Safety and Pharmacokinetics of Quizartinib Combination Therapy With Standard Induction and Consolidation Chemotherapy in Patients With Newly Diagnosed Acute Myeloid Leukemia: Results from Two Phase 1 Trials in Japan and China.

Quizartinib is a potent, oral, second-generation, selective type II FMS-like receptor tyrosine kinase 3 (FLT3) inhibitor. It has shown improved overall survival in a randomized, multinational, Phase 3 (QuANTUM-First) study in patients with FLT3-internal tandem duplication (ITD)-positive newly diagnosed acute myeloid leukemia. We conducted 2 Phase 1b studies in Japan and China to evaluate the safety, pharmacokinetics, and efficacy of quizartinib in combination with standard induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. Quizartinib was started at a dose level of 20 mg/day and then escalated to 40 mg/day, the dose used in the Phase 3 study. Seven patients were enrolled according to the 3 + 3 dose-escalation method in each study, including 3 patients who were FLT3-ITD positive. No dose-limiting toxicities were observed at dose levels up to 40 mg/day in both studies. Grade 3 or higher, quizartinib-related, treatment-emergent adverse events included febrile neutropenia, hematologic toxicities, and infections. QT prolongation on electrocardiogram was observed in 5 patients. The pharmacokinetics of quizartinib and its metabolite AC886 were similar between the studies and consistent with previous findings in the United States. We confirmed the tolerability of Japanese and Chinese patients to the dose of quizartinib and chemotherapy regimens used in the QuANTUM-First study.

Zishen pingchan granules combined with pramipexole in the improvement of depressive symptoms in Parkinson's disease: a prospective, multicenter, randomized, double-blind, controlled clinical study.

BACKGROUND AND OBJECTIVE: Zishen Pingchan granule (ZPG), a traditional Chinese herbal recipe for treating Parkinson's disease (PD), is usually used as an add-on drug with some antiparkinsonian drugs in China. The objectives of this study were to evaluate the efficacy, safety, and tolerability of ZPG combined with pramipexole in the treatment of depression in PD (dPD). METHODS: A 12-week, multicenter, randomized, double-blind, and placebo-controlled study on ZPG was performed on a total of 200 patients who were treated with pramipexole but still had mild to moderate depressive symptoms. Patients were randomly divided into ZPG (n = 100) or placebo (n = 100). The primary effective result was the mean change from the baseline on the Hamilton Depression Scale 17 items (HAM-D-17) over 12 weeks and the clinical efficacy rate. Secondary endpoints were the mean change from the baseline in the Geriatric Depression Scale (GDS-15), Unified Parkinson's disease rating scale Part III (UPDRS III), Parkinson's quality of life scale (PDQ-8), and Parkinson's disease sleep scale (PDSS-2) over 12 weeks. RESULTS: After 12 weeks of treatment, ZPG significantly reduced the mean [95% confidence interval] HAMD score vs. placebo (- 1.43 scores [- 2.50, - 0.36]; p = 0.009). The clinical remission rate and responders of the ZPG group were higher than those of the placebo (46.1% vs. 31.0%; p = 0.041; 34.8% vs. 18.4%; p = 0.014). A significant improvement in the PDSS-2 score was also observed in the ZPG group compared with that in the placebo group (- 3.56 scores [- 5.77, - 1.35]; p = 0.002). A total of 7 patients (7.1%) in the ZPG group had mild adverse events (AEs) vs 9 patients (9%) in the placebo group. No severe AEs were observed in either group. The randomization and controlled clinical study revealed that ZPG was effective, safe, and well-tolerated. CONCLUSION: ZPG combined with pramipexole further reduced the depressive symptoms and improved the sleeping quality of PD patients. Trial registration The protocol was retrospectively registered at the Chinese Clinical Trial Registry, Unique identifier: ChiCTR1800019942, date of registration: December 9, 2018; http://www.chictr.org.cn/showproj.aspx?proj=30432.

[Gambling addiction as a side effect of low dose pramipexole in the treatment of restless legs syndrome].

Pathologic gambling is a rare but severe side effect of dopamine agonists (DA). Low dosage DA, as given when treating restless legs syndrome (RLS), has been thought only to have mild side effects. This case report describes two patients with low dosage pramipexole for RLS, who developed gambling addiction for a decade, highly affecting their quality of life. After stopping the treatment, the patients' gambling addiction ceased. Even though this is a very rare side effect, patients prescribed a DA should be informed of the risk of gambling addiction, independently of dosage.

