2B). Compared with placebo, the corresponding between-group differences at week 34 for the verinurad 12 mg group was −17.0% (95% CI, −31.9 to 1.2; P = 0.07), −16.3% (95% CI, −31.1 to +1.7; P = 0.07) for the verinurad 7.5 mg group, and −15.0% (95% CI, −30.2 to +3.2; P = 0.10) for the verinurad 3 mg group. In the allopurinol 300 mg/day group, geometric mean percent change in UACR from baseline was 9.9% (95% CI, −6.6 to 29.4) at week 34. Compared with allopurinol, the between-group difference at week 34 for the combined verinurad 12 mg and 7.5 mg group was +4.3% (95% CI, −12.1 to 23.7; P = 0.63).
Figure 2.
UACR over time. (A) Geometric mean (95% CI) UACR over time in each treatment group (mg/g). (B) Mean percent change from baseline in UACR at week 34 in each treatment group. (A) The descriptive geometric mean (95% CI) values over time. The verinurad 24 mg dose group represents patients who were treated with verinurad 3 mg until week 48 and were then switched to verinurad 24 mg. CI, confidence interval; UACR, urinary albumin-creatinine ratio.
Secondary Outcomes
At week 60, a numerical increase from baseline in UACR was observed in participants who switched from verinurad 3 mg to 24 mg (17.3% [95% CI, −9.9 to 52.5]). Four weeks after study drug discontinuation, UACR levels remained stable compared with baseline in all randomized groups. Absolute changes in UACR at week 34 and 60 did also not change from baseline in any randomized group (Supplement Table 1). Subgroup analyses of the geometric mean percent change and absolute change in UACR comparing verinurad 12 mg versus placebo at week 34 demonstrated consistent results in all examined subgroups (Figure 3 and Supplemental Table 2). The results were also consistent when applying a sex-specific hyperuricemia threshold of serum urate >7 mg/dl for men and >6 mg/dl for women (Supplemental Table 3).
Figure 3.
Changes from baseline in UACR at week 34 comparing verinurad 12 mg versus placebo according to prespecified subgroups at baseline. NT-proBNP, N terminal pro B-type natriuretic peptide; SGLT2i, sodium-glucose cotransporter-2 inhibitor.
Overall, the mean serum urate ranged from 7.7 to 8.2 mg/dl across treatment groups at baseline (Table 1). Serum urate levels remained stable in the placebo group, while they decreased in all active groups between baseline and week 60 (Figure 4). Compared with placebo, verinurad 12 mg/day, 7.5 mg/day, and 3 mg/day reduced serum urate by 49.0% (95% CI, 44.7 to 53.0), 41.9 (95% CI, 37.0 to 46.4), and 39.0 (95% CI, 33.9 to 43.8), respectively. Decrease in serum urate was greater in the allopurinol 300 mg/day group than in the placebo group by 37.7% (95% CI, 32.4 to 42.6). Compared with allopurinol, 34-week treatment with verinurad 12 mg further changed serum urate by −18.2% (95% CI, −24.6 to −11.2; P < 0.001). The difference between verinurad 7.5 mg and allopurinol was −6.7% (95% CI, −14.0 to 1.1; P = 0.09). Verinurad 3 mg induced a similar reduction in serum urate as allopurinol (Figure 4). Transitioning patients from verinurad 3 mg/day to 24 mg/day at week 48 resulted in a further reduction in serum urate at 60 weeks (Figure 4). There was no correlation between change in UACR and serum urate in any dose group at week 34 (Figure 5).
Figure 4.
Mean (95% CI) serum urate levels over time. The number of patients achieving the target level of urate ≤5.5 mg/dl in the placebo, allopurinol, and verinurad 3, 7.5, and 12 mg dose groups were 6 (3.5%), 98 (57.3%), 95 (55.2%), 105 (61.0%), and 105 (61.0%), respectively. The verinurad 24 mg dose group represents patients who were treated with verinurad 3 mg until week 48 and were then switched to verinurad 24 mg.
Figure 5.
Correlation between change from baseline in UACR and serum urate for the different dose groups. The verinurad 24 mg dose group represents patients who were treated with verinurad 3 mg until week 48 and were then switched to verinurad 24 mg.
