Abstract
Objective
Dotinurad is a selective urate reabsorption inhibitor that reduces serum urate levels. We compared the efficacy and safety of dotinurad with febuxostat in Chinese patients with gout.
Methods
This phase 3, multicenter, randomized, double‐blind, parallel‐group study randomly allocated (1:1) eligible patients with gout to receive oral dotinurad or febuxostat. The primary end point was the responder rate (proportion of patients achieving serum urate levels ≤6.0 mg/dL) at week 24 in the full analysis set (FAS) to demonstrate superiority of dotinurad 4 mg/day to febuxostat 40 mg/day. The secondary end points included the responder rate at week 12 to show the noninferiority of dotinurad 2 mg/day to febuxostat 40 mg/day. Treatment‐emergent adverse events (TEAEs) were also recorded.
Results
A total of 451 patients were randomized, and 441 were included in the FAS. Baseline characteristics were well balanced between treatment groups. The responder rate at week 24 was significantly higher for dotinurad 4 mg/day versus febuxostat 40 mg/day (73.6% vs 38.1%; adjusted difference 35.9% [95% confidence interval (CI) 27.4%–44.4%]; P < 0.0001), and at week 12, dotinurad 2 mg/day was noninferior to febuxostat 40 mg/day (55.5% vs 50.5%; adjusted difference 5.2% [95% CI −3.7% to 14.2%]). Incidences of TEAEs in the dotinurad and febuxostat groups were similar.
Conclusion
Dotinurad 4 mg/day was superior to febuxostat 40 mg/day in achieving serum urate levels ≤6.0 mg/dL at week 24 and was well tolerated in Chinese patients with gout.
INTRODUCTION
Gout is the most common form of inflammatory arthritis in adults worldwide. 1 Its prevalence has increased rapidly since 1990, and it currently affects an estimated 55.8 million people worldwide. 2 The disease is characterized by hyperuricemia, defined as a serum urate level >7.0 mg/dL, resulting from either excessive uric acid production, decreased uric acid excretion, or a combination of these, leading to painful joint inflammation. 3 Gout is associated with several other diseases, including chronic kidney disease, hypertension, coronary heart disease, cardiovascular disease, and type 2 diabetes mellitus, and is also an independent predictor of premature death. 4 , 5 Effective management of hyperuricemia in patients with gout is important for preventing gout flares, urate nephropathy, and urate nephrolithiasis. 3 , 6
Urate‐lowering treatment is an important therapeutic strategy for hyperuricemia in patients with gout according to the American College of Rheumatology (ACR), EULAR, and Chinese Rheumatology Association guidelines. 7 , 8 , 9 Allopurinol is recommended as the first‐line urate‐lowering treatment in ACR and EULAR guidelines and is recommended as one of the urate‐lowering drugs used in China. However, Han Chinese patients have a higher risk of severe cutaneous adverse reactions to allopurinol due to the HLA allele HLA–B*58:01, which limits the use of this drug in clinical practice. 10 Febuxostat (a xanthine oxidase inhibitor) is a urate‐lowering treatment that is used globally and predominately in China; 11 , 12 , 13 however, the use of febuxostat in patients with cardiovascular disease should be exercised cautiously and monitored regularly according to the prescribing information and certain guidelines. 14 , 15 , 16 , 17 , 18 Another urate‐lowering drug, benzbromarone, is associated with safety concerns such as hepatic disorders. 19 Therefore, there is a need for a potent, well‐tolerated, and selective uricosuric agent with a better safety profile.
In kidneys, transporters play important roles in urate reabsorption and secretion. Urate transporter 1 (URAT1), organic anion transporter 10, and organic anion transporter 4 are localized on the apical membrane of the renal proximal tubule epithelial cells and reabsorb urate from glomerular filtrate. The reabsorbed urate is transported into the blood stream primarily via glucose transporter 9. 20 Dotinurad is a selective urate reabsorption inhibitor that reduces serum urate levels by selective inhibition of URAT1. 21 , 22 In phase 3 studies in Japan, dotinurad led to a reduction in serum urate levels in patients with hyperuricemia and gout 23 , 24 and was noninferior to benzbromarone 24 and febuxostat. 23 Based on the results of these and other Japanese studies, 25 dotinurad was approved for the treatment of hyperuricemia and gout in Japan in 2020.
The aim of this study was to compare the efficacy and safety of dotinurad with febuxostat in Chinese patients with gout. The primary objective was to demonstrate the superiority of dotinurad 4 mg/day to febuxostat 40 mg/day in reducing serum urate levels at week 24.
PATIENTS AND METHODS
Study design
This phase 3, multicenter, randomized, double‐blind, double‐dummy, active‐controlled, parallel‐group study (ClinicalTrials.gov registration NCT05007392) was conducted between December 21, 2021, and June 14, 2023, at 30 study sites in China (Supplemental Table 1).