Enhanced Taste Recognition Following Subacute Treatment With The Dopamine D2/D3 Receptor Agonist Pramipexole in Healthy Volunteers.

BACKGROUND: Patients with Parkinson's disease (PD) show impaired performance in taste recognition tests, which suggests a possible dopaminergic influence on gustatory functioning. To experimentally test this hypothesis, we assessed whether pharmacological manipulation of dopaminergic signaling in healthy volunteers can affect performance in a standardized taste recognition test. METHODS: Physically and mentally healthy volunteers (n = 40, age 18-43 years) were randomly allocated to treatment with either pramipexole or placebo using a double-blind, parallel-group design. After 12 to 15 days of treatment (dose titrated up from 0.25 mg/d of pramipexole salt to 1.0 mg/d), taste recognition performance was assessed using a standardized and validated assay (taste strip test). Additionally, visual analogue scale ratings of subjective pleasantness and disgustingness of taste samples were obtained. RESULTS: Compared with the placebo group, participants receiving pramipexole showed significantly higher total recognition accuracy (medianpramipexole = 14.0, medianplacebo = 13.0, U = 264.5, P = .04). This was driven by a higher sensitivity for taste in the pramipexole group. Exploratory analysis of pleasantness and disgustingness ratings of appetitive (sweet) vs aversive (bitter) stimuli suggested that pramipexole treatment was associated with overall blunted hedonic responses, but this effect did not survive the inclusion of nausea (a side effect of treatment) as a covariate in the analysis. CONCLUSIONS: Healthy volunteers who received subacute pramipexole treatment exhibited higher taste recognition performance compared with the placebo group. This finding is consistent with a proposed role of the dopaminergic system in gustatory functioning and could have important theoretical and clinical implications.

High national rates of high-dose dopamine agonist prescribing for restless legs syndrome.

STUDY OBJECTIVES: Long-term dopamine agonist (DA) use in restless legs syndrome (RLS) is associated with augmentation, a dose-related symptom worsening leading to further dose escalation to manage RLS. This study investigated rates and factors of high-dose DA prescribing in US RLS patients. METHODS: This retrospective analysis examined data from a US longitudinal prescriptions database (October 2017-September 2018). Patients diagnosed with RLS (ICD-10 G255.81) without Parkinson's disease who were prescribed ropinirole, pramipexole, and/or rotigotine were included. Daily DA dosage was categorized: LOW/MID (US Food and Drug Administration [FDA]-approved/guideline or slightly above FDA-approved [pramipexole]); HIGH (101%-149%); VERY HIGH (>150%). Patient counts were converted to US national estimates. Logistic regression of patient counts evaluated factors associated with HIGH/VERY HIGH DA dosing. RESULTS: Of 670,404 RLS patients (131,289,331 therapy days), 58.8% were prescribed DA therapy. Overall, 19.1% of RLS patients were prescribed DAs above maximum FDA-approved/guideline daily doses-over half of these were >150% maximum recommended doses; 67.6% of HIGH/VERY HIGH-dose prescriptions were pramipexole (OR [95% CI] pramipexole vs ropinirole, 5.8 [5.7 to 6.0]). The highest 1% of DA prescriptions were ≥10× the FDA-recommended maximum daily dose. Rates of HIGH/VERY HIGH DA dosing increased with patient age. Twice as many neurologists (31.1%) prescribed HIGH/VERY HIGH doses vs other specialties (OR [95% CI], 2.1 [1.2 to 2.0]). CONCLUSIONS: Approximately 20% of DA-treated RLS patients were prescribed doses above the approved and guideline daily maximum. Pramipexole, Neurology as specialty, and patient age were independently associated with HIGH/VERY HIGH DA dosing. Increased education is warranted regarding risks of high-dose DA exposure in RLS.

A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH.

BACKGROUND: Management of nonalcoholic steatohepatitis (NASH) is an unmet clinical need. Lanifibranor is a pan-PPAR (peroxisome proliferator-activated receptor) agonist that modulates key metabolic, inflammatory, and fibrogenic pathways in the pathogenesis of NASH. METHODS: In this phase 2b, double-blind, randomized, placebo-controlled trial, patients with noncirrhotic, highly active NASH were randomly assigned in a 1:1:1 ratio