Overall, the mean (SD) eGFR at baseline was 48 (18) ml/min per 1.73 m2. There were no obvious changes in eGFR during the 60-week follow-up period (Figure 6). Serum creatinine and plasma cystatin C also did not change during the study (Supplemental Figure 1). Four (2%) patients experienced a confirmed 40% reduction in eGFR at week 60 in the verinurad 12 mg group, two (1%) patients in each of the verinurad 7.5 mg and 3 mg groups, six (4%) in the allopurinol group, three (2%) in the placebo group, and none of the participants who transitioned from verinurad 3 mg to 24 mg at week 48.
Figure 6.
Mean eGFR (95% CI) over time.
Safety Outcomes and Adverse Events
In the verinurad 3, 7.5, and 12 mg groups, the proportion of participants with adverse events, serious adverse events, or adverse events leading to discontinuation of study drug was similar to the proportions observed in the allopurinol alone and placebo groups (Table 2). The small group of participants who switched to the highest dose of verinurad (24 mg) did not allow for meaningful safety and tolerability comparisons due to the short exposure and low number of participants.
Table 2.
Adverse eventsa
| AE Category | Verinurad 12 mg (N=172) | Verinurad 7.5 mg (N=172) | Verinurad 3 mgb (N=172) | Allopurinol (N=171) | Placebo (N=173) |
|---|---|---|---|---|---|
| Any SAE (including events with outcome of death) | 36 (21) | 39 (23) | 40 (23) | 42 (25) | 35 (20) |
| Any AE | 124 (72) | 125 (73) | 121 (70) | 123 (72) | 128 (74) |
| Leading to discontinuation of IP | 27 (16) | 25 (15) | 23 (13) | 30 (18) | 25 (15) |
| Leading to dose reduction | 1 (0.6) | 3 (1.7) | 1 (0.6) | 3 (1.8) | 1 (0.6) |
| Death | 14 (8) | 8 (5) | 13 (8) | 10 (6) | 11 (6) |
| Infections and infestations | 48 (28) | 49 (29) | 48 (28) | 47 (28) | 49 (28) |
| COVID-19 | 8 (5) | 11 (6) | 12 (7) | 11 (6) | 10 (6) |
| Urinary tract infection | 9 (5) | 5 (3) | 6 (4) | 10 (6) | 7 (4) |
| Metabolism and nutrition disorders | 24 (14) | 27 (16) | 30 (17) | 34 (20) | 39 (23) |
| Gout | 3 (2) | 6 (4) | 9 (5) | 5 (3) | 13 (8) |
| Hyperkalaemia | 6 (4) | 4 (2) | 3 (2) | 5 (3) | 10 (6) |
| Nervous system disorders | 15 (9) | 16 (9) | 24 (14) | 20 (12) | 25 (15) |
| Headache | 8 (5) | 4 (2) | 6 (4) | 3 (2) | 11 (6) |
| Vascular disorders | 20 (12) | 15 (9) | 12 (7) | 17 (10) | 16 (9) |
| Hypertension | 6 (4) | 9 (5) | 5 (3) | 12 (7) | 8 (5) |
| Gastrointestinal disorders | 33 (19) | 25 (15) | 23 (13) | 23 (14) | 29 (17) |
| Diarrhea | 7 (4) | 5 (3) | 2 (1) | 8 (5) | 11 (6) |
| Musculoskeletal and connective tissue disorders | 32 (19) | 29 (17) | 17 (10) | 22 (13) | 26 (15) |
| Arthralgia | 9 (5) | 5 (3) | 4 (2) | 5 (3) | 11 (6) |
| Investigations | 22 (13) | 26 (15) | 9 (5) | 33 (19) | 17 (10) |
| Blood creatinine increased | 0 | 5 (3) | 2 (1) | 9 (5) | 2 (1) |
| Participants with any adjudicated CV events | 6 (4) | 12 (7) | 13 (8) | 14 (8) | 9 (5) |
| Cardiac arrhythmia | 0 | 1 (0.6) | 5 (3) | 3 (2) | 1 (0.6) |
| Heart failure | 3 (2) | 5 (3) | 2 (1) | 4 (2) | 3 (2) |
| Hospitalized unstable angina | 0 | 1 (0.6) | 0 | 3 (2) | 0 |
| Myocardial infarction | 0 | 1 (0.6) | 2 (1) | 1 (0.6) | 3 (2) |
| Revascularization | 0 | 4 (2) | 1 (0.6) | 0 | 1 (0.6) |
| Stroke | 3 (2) | 3 (2) | 3 (2) | 4 (2) | 2 (1) |
| Participants with adjudicated CV deaths | 4 (2.3) | 1 (0.6) | 5 (3) | 2 (2) | 3 (2) |
AE, adverse event; COVID-19, coronavirus disease 2019; CV, cardiovascular; IP, investigational product; N, number of participants in treatment group; SAE, serious AE.