The study evaluated the efficacy and safety of dotinurad (2 mg/day and 4 mg/day) versus febuxostat (40 mg/day) in Chinese patients with gout aged ≥18 years. The study comprised a screening phase (days −28 to −4), treatment phase I (4 weeks), and treatment phase II (20 weeks). The study design is shown in Supplemental Figure 1.
The study was approved by an independent ethics committee and performed in accordance with the standard operating procedures of the sponsor, which were designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the Declaration of Helsinki, China‐GCP, and other applicable regulatory authorities’ requirements or directives. Written informed consent was obtained from all patients. The protocol is available via ClinicalTrials.gov (https://clinicaltrials.gov/study/NCT05007392).
Participants
The full list of eligibility criteria is provided in Supplemental Table 2. Eligible patients were aged ≥18 years at the time of informed consent and had a diagnosis of gout according to the 2015 ACR/EULAR gout classification criteria 26 (with a history of gout flare or concurrent gouty tophi), with serum urate levels >7.0 mg/dL at screening.
Randomization and masking
Approximately 450 patients were planned to be randomly allocated (1:1) to the two treatment groups using a stratified permuted block randomization with a fixed block size of four and with baseline serum urate level (<9, 9 to <10, 10 to <11, ≥11 mg/dL) and baseline body mass index (BMI) (<25, ≥25) as stratification factors. Additional details of the randomization are provided in the Supplemental Methods.
Procedures
The rationale for the drug dose, titration, and duration is described in the Supplemental Methods. In treatment phase I (weeks 0–4), patients received either oral dotinurad 1 mg/day plus febuxostat‐matched placebo or oral febuxostat 20 mg/day plus dotinurad‐matched placebo. During treatment phase II, participants in the dotinurad group took oral dotinurad 2 mg/day plus febuxostat‐matched placebo for 8 weeks followed by dotinurad 4 mg/day plus febuxostat‐matched placebo for 12 weeks, and those in the febuxostat group took oral febuxostat 40 mg/day plus dotinurad‐matched placebo for 20 weeks. Prophylaxis for gout flare (eg, nonsteroidal anti‐inflammatory drugs and colchicine) was not permitted during the study to assess the incidence of gout flare.
Outcomes
The primary end point was the proportion of patients who achieved a serum urate level ≤6.0 mg/dL (hereafter referred to as the responder rate) at week 24 using the last observation carried forward (LOCF) method for imputing missing values. The secondary end points were the responder rate at week 12 (LOCF) and at each time point (weeks 4, 8, 12, 16, 20, and 24), the mean percentage reduction from baseline in serum urate level at each time point, mean change from baseline in serum urate level at each time point, and mean serum urate level at each time point.
Safety and tolerability assessments included adverse events (AEs), clinical laboratory parameters, vital signs, 12‐lead electrocardiography, and physical examinations. AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA) Version 26.0 (Supplemental Methods). AEs of special interest included urinary calculi, liver injury, and renal injury.
Statistical analysis
The full analysis set (FAS) was used as the primary population for all efficacy analyses. Supplemental analyses were performed in the per‐protocol set (PPS), and safety assessments were performed in the safety analysis set. To determine the responder rate, assuming a rate of 45% for febuxostat 40 mg/day and 60% for dotinurad 4 mg/day, a sample size of 225 patients in each group (450 total) was considered to provide approximately 90% power to detect a between‐group difference in the responder rate based on a two‐group chi‐square test with a two‐sided significance level of 0.05.
The primary analysis was to demonstrate the superiority of dotinurad 4 mg/day to febuxostat 40 mg/day regarding the primary end point. Analyses were also performed on subgroups divided by baseline serum urate level, baseline BMI, and baseline hyperuricemia classification, as described in the Supplemental Methods. The primary analysis of the difference in the primary end point was performed using the Cochran–Mantel–Haenszel test stratified by baseline serum urate level and baseline BMI, with a two‐sided test and α level of 0.05. For cases in which the serum urate level was missing at weeks 12 and 24, data were imputed using the LOCF method. The difference in responder rate at week 12 and the stratified 95% confidence intervals (CIs) were estimated, with a prespecified noninferiority margin of −10% for the lower limit of the 95% CI. For the primary efficacy end point, a prespecified sensitivity analysis using a nonresponder imputation (NRI) method was also conducted, which treated patients with missing serum urate data at week 24 as nonresponders. Additionally, an ad hoc sensitivity analysis was conducted by imputing missing values using the multiple imputation (MI) method under the assumption that the missing data were missing at random (MAR). MI was applied with 100 imputed data sets generated using a regression method, with the measurements at previous postbaseline visits, baseline covariates, and treatment group as covariates. These multiple imputed data sets were then analyzed using the primary analysis method, and the results were combined using Rubin's rule. The mean serum urate level and the percentage reduction in serum urate level at each time point were also summarized (Supplemental Methods).