Number (%) of patients with AEs, sorted by international order for system organ class and by descending frequency then alphabetically for preferred term. Patients with multiple events in the same system organ class/preferred term are counted only once in that system organ class/preferred term. Patients with events in more than one system organ class/preferred term are counted once in each of those system organ classes/preferred terms.
Contains events for all patients randomized to the low-dose group while on the low dose (i.e., prior to switching or if never switching).
Within the active verinurad groups, the proportion of patients with adjudicated-confirmed cardiovascular events was similar between groups ranging from 8% to 4% in the 3 mg to 12 mg verinurad groups, respectively (Table 2). The corresponding numbers for the allopurinol monotherapy and the placebo groups were 8% and 5%, respectively. Eighteen adverse events of blood creatinine increase were reported; none in the 12 mg verinurad group; the frequencies ranged from 1% of the patients in the placebo group to 5% of the patients in the allopurinol-alone group. No clinically meaningful changes from baseline or trends over time were observed for serum creatinine.
Discussion
In the SAPPHIRE trial, we found that verinurad in combination with allopurinol compared with placebo reduced serum urate but did not reduce albuminuria or slow eGFR decline over time in participants with CKD and hyperuricemia, with and without type 2 diabetes. The trial also demonstrated modest additional uric acid reductions with verinurad and allopurinol, compared with allopurinol alone, but no difference in any of the kidney-related outcomes. While a growing body of literature suggests that urate lowering does not prevent kidney function loss, this trial extends this by effectively excluding clinically meaningful kidney effects via inhibition of the URAT1 transporter.
The SAPPHIRE trial was designed to confirm and extend a finding in the phase 2 CITRINE trial of verinurad and febuxostat in people with diabetes and albuminuria, where albuminuria was significantly reduced by over one third.12 That finding was not confirmed in SAPPHIRE, despite being well powered to detect a clinically important reduction. This discrepancy in the results of the two trials could be the result of differences in cotherapies between the two trials. Specifically, it is possible that the effect observed in CITRINE were primarily due to febuxostat rather than verinurad, given that there was no febuxostat-only arm in that trial. This possibility is supported by previous studies that have suggested febuxostat may lower albuminuria when compared with allopurinol,17 and the open-label FREED trial that suggested a lower rate of kidney events with febuxostat therapy than allopurinol, although this explanation would require a febuxostat-specific action not related to serum urate lowering per se.18,19 The reason for using allopurinol in the SAPPHIRE trial instead of febuxostat, as in the CITRINE study, was that during the design of the SAPPHIRE trial, the CARES trial reported that febuxostat may increase all-cause and cardiovascular mortality,20 leading to a black-box warning in the United States. On the basis of these findings, it was decided to replace febuxostat for allopurinol in the SAPPHIRE trial. However, after the SAPPHIRE trial had started, results of the FAST trial showed no difference in cardiovascular risk between the two compounds.21,22 It is also possible that differences in study populations between CITRINE and SAPPHIRE may be relevant, but it appears unlikely that these would produce such a substantive difference, given the consistent findings across subgroups. Finally, it is also possible that the CITRINE trial result was a chance finding, or an overestimation of the true effect that may have led to the absence of effect observed in SAPPHIRE.
The rationale for lowering serum urate concentrations to prevent CKD and its progression is primarily based on both biologic plausibility and findings from observational studies.23–25 There are several biologic pathways through which hyperuricemia may induce early kidney injury, including induction of a specific afferent arteriolar vasculopathy, promotion of endothelial dysfunction through nitric oxide inhibition, and activation of the renin–angiotensin–aldosterone system.26 Observational studies have found strong associations between hyperuricemia and the risk of new-onset kidney disease,27 while pooled analysis of clinical trial data has suggested that lowering serum urate concentrations resulted in few major kidney events.28 Thus, lowering serum urate concentrations would seem to be a potential kidney protection strategy. However, this trial adds to a growing body of evidence suggesting that uric acid–lowering therapy has little if any kidney benefit in people with CKD. The PERL trial randomized 530 participants with type 1 diabetes, albuminuria, and evidence of kidney disease to allopurinol or placebo and found no effects on eGFR and, if anything, an increase in urine albumin excretion rate.8 Similarly, the CKD FIX trial randomized 369 participants with stage 3 or 4 CKD to allopurinol or placebo and found no effect on eGFR, composite kidney outcomes, or albuminuria.9 Taken together, the existing data do not support nephroprotective effects of serum urate lowering.
Hyperuricemia is common in patients with CKD, and its prevalence increases when eGFR declines.25 Effective and safe therapies to lower urate in patients with CKD are warranted. In some studies, febuxostat was a more effective urate-lowering strategy than allopurinol in patients with and without CKD and in patients with and without gout.29,30 However, in a recent study, both agents were equally effective in lowering urate.31 The addition of URAT1 inhibitors, such as verinurad, however, provides even greater reductions in serum urate levels.32 In the CITRINE trial, verinurad plus febuxostat resulted in serum urate reductions of between 59.6% and 63.7% lower than placebo at 12 and 24 weeks. In comparison, observed reductions in serum urate in the SAPPHIRE trial with allopurinol and verinurad were more modest. One might speculate that greater lowering of serum urate may have yielded greater impact with a reduction in albuminuria. However, neither the CITRINE nor the present SAPPHIRE trial found any correlation between serum urate lowering and degree of albuminuria. These findings argue against serum urate as a causal risk factor for CKD and suggest that urate-independent mechanisms may be the more likely culprits.
Potent URAT1 inhibition with lesinurad and verinurad has been associated with serum creatinine elevations, potentially related to increased urinary uric acid peak concentrations in the proximal tubule lumen of the kidney.33 Verinurad was therefore given as an extended release formulation, as a low maximum concentration is expected to further reduce or eliminate the risk of creatinine elevations. Furthermore, in this study, verinurad was administered in combination with allopurinol to reduce urate production and further decrease the risk for high, potentially harmful, peak urinary concentrations of uric acid. Indeed, no kidney or cardiovascular safety concerns were identified during the trial, suggesting that these precautionary measures were successful to optimize tolerability and mitigate adverse events.
This study has limitations. First, after the first interim analysis, a protocol amendment was introduced to test a higher dose of verinurad since the systemic exposure in the ongoing doses was lower than expected. The protocol amendment permitted patients in the verinurad 3 mg group to continue double-blind verinurad 3 mg/day or transition to verinurad 24 mg/day. At completion of the trial, adherence to verinurad 24 mg/day was poor with undetectable verinurad concentrations or missing values in more than 25% of the 37 participants. It is unlikely that this affected the albuminuria-lowering efficacy because the transition to verinurad 24 mg/day resulted in an additional urate-lowering effect. Nevertheless, the poor adherence and the relatively shorter treatment duration compared with the other verinurad dose groups limit the reliability of these findings. Second, although 42% of all participants had severe albuminuria (UACR >300 mg/g), GFR was stable during follow-up in the placebo group. This limited our ability to detect differences in GFR slope, although we do not anticipate a treatment effect because verinurad did not reduce UACR. In addition, since more than half of all participants had moderate albuminuria (UACR 30–300 mg/g), it remains unknown if verinurad is effective in reducing UACR and eGFR decline in participants with CKD and overt proteinuria who are at high risk of kidney failure. Fourth, 30% of the participants discontinued the study treatment, which may have affected our ability to detect treatment effects. Finally, most participants were White, limiting generalizability to other races.
In conclusion, URAT1 inhibition with verinurad in combination with allopurinol reduced serum urate but did not reduce albuminuria or slow eGFR decline in patients with CKD and hyperuricemia, with or without diabetes. These data do not support the proposition that urate lowering per se inhibits albuminuria or slows the progression of CKD.
Supplementary Material
Acknowledgments
The authors thank all investigators, trial teams, and patients for their participation in the trial. Editorial assistance was provided by Core Medica, London, UK, funded by AstraZeneca according to Good Publication Practice guidelines.