Safety data were summarized using descriptive statistics or frequency counts by MedDRA System Organ Class and Preferred Terms. No hypothesis testing was performed for the safety analyses. Statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc), and all statistical comparisons had a two‐sided 5% significance level. The data sets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.
RESULTS
Between December 21, 2021, and December 29, 2022, 604 patients were recruited to the study, of whom 153 failed screening (Figure 1). A total of 451 patients were randomized; two patients in the dotinurad group and one in the febuxostat group did not receive the study drug. Overall, 448 patients (dotinurad n = 223, febuxostat n = 225) received at least one dose of the study drug. The percentages of patients who discontinued the study were similar between the dotinurad and febuxostat groups (12.6% vs 12.4%, respectively). Common primary reasons for discontinuation were patient decision, AEs, and withdrawal of consent. The FAS, safety analysis set, and PPS included 441, 448, and 410 patients, respectively.
Figure 1.
Patient disposition. aAs reported on the patient disposition case report form. bCorresponding adverse event(s) leading to withdrawal from the study were reported on the adverse event case report form. cGout flare at week 4 or 12; did not resolve within 1 week. dExcluding at the final visit. ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal.
Overall, 433 of 441 patients (98.2%) were male; the mean age was 39.1 (SD 11.3) years, BMI was ≥25 kg/m2 in 72.8% of patients, the mean baseline serum urate level was 9.7 (SD 1.4) mg/dL, the mean time since gout diagnosis was 5.3 (SD 5.5) years, and 95.9% of patients had experienced gouty flare before screening (Table 1). The most common hyperuricemia classification was underexcretion (75.7%). The demographic, baseline, and disease history characteristics were well balanced between the two treatment groups. There were no notable differences between the treatment groups regarding type or frequency of comorbidities.
Table 1.
Demographic, baseline, and disease history characteristics of the patients in the FAS*
| Dotinurad (n = 221) | Febuxostat (n = 220) | Total (N = 441) | |
|---|---|---|---|
| Age, y a | 38.9 ± 11.6 | 39.2 ± 11.0 | 39.1 ± 11.3 |
| 38.0 (31.0–45.5) | 38.0 (30.0–46.0) | 38.0 (31.0–46.0) | |
| <45 | 156 (70.6%) | 158 (71.8%) | 314 (71.2%) |
| 45 to <55 | 40 (18.1%) | 40 (18.2%) | 80 (18.1%) |
| 55 to <65 | 17 (7.7%) | 17 (7.7%) | 34 (7.7%) |
| ≥65 | 8 (3.6%) | 5 (2.3%) | 13 (2.9%) |
| Sex, male | 218 (98.6%) | 215 (97.7%) | 433 (98.2%) |
| Ethnicity | |||
| Chinese | 221 (100.0%) | 220 (100.0%) | 441 (100.0%) |
| Height, cm | 173.4 ± 6.8 | 172.5 ± 6.6 | 172.9 ± 6.7 |
| 174.0 (169.0–178.0) | 173.0 (168.0–177.1) | 173.0 (168.2–177.7) | |
| Weight, kg | 83.3 ± 15.5 | 81.2 ± 13.9 | 82.2 ± 14.7 |
| 81.4 (73.7–90.6) | 78.9 (71.0–88.3) | 80.0 (73.0–89.7) | |
| BMI, kg/m2 | 27.6 ± 4.3 | 27.2 ± 3.7 | 27.4 ± 4.0 |
| 26.8 (24.8–29.6) | 26.7 (24.6–29.0) | 26.8 (24.7–29.2) | |
| <25 | 60 (27.1%) | 60 (27.3%) | 120 (27.2%) |
| ≥25 | 161 (72.9%) | 160 (72.7%) | 321 (72.8%) |
| Serum urate level, mg/dL | 9.7 ± 1.5 | 9.6 ± 1.4 | 9.7 ± 1.4 |
| 9.5 (8.7–10.6) | 9.4 (8.6–10.5) | 9.4 (8.6–10.5) | |
| <9 | 79 (35.7%) | 79 (35.9%) | 158 (35.8%) |
| 9 to <10 | 56 (25.3%) | 58 (26.4%) | 114 (25.9%) |
| 10 to <11 | 49 (22.2%) | 48 (21.8%) | 97 (22.0%) |
| ≥11 | 37 (16.7%) | 35 (15.9%) | 72 (16.3%) |
| eGFR, mL/min/1.73 m2 | 96.4 ± 16.9 | 98.0 ± 16.7 | 97.2 ± 16.8 |
| 99.0 (88.0–108.0) | 100.5 (87.0–110.0) | 100.0 (88.0–109.0) | |
| 30 to <60 | 5 (2.3%) | 2 (0.9%) | 7 (1.6%) |
| 60 to <90 | 57 (25.8%) | 60 (27.3%) | 117 (26.5%) |
| ≥90 | 159 (71.9%) | 158 (71.8%) | 317 (71.9%) |