Footnotes
SAPPHIRE Investigators: Czech Republic: Hana Chmelickova, Martin Lukac, Petr Bucek, Tomas Drasnar; France: Bertrand Dussol, Dominique Guerrot, Eric Legrand, Jean-Jacques Boffa, Jean-Michel Halimi, Philippe Zaoui; Hungary: Annamaria Letoha, Csaba Hajdu, Denes Pall, Eva Peterfai, Gyöngyi Csécsei, Katalin Bezzegh, Laszlo Deak, Laszlo Konyves, Marianna Zsom, Peter Danos, Sandor Vangel, Szilard Vasas, Tamas Oroszlan, Zsolt Zilahi; Israel: Adi Leiba, Alon Grossman, Avshalom Leibowitz, Baruch Itzhak, Deeb Daoud, Evgeny Farber, Faiad Adawi, Farid M. Nakhoul, Gil Chernin, Irina Kenis, Julio Wainstein, Lior Zeller, Mazen Elias, Shaul Atar, Victor Frajewicki, Yoram Yagil, Zaher A. Armaly; Italy: Ciro Esposito, Francesca Viazzi, Giovanni Gambaro, Piermarco Piatti, Riccardo C. Bonadonna; Mexico: Cristhian Ronaldt Arias Delgadillo, Fernando Jimenez Flores, Manuel Enrique Aguilera Real, Pedro Fajardo-Campos, Rafael Margarito Violante Ortiz, Rosa Isela Luna Ceballos, Sergio Duran-Barragan; Poland: Danuta Zytkiewicz-Jaruga, Ewa Krzyzagorska, Ewa Skokowska, Katarzyna Klodawska, Robert Mordaka, Stanislaw Mazur, Teresa Stasinska, Wladyslaw Sulowicz; Romania: Ciprian Constantin, Doru Negru, Fraga-Silvia Paveliu, Gabriela Doina Negrisanu, Iosif Szilagyi, Mihaela Magdalena G. Busegeanu, Mihai Cosmin Pena, Rodica Ioana Avram, Silvia Luminita Ardelean; Slovakia: Adriana Ilavska, Andrej Dzupina, Aniko Oroszova, Eva Kolesarova, Ida Obetkova, Iveta Smatanova, Jana Babikova, Peter Fulop, Radovan Haffner; South Africa: Brian L. Rayner, Dawid Stephanus Kruger, Dorothea Vera Urbach, Essack Mitha, Gulam Hoosain Vally Mahomed Latiff, Hemant Makan, Hermanus du Plessis, Jaco Cornelius Jurgens, Jeevren Reddy, Julien S. Trokis, Kirsten McHarry, Lawrence Allen Distiller, Leila Mayet, Lesley Jean Burgess, Louis Johan Van Zyl, Mukesh P. Joshi, Peter John Sebastian, Samantha Maria Du Toit, Suzanne C. Blignaut; Spain: Antonio Galan Serrano, Cristobal Morales, Esteban Poch, Eva Marquez Mosquera, Fernando Cereto Castro, Francisco Javier Gonzalez Martinez, Francisco Javier Perez- Contreras, Gema Fernandez-Fresnedo, Isabel Fuencisla Garcia Mendez, Jonay Pantoja Perez, Jordi Calabia Martinez, Jose Luis Gorriz Teruel, Luis Javier Nieto Iglesias, Manuel Munoz-Torres, Maria Antonia Munar Vila, Maria Dolores Arenas Jimenez, Marta E. Dominguez-Lopez, Miguel Hueso Val, Natalia Ramos Terrades, Rafael Santamaria Olmo, Tamara Gelen Malek Marin; United States: Ahmed A. Arif, Benjamin J. Lee, Bhasker R. Mehta, Bruce H. Baker, Charles S. Jere, David G. Bains, David G. Stricklin, Deanna Cheung, Diego Echeverri, Edgard Vera, Eva-Maria Heurich, Gary A. Sterba, German T. Hernandez, Henry E. Paez, Idalia A. Acosta, Intekhab Ahmed, Issac Sachmechi, Ivy-Joan E. Madu, Jagdeep Singh Obhrai, Jamal A. Hammoud, James A. Tumlin, James Cain, Jaynier Moya-Hechevarria, Jeffrey J. Connaire, Jehad Haggiagi, Jennifer A. Odren, Jennifer M. Bellucci-Jackson, Jieshi Yan, John C. Parker, Jonathan P. Tolins, Jose D. Gomez-Cortes, Jose F. Cardona, Jose M. Mandry, Juan Jorge Olivero, Kendra S. Hendon, Kianoosh Kaveh, Laura A. Kooienga, Lidia R. Bermudez, Lisa M. Rich, Marina Gold, Marisela Gonzalez, Matthew E. Schaefer, Michelle Welch, Moustafa A. Moustafa, Murtaza Mussaji, Pablo E. Pergola, Piangwarin Phaosawasdi, Ricardo A. Silva, Ricardo Presas, Robert I. Lynn, Saeed J. Kronfli, Sailaja V. Ventrapragada, Sankar N. Niranjan, Sayed Husain, Scott Satko, Serge A. Jabbour, Sergio F. Rovner, Steven F. Gouge, Sudhir S. Joshi, Varagur Bala Ramachandran Subramanian, Wendy Lane, Wesley Calhoun, William Durham.
Present address: Magnus Bjursell, Global Medical Affairs, Clinical, Cardiovascular, Renal and Metabolic (CVRM), BioPharmaceuticals Medical, AstraZeneca, Gothenburg, Sweden.
See related editorial, “Requiem for Urate Lowering in CKD?,” on pages 525–527.
Contributor Information
Austin G. Stack, Email: Austin.Stack@ul.ie.
Robert Terkeltaub, Email: rterkeltaub@health.ucsd.edu.
Niels Jongs, Email: n.jongs@umcg.nl.
Lesley A. Inker, Email: Lesley.Inker@tuftsmedicine.org.
Magnus Bjursell, Email: Magnus.Bjursell@astrazeneca.com.
Noha Maklad, Email: noha.maklad@astrazeneca.com.
Shira Perl, Email: shira.perl@astrazeneca.com.
Olof Eklund, Email: olof.eklund@astrazeneca.com.
Tord Rikte, Email: tord.rikte@astrazeneca.com.
C. David Sjöström, Email: david.sjostrom1@astrazeneca.com.
Vlado Perkovic, Email: VPerkovic@georgeinstitute.org.au.
Collaborators: Hana Chmelickova, Martin Lukac, Petr Bucek, Tomas Drasnar, Bertrand Dussol, Dominique Guerrot, Eric Legrand, Jean-Jacques Boffa, Jean-Michel Halimi, Philippe Zaoui, Annamaria Letoha, Csaba Hajdu, Denes Pall, Eva Peterfai, Gyöngyi Csécsei, Katalin Bezzegh, Laszlo Deak, Laszlo Konyves, Marianna Zsom, Peter Danos, Sandor Vangel, Szilard Vasas, Tamas Oroszlan, Zsolt Zilahi, Adi Leiba, Alon Grossman, Avshalom Leibowitz, Baruch Itzhak, Deeb Daoud, Evgeny Farber, Faiad Adawi, Farid M. Nakhoul, Gil Chernin, Irina Kenis, Julio Wainstein, Lior Zeller, Mazen Elias, Shaul Atar, Victor Frajewicki, Yoram Yagil, Zaher A. Armaly, Ciro Esposito, Francesca Viazzi, Giovanni Gambaro, Piermarco Piatti, Riccardo C. Bonadonna, Cristhian Ronaldt Arias Delgadillo, Fernando Jimenez Flores, Manuel Enrique Aguilera Real, Pedro Fajardo-Campos, Rafael Margarito Violante Ortiz, Rosa Isela Luna Ceballos, Sergio Duran-Barragan, Danuta Zytkiewicz-Jaruga, Ewa Krzyzagorska, Ewa Skokowska, Katarzyna Klodawska, Robert Mordaka, Stanislaw Mazur, Teresa Stasinska, Wladyslaw Sulowicz, Ciprian Constantin, Doru Negru, Fraga-Silvia Paveliu, Gabriela Doina Negrisanu, Iosif Szilagyi, Mihaela Magdalena G. Busegeanu, Mihai Cosmin Pena, Rodica Ioana Avram, Silvia Luminita Ardelean, Adriana Ilavska, Andrej Dzupina, Aniko Oroszova, Eva Kolesarova, Ida Obetkova, Iveta Smatanova, Jana Babikova, Peter Fulop, Radovan Haffner, Brian L. Rayner, Dawid Stephanus Kruger, Dorothea Vera Urbach, Essack Mitha, Gulam Hoosain Vally Mahomed Latiff, Hemant Makan, Hermanus du Plessis, Jaco Cornelius Jurgens, Jeevren Reddy, Julien S. Trokis, Kirsten McHarry, Lawrence Allen Distiller, Leila Mayet, Lesley Jean Burgess, Louis Johan Van Zyl, Mukesh P. Joshi, Peter John Sebastian, Samantha Maria Du Toit, Suzanne C. Blignaut, Antonio Galan Serrano, Cristobal Morales, Esteban Poch, Eva Marquez Mosquera, Fernando Cereto Castro, Francisco Javier Gonzalez Martinez, Francisco Javier Perez- Contreras, Gema Fernandez-Fresnedo, Isabel Fuencisla Garcia Mendez, Jonay Pantoja Perez, Jordi Calabia Martinez, Jose Luis Gorriz Teruel, Luis Javier Nieto Iglesias, Manuel Munoz-Torres, Maria Antonia Munar Vila, Maria Dolores Arenas Jimenez, Marta E. Dominguez-Lopez, Miguel Hueso Val, Natalia Ramos Terrades, Rafael Santamaria Olmo, Tamara Gelen Malek Marin, Ahmed A. Arif, Benjamin J. Lee, Bhasker R. Mehta, Bruce H. Baker, Charles S. Jere, David G. Bains, David G. Stricklin, Deanna Cheung, Diego Echeverri, Edgard Vera, Eva-Maria Heurich, Gary A. Sterba, German T. Hernandez, Henry E. Paez, Idalia A. Acosta, Intekhab Ahmed, Issac Sachmechi, Ivy-Joan E. Madu, Jagdeep Singh Obhrai, Jamal A. Hammoud, James A. Tumlin, James Cain, Jaynier Moya-Hechevarria, Jeffrey J. Connaire, Jehad Haggiagi, Jennifer A. Odren, Jennifer M. Bellucci-Jackson, Jieshi Yan, John C. Parker, Jonathan P. Tolins, Jose D. Gomez-Cortes, Jose F. Cardona, Jose M. Mandry, Juan Jorge Olivero, Kendra S. Hendon, Kianoosh Kaveh, Laura A. Kooienga, Lidia R. Bermudez, Lisa M. Rich, Marina Gold, Marisela Gonzalez, Matthew E. Schaefer, Michelle Welch, Moustafa A. Moustafa, Murtaza Mussaji, Pablo E. Pergola, Piangwarin Phaosawasdi, Ricardo A. Silva, Ricardo Presas, Robert I. Lynn, Saeed J. Kronfli, Sailaja V. Ventrapragada, Sankar N. Niranjan, Sayed Husain, Scott Satko, Serge A. Jabbour, Sergio F. Rovner, Steven F. Gouge, Sudhir S. Joshi, Varagur Bala Ramachandran Subramanian, Wendy Lane, Wesley Calhoun, and William Durham