| Time since gout diagnosis, y | 5.3 ± 5.5 | 5.4 ± 5.5 | 5.3 ± 5.5 |
| 3.5 (1.3–7.7) | 4.0 (1.1–7.8) | 3.8 (1.2–7.7) | |
| Time since diagnosis of asymptomatic hyperuricemia, y | 7.1 ± 5.2 (n = 33) | 7.1 ± 6.0 (n = 31) | 7.1 ± 5.5 (n = 64) |
| 5.9 (3.3–11.7) | 5.4 (1.6–10.2) | 5.7 (3.2–10.8) | |
| Previous urinary calculi | 12 (5.4%) | 13 (5.9%) | 25 (5.7%) |
| Family history of gout/hyperuricemia | 39 (17.6%) | 35 (15.9%) | 74 (16.8%) |
| Previous gouty flare | 214 (96.8%) | 209 (95.0%) | 423 (95.9%) |
| Previous gouty tophi b | 40 (18.1%) | 38 (17.3%) | 78 (17.7%) |
| All medications used in the past for gout/hyperuricemia | |||
| None | 9 (4.1%) | 4 (1.8%) | 13 (2.9%) |
| Benzbromarone | 59 (26.7%) | 74 (33.6%) | 133 (30.2%) |
| Allopurinol | 25 (11.3%) | 34 (15.5%) | 59 (13.4%) |
| Febuxostat | 128 (57.9%) | 129 (58.6%) | 257 (58.3%) |
| Other | 174 (78.7%) | 168 (76.4%) | 342 (77.6%) |
| Classification of hyperuricemia | |||
| Overproduction | 6 (2.7%) | 6 (2.7%) | 12 (2.7%) |
| Underexcretion | 167 (75.6%) | 167 (75.9%) | 334 (75.7%) |
| Combined | 42 (19.0%) | 35 (15.9%) | 77 (17.5%) |
| Other | 6 (2.7%) | 12 (5.5%) | 18 (4.1%) |
| Comorbidities present in ≥10% of each group c | |||
| Hepatic steatosis | 81 (36.3%) | 69 (30.7%) | 150 (33.5%) |
| Hyperlipidemia | 60 (26.9%) | 50 (22.2%) | 110 (24.6%) |
| Hypertension | 54 (24.2%) | 50 (22.2%) | 104 (23.2%) |
| Dyslipidemia | 35 (15.7%) | 28 (12.4%) | 63 (14.1%) |
Data are mean ± SD, median (IQR), or n (%). Percentages are based on the total number of patients with nonmissing values in the relevant treatment group. BMI, body mass index; eGFR, estimated glomerular filtration rate; FAS, full analysis set; IQR, interquartile range.
Age was determined at the date of informed consent.
Presence of tophus assessed before screening.
Based on the safety analysis set; dotinurad group n = 223, febuxostat group n = 225 (total N = 448).
The primary efficacy end point results are shown in Table 2. At week 24 (LOCF), the responder rate (serum urate level ≤6.0 mg/dL) was significantly higher in the dotinurad 4 mg/day group than in the febuxostat 40 mg/day group (73.6% [95% CI 67.8%–79.5%] vs 38.1% [95% CI 31.6%–44.5%]). The proportion of patients without serum urate data at week 24 was 13.6% (60 of 441 in the FAS, including 29 in the dotinurad group and 31 in the febuxostat group). The difference in responder rates after adjustment for baseline serum urate level and baseline BMI category was 35.9% (95% CI 27.4%–44.4%; P < 0.0001), demonstrating superiority of dotinurad 4 mg/day to febuxostat 40 mg/day in the primary efficacy end point. In the prespecified sensitivity analysis, the responder rate at week 24 (NRI) was significantly higher in the dotinurad 4 mg/day group than in the febuxostat 40 mg/day group (67.9% [95% CI 61.7%–74.0%] vs 34.5% [95% CI 28.3%–40.8%]). Those results were supported in the ad hoc sensitivity analysis using the MI method. Furthermore, as an additional ad hoc sensitivity analysis, LOCF, NRI, and MI were applied to the intention‐to‐treat population (ie, randomized patients), and the results are presented in Supplemental Table 3. The difference in responder rates after adjustment for baseline serum urate level and baseline BMI category was 33.7% (95% CI 25.0%–42.4%; P < 0.0001), supporting the superiority of dotinurad 4 mg/day to febuxostat 40 mg/day in the primary efficacy end point. The supplemental analysis of the primary efficacy end point in the PPS also showed a similar result to the primary analysis. The subgroup analysis results of the primary efficacy end point with patients stratified by baseline serum urate level, baseline BMI, and baseline hyperuricemia classification are shown in Supplemental Table 4.
Table 2.
Responder rates at week 24 (LOCF, NRI, MI) and week 12 (LOCF) in the FAS (primary and sensitivity analyses) and the PPS (supplemental analysis)*
| Dotinurad (n = 221) | Febuxostat (n = 220) | |
|---|---|---|
| Primary analysis (LOCF‐FAS) | 4 mg/day | 40 mg/day |
| Responder rate at week 24, n (%) (95% CI) | 162 (73.6) | 83 (38.1) |
| (67.8 to 79.5) | (31.6 to 44.5) | |
| Difference in rate at week 24, % (95% CI) a | 35.9 | – |
| (27.4 to 44.4) | ||
| P value b | <0.0001 | – |
| Prespecified sensitivity analysis (NRI‐FAS) | 4 mg/day | 40 mg/day |
| Responder rate at week 24, n (%) (95% CI) c | 150 (67.9) | 76 (34.5) |
| (61.7 to 74.0) | (28.3 to 40.8) | |
| Difference in rate at week 24, % (95% CI) a | 33.7 | – |
| (25.0 to 42.4) | ||
| P value b | <0.0001 | – |
| Ad hoc sensitivity analysis (MI‐FAS) d | 4 mg/day | 40 mg/day |
| Responder rate at week 24, % (95% CI) | 75.7 | 37.9 |
| (69.7 to 81.7) | (31.2 to 44.6) | |
| Difference in rate at week 24, % (95% CI) | 38.1 | – |
| (29.3 to 46.8) | ||
| P value | <0.0001 | – |
| Secondary analysis (LOCF‐FAS) | 2 mg/day | 40 mg/day |
| Responder rate at week 12, n (%) (95% CI) | 122 (55.5) | 109 (50.5) |
| (48.9 to 62.0) | (43.8 to 57.1) | |
| Difference in rate at week 12, % (95% CI) a | 5.2 | |
| (−3.7 to 14.2) | ||
| Supplemental analysis (LOCF‐PPS) | 4 mg/day (n = 205) | 40 mg/day (n = 205) |
| Responder rate at week 24, n (%) (95% CI) | 158 (77.1) | 82 (40.0) |
| (71.3 to 82.8) | (33.3 to 46.7) | |
| Difference in rate at week 24, % (95% CI) a | 37.1 | – |
| (28.5 to 45.7) | ||
| P value b | <0.0001 | – |
Response was achievement of a serum urate level ≤6.0 mg/dL. The responder (yes or no) rate is based on the number of patients with nonmissing data (LOCF) in the relevant treatment group. CI, confidence interval; FAS, full analysis set; LOCF, last observation carried forward; MAR, missing at random; MI, multiple imputation; NRI, nonresponder imputation; PPS, per‐protocol set.
Stratified 95% CI based on the Mantel–Haenszel method.
P value based on the Cochran–Mantel–Haenszel test stratified by baseline serum urate level and baseline body mass index.
The number of patients with missing data at week 24 was 29 patients in the dotinurad group and 31 patients in the febuxostat group.
MI assuming MAR was conducted as an ad hoc sensitivity analysis. The analysis results were combined using Rubin's rule.
The secondary efficacy end point results are shown in Table 2. For the responder rates at week 12 (LOCF), dotinurad 2 mg/day was noninferior to febuxostat 40 mg/day based on the lower limit of the two‐sided 95% CI being greater than the prespecified noninferiority margin of −10%; the responder rates were 55.5% and 50.5% for dotinurad and febuxostat, respectively, with a treatment difference of 5.2% (95% CI −3.7% to 14.2%). Regarding the responder rate at each time point in the FAS (Figure 2), the rates were consistently higher in the dotinurad group than in the febuxostat group, with greater differences at week 16 or later time points.
Figure 2.
Responder rate (serum urate level ≤6.0 mg/dL) over time (full analysis set). LOCF, last observation carried forward.
The mean percentage reduction from baseline in serum urate level at each visit is shown in Supplemental Table 5. The change over time in percentage reduction in serum urate level from baseline in the FAS is provided in Supplemental Figure 2a. The mean percentage reductions from baseline in serum urate level at weeks 12 (LOCF) and 24 (LOCF) were 37.9% and 45.9%, respectively, in the dotinurad group and 35.0% and 30.6%, respectively, in the febuxostat group. The dotinurad group showed a greater percentage reduction in serum urate level at week 24 (LOCF) than the febuxostat group. The mean serum urate level at each time point and the mean change from baseline in serum urate level are shown in Supplemental Table 5, and Supplemental Figure 2b shows the serum urate levels over time.