Disclosures
M. Bjursell reports employment with AstraZeneca and ownership interest (shares) in AstraZeneca, Medivir, and Swedish Orphan Biovitrum. O. Eklund reports employment with and ownership interest in AstraZeneca. H.J.L. Heerspink reports ongoing consultancy agreements with AstraZeneca, Bayer, BioChryst, Boehringer Ingelheim, Chinook, CSL Behring, Dimerix, Eli Lilly, Gilead, Janssen, Merck, Novartis, Novo Nordisk, and Travere Pharmaceuticals; research funding from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk, and Janssen research support (grant funding directed to employer); lecture fees from AstraZeneca and Novo Nordisk; and speakers bureau for AstraZeneca. L.A. Inker reports consultancy for Diamtrix; consulting agreements to Tufts Medical Center with Tricida; funding to institute, Tufts Medical Center, for research and contracts with the National Institutes of Health, National Kidney Foundation, Chinook, Omeros, and Reata Pharmaceuticals; consulting agreements with Tricida Inc.; advisory or leadership role for Alport Foundation Medical Advisory Council and National Kidney Foundation Scientific Advisory Board; and other interests or relationships as an American Society of Nephrology member and National Kidney Foundation member. N. Jongs reports serving on speakers bureau for AstraZeneca and travel support from AstraZeneca. N. Maklad reports employment with AstraZeneca. V. Perkovic reports consultancy for AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Otsuka, Travere, Tricida, and UpToDate; ownership interest in George Clinical; research funding from AstraZeneca, Bayer, Chinook, Gilead, GlaxoSmithKline, Janssen, Novartis, Novo Nordisk, Otsuka, Travere, and Tricida; honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Otsuka, Travere, Tricida, and UpToDate; honoraria for Steering Committee roles, scientific presentations, and/or advisory board attendance from Abbvie, Amgen, AstraZeneca, Baxter, Bayer, Boehringer Ingelheim, Chinook, Durect, Eli Lilly, Gilead, GSK, Janssen, Merck, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Otsuka, Pfizer, Pharmalink, Reata, Relypsa, Roche, Sanofi, Servier, Travere, and Tricida; advisory or leadership roles on Steering Committees for Bayer, Chinook, GlaxoSmithKline, Janssen, Novartis, Novo Nordisk, Otsuka, Pfizer, and Travere; and advisory or leadership role as Board Director for St Vincents Health Australia, George Clinical. S. Perl reports employment with, ownership interest in, and other interests or relationships with AstraZeneca. T. Rikte reports employment with AstraZeneca and ownership interest in Novo Nordisk A/S, Denmark and Telia, Sweden. T. Rikte's partner is a nurse (anesthesia) at Skånes Universitetssjukhus (“University hospital of Scania”), Malmö, Sweden. C.D. Sjostrom reports employment with and ownership interest in AstraZeneca LP. A.G. Stack reports consultancy for AstraZeneca, Menarini, and Vifor Pharma; educational grant from Vifor Pharma and research funding from AstraZeneca; honoraria from AstraZeneca, Menarini, and Vifor; patents or royalties from Preserva Medical; role on Editorial Board of BMC Nephrology; and speakers bureau for Vifor Pharma. R. Terkeltaub has recently served, or currently serves, as a consultant for Acquist Therapeutics, Allena, AstraZeneca, Atom