The mean ± SD duration of exposure was similar between the dotinurad (160.2 ± 31.4 days) and febuxostat groups (157.5 ± 36.6 days). The overall incidence of treatment‐emergent adverse events (TEAEs) was similar between the dotinurad (202 of 223, 90.6%) and febuxostat (203 of 225, 90.2%) groups (Table 3). The dotinurad and febuxostat groups had similarly low incidences of severe TEAEs (2 of 233 [0.9%] and 3 of 225 [1.3%], respectively) and serious TEAEs (3 of 223 [1.3%] and 4 of 225 [1.8%], respectively). The incidence of treatment‐related TEAEs was also similar between the dotinurad and febuxostat groups (146 of 223 [65.5%] and 147 of 225 [65.3%], respectively). None of the severe or serious TEAEs were judged as related to dotinurad, and only one patient in the dotinurad group withdrew from the study treatment because of severe or serious TEAEs (ankle fracture, joint dislocation, and ligament injury simultaneously). The most common TEAEs (incidence ≥5%) for dotinurad and febuxostat were gout flare (including reports of both MedDRA Preferred Terms of “gout” and “gouty arthritis”) (106 of 223 [47.5%] and 90 of 225 [40.0%], respectively), COVID‐19 (57 of 223 [25.6%] and 57 of 225 [25.3%], respectively), increased alanine aminotransferase levels (18 of 223 [8.1%] and 28 of 225 [12.4%], respectively), and abnormal hepatic function (24 of 223 [10.8%] and 18 of 225 [8.0%], respectively) (Supplemental Table 6). One treatment‐related acute kidney injury, which was moderate in severity as judged by the investigator, was reported in the dotinurad group, resulting in drug withdrawal with subsequent recovery.
Table 3.
Summary of TEAEs (safety analysis set)*
| Dotinurad (n = 223) | Febuxostat (n = 225) | |
|---|---|---|
| All TEAEs | 202 (90.6%) | 203 (90.2%) |
| Treatment‐related TEAEs a | 146 (65.5%) | 147 (65.3%) |
| Severe TEAEs | 2 (0.9%) | 3 (1.3%) |
| Serious TEAEs b | 3 (1.3%) | 4 (1.8%) |
| TEAEs leading to study drug dose adjustment | 10 (4.5%) | 12 (5.3%) |
| Drug withdrawal | 6 (2.7%) | 11 (4.9%) |
| Dose interruption | 4 (1.8%) | 1 (0.4%) |
| TEAEs of special interest | ||
| Treatment‐emergent urinary calculi c | 14 (6.3%) | 19 (8.4%) |
| Treatment‐emergent liver injury d | 58 (26.0%) | 60 (26.7%) |
| Treatment‐emergent renal injury e | 18 (8.1%) | 20 (8.9%) |
Data are n (%). Events were coded according to MedDRA Version 26.0. MedDRA, Medical Dictionary for Regulatory Activities; SMQ, standardized MedDRA query; TEAE, treatment‐emergent adverse event.
Includes TEAEs considered by the investigator to be related to the study drug or TEAEs with uncertain causality.
Includes all patients with a serious TEAE; no patients died during this study.
Includes all patients with a TEAE classified under the MedDRA high‐level group term “urolithiases.”
Includes all patients with a TEAE classified under the MedDRA SMQ “hepatic disorders.”
Includes all patients with a TEAE classified under the MedDRA SMQ “acute renal failure.”
Treatment‐related TEAEs with an incidence ≥5% were gouty arthritis (dotinurad: 87 of 223 [39.0%]; febuxostat: 71 of 225 [31.6%]), abnormal hepatic function (dotinurad: 19 of 223 [8.5%]; febuxostat: 17 of 225 [7.6%]), increased alanine aminotransferase levels (dotinurad: 16 of 223 [7.2%]; febuxostat: 24 of 225 [10.7%]), nephrolithiasis (dotinurad: 11 of 223 [4.9%]; febuxostat: 16 of 225 [7.1%]), and increased α1‐microglobulin levels (dotinurad: 11 of 223 [4.9%]; febuxostat: 15 of 225 [6.7%]) (Supplemental Table 7). The incidences of these frequently reported treatment‐related TEAEs in the dotinurad group were similar to those in the febuxostat group.
The incidence of gout flare over time is shown in Table 4. In the dotinurad group, the incidence of gout flare at weeks 0 to 4 (start of treatment) was 26.0%, and at weeks 12 to 16 (initiation of 4 mg/day), the incidence of gout flare was 18.1%. The incidence decreased during weeks 4 through 12 and 16 through 24. In the febuxostat group, the incidence of gout flare was 20.9% at weeks 0 to 4, decreased to 12.7% at weeks 8 to 12, and remained consistent during weeks 12 through 24.
Table 4.
Incidence of gout flare over time (safety analysis set)*
| Dotinurad | Febuxostat | |
|---|---|---|
| Overall | 106/223 (47.5%) | 90/225 (40.0%) |
| Weeks 0–4 | 58/223 (26.0%) | 47/225 (20.9%) |
| Weeks 4–8 | 47/223 (21.1%) | 44/225 (19.6%) |
| Weeks 8–12 | 32/218 (14.7%) | 28/221 (12.7%) |
| Weeks 12–16 | 39/215 (18.1%) | 25/212 (11.8%) |
| Weeks 16–20 | 25/213 (11.7%) | 23/206 (11.2%) |
| Weeks 20–24 | 11/207 (5.3%) | 20/199 (10.1%) |
| >Week 24 | 4/199 (2.0%) | 4/198 (2.0%) |
Data are n/N (%). Gout flare includes the MedDRA Preferred Terms “gout” and “gouty arthritis.”
Treatment‐emergent urinary calculi were reported in 6.3% (14 of 223) and 8.4% (19 of 225) of patients in the dotinurad and febuxostat groups, respectively. The incidence of treatment‐emergent renal injury was similar between groups (dotinurad: 18 of 223 [8.1%]; febuxostat: 20 of 225 [8.9%]) (Table 3). Treatment‐emergent liver injury was also similar between the dotinurad (58 of 223 [26.0%]) and febuxostat groups (60 of 225 [26.7%]). Supplemental Table 8 shows details of the TEAEs of special interest. No clinically significant findings were observed for clinical laboratory tests, vital signs, or 12‐lead electrocardiography for patients treated with dotinurad.
DISCUSSION
The present phase 3 trial in Chinese patients with gout is the first study to demonstrate the superiority of dotinurad 4 mg/day to febuxostat 40 mg/day in achieving a serum urate level ≤6.0 mg/dL at week 24. To assess the robustness of the primary analysis results, sensitivity analyses were conducted using a different approach to handle missing data. A prespecified sensitivity analysis using a conservative method of handling missing data and ad hoc results using MI both supported the efficacy of dotinurad. The results of the supplemental and subgroup analyses were also consistent with those of the primary analysis, illustrating the robustness of the primary analysis results. Moreover, the secondary efficacy end point analysis showed that dotinurad 2 mg/day was noninferior to febuxostat 40 mg/day in the responder rate at week 12.
In the present study, patients were young (mean age 39.1 years), predominately male (98.6%), had high serum urate levels at baseline (mean baseline level: 9.7 mg/dL), and had high BMIs (mean at baseline: 27.4). This differs from the profile of patients with gout in some clinical studies in Japan (mean age, 56.1 years; male, 100.0%; mean serum urate level, 8.6 mg/dL; mean BMI, 26.4) and the United States (mean age, 55.1 years; male, 88.4%; mean serum urate level, 9.6 mg/dL; mean BMI, 34.3). 23 , 27 The predominance of male participants in this study is consistent with a national registry of gout patients in China, in which the ratio of males to females was 15:1. 16 The characteristics of patients in our study are similar to those of Chinese patients with gout or hyperuricemia in previous studies (mean age, 36.8–42 years; male, 98.8–99.5%; mean serum urate level, 9.94–10.0 mg/dL; BMI, 26.2–26.8 kg/m2). 28 , 29 The responder rate with febuxostat was 38.1% in the present study, which is similar to that in previous studies in China and the United States. 27 , 30 This indicates that conventional treatment with febuxostat 40 mg/day has an unsatisfactory response rate (below 50%) in Chinese and Western patients with gout. In contrast, the responder rate with dotinurad 4 mg/day in the present study was almost double that of febuxostat 40 mg/day. In particular, dotinurad was more effective than febuxostat in subgroups with higher baseline serum urate levels (≥9 mg/dL) and baseline BMI ≥25 kg/m2, although no statistical significance tests were conducted. Because a high proportion of the patients had high baseline serum urate levels and higher BMI, the improved efficacy of dotinurad in these patients with these backgrounds is clinically meaningful.
In this study, the incidence of TEAEs was similar between the two treatment groups (90.6% in the dotinurad group, 90.2% in the febuxostat group). Similar incidences of gout flare occurred in the dotinurad group (47.5%) and the febuxostat group (40.0%), which were comparable to the reported incidence in Chinese patients (43.1%–50.8%). 29 , 30 In line with previous Japanese trials of dotinurad as well as several other trials in China, 23 , 24 , 29 , 30 flare prophylaxis was prohibited in the present study. Prophylaxis is recommended by clinical guidelines; therefore, it is likely that a lower frequency of gout flare would occur in a clinical setting. It is known that gout flare tends to occur following initiation of urate‐lowering therapy due to a rapid reduction in serum urate levels. 31 The overall incidence of gout flare was numerically higher in the dotinurad group than in the febuxostat group, which may be explained by the second dose escalation in the dotinurad group. Longer studies using maintenance doses are required to see whether gout flares are controlled in the long term in Chinese patients with gout.