Bioscience, Fortress/Urica, Generate Biomedicines, Horizon Therapeutics, LG Chem, Selecta Biosciences, and Synlogic; honoraria from Acquist Therapeutics, Allena, AstraZeneca, Atom Bioscience, Fortress/Urica, Generate Biomedicines, Horizon Therapeutics, LG Chem, Selecta Biosciences, and Synlogic; research funded by the NIH (AR060772); previous recipient of a research grant from AstraZeneca; paid role on Scientific Advisory Board for Acquist and Inozyme; and serves as the nonsalaried President of the GCAN (Gout, Hyperuricemia, and Crystal-Associated Disease Network) research society, a charitable research society, which annually receives unrestricted arms-length grant support from pharma donors.
Funding
Supported by AstraZeneca.
Author Contributions
Conceptualization: Hiddo J. Lambers Heerspink, Tord Rikte.
Methodology: Hiddo J. Lambers Heerspink.
Writing – original draft: Hiddo J. Lambers Heerspink.
Writing – review & editing: Magnus Bjursell, Olof Eklund, Lesley A. Inker, Niels Jongs, Noha Maklad, Shira Pearl, Vlado Perkovic, C. David Sjöström, Austin G. Stack, Robert Terkeltaub.
Data Sharing Statement
Due to local privacy regulations, data cannot be deposited in a persistent repository. Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca's data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Anonymized patient-level clinical data and/or anonymized clinical study documents can be obtained through Vivli's web-based request platform (www.vivli.org). All requests will be reviewed by an independent scientific review board. AstraZeneca-sponsored studies for products that have been approved in the United States and the European Union are in scope for data requests. Additionally, AstraZeneca-sponsored studies, with published primary end point results can be requested and may be considered for data and document sharing. When sharing anonymized patient level data, complete datasets may not be shared as a result of patients withdrawing their informed consent, when clinical trial informed consent prohibits secondary use of data, or other aspects taken into consideration to protect patient privacy.
Supplemental Material
This article contains the following supplemental material online at http://links.lww.com/JSN/E595.
Supplemental Table 1. Mean (SD) absolute change in UACR from baseline at weeks 34 and 60 in the overall population and participant subgroups defined by baseline albuminuria.
Supplemental Table 2. Geometric mean percentage change from baseline at weeks 34 and 60 in male participants with urate >7 mg/dl and female participants with urate >6 mg/dl.
Supplemental Figure 1. (A) Mean cystatin C (95% CI) over time; (B) mean serum creatinine (95% CI) over time.
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Data Availability Statement
Due to local privacy regulations, data cannot be deposited in a persistent repository. Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca's data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Anonymized patient-level clinical data and/or anonymized clinical study documents can be obtained through Vivli's web-based request platform (www.vivli.org). All requests will be reviewed by an independent scientific review board. AstraZeneca-sponsored studies for products that have been approved in the United States and the European Union are in scope for data requests. Additionally, AstraZeneca-sponsored studies, with published primary end point results can be requested and may be considered for data and document sharing. When sharing anonymized patient level data, complete datasets may not be shared as a result of patients withdrawing their informed consent, when clinical trial informed consent prohibits secondary use of data, or other aspects taken into consideration to protect patient privacy.