In our study, the incidences of treatment‐emergent urinary calculi, renal injury, and liver injury were similar between the dotinurad and febuxostat groups. Of the 14 patients who experienced urinary calculi in the dotinurad group, most cases were asymptomatic and were detected via imaging at the last study visit. Additionally, no cases of serious renal injury were reported in either treatment group. All reported TEAEs were mild except for one case of treatment‐related acute kidney injury, which was moderate in severity, in the dotinurad group, resulting in drug withdrawal. No serious liver injuries occurred in either group, and no TEAEs leading to study drug withdrawal or severe treatment‐emergent liver injury occurred in the dotinurad group.
No acute kidney injury was reported in the previous Japanese studies of dotinurad 23 , 24 ; in the present study, only the one aforementioned patient experienced acute kidney injury, leading to discontinuation of study treatment with subsequent recovery. Thus, we considered this case to be an isolated incident.
Lesinurad, the first approved selective URAT1 inhibitor, exhibits dose‐dependent nephrotoxicity and thus cannot be used as monotherapy because it increases the risk of acute renal failure. 32 In contrast, dotinurad has an acceptable renal safety profile and can be used as monotherapy. Moreover, dotinurad does not have any known drug–drug interactions and thus raises fewer drug–drug interaction concerns than existing urate‐lowering drugs. 33 , 34 Taken together, these safety results indicate that dotinurad was well tolerated in Chinese patients with gout, and no new safety signals were identified.
This study had some limitations. The LOCF method used in the primary analysis may lead to bias in the estimation because of the uncertainty associated with missing data. Although the extent of missing efficacy data at week 24 was generally balanced across the treatment groups, to address this, a prespecified sensitivity analysis that considered patients with missing data at week 24 was conducted, which supported the findings of the primary analysis. Another potential limitation of this study may include the selection bias in per‐protocol estimates. Although the reduction in serum urate level was observed, the relatively short study duration may have limited the observable effects on gout flare recurrence. Assessment of tophi was not included in the study protocol because we expected that very few patients would experience tophi in this study. Therefore, a longer and larger study will be needed to assess the incidence of tophi. Additionally, the incidence of gout flare in clinical practice is unknown because flare prophylaxis was not permitted in this study. Further data, including association with prophylaxis, need to be gathered in future research. In clinical practice, febuxostat can be increased to 80 mg/day in patients who do not adequately respond to 40 mg/day. Although febuxostat 80 mg/day is used for most patients with an initial dose of 40 mg/day in Western countries, dotinurad 4 mg/day was not compared with febuxostat 80 mg/day in this study. Additionally, very few of the enrolled patients were female, limiting any comparison of sex differences, and the participants were relatively young. Therefore, further studies will be necessary to evaluate dotinurad 4 mg/day compared with febuxostat 80 mg/day and in a wider population of patients with gout. Finally, the study results are only directly applicable to Chinese patients, albeit supplementing existing data on patients with different backgrounds. In conclusion, dotinurad may offer a new urate‐lowering treatment option to Chinese patients with gout, as it demonstrated both efficacy and a good safety profile overall.
AUTHOR CONTRIBUTIONS
All authors contributed to at least one of the following manuscript preparation roles: conceptualization AND/OR methodology, software, investigation, formal analysis, data curation, visualization, and validation AND drafting or reviewing/editing the final draft. As corresponding author, Dr Zhang confirms that all authors have provided final approval of the version to be published and take responsibility for the affirmations regarding article submission (eg, not under consideration by another journal), the integrity of the data presented, and the statements regarding compliance with institutional review board/Declaration of Helsinki requirements.
ROLE OF THE STUDY SPONSOR
This work was supported by funding from Eisai Co., Ltd. Eisai Co., Ltd. was involved in study design, data collection, analysis, and interpretation of data. The authors thank Hannah Read, PhD, of Edanz (www.edanz.com) for providing medical writing support, which was funded by Eisai Co., Ltd., in accordance with Good Publication Practice guidelines (https://www.ismpp.org/gpp-2022). Publication of this article was not contingent upon approval by Eisai Co., Ltd.
Supporting information
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Appendix S1: Supplementary Information
ClinicalTrials.gov identifier NCT05007392.
Some results reported in this article were presented as a poster at the EULAR 2024 congress in Vienna, Austria, June 12–15, 2024.
Supported by Eisai Co., Ltd.
Drs Sun and Wang are co‐first authors and contributed equally to this work.
Additional supplementary information cited in this article can be found online in the Supporting Information section (https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/art.43261).
Author disclosures are available at https://onlinelibrary.wiley.com/doi/10.1002/art.43261.
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Appendix S1: Supplementary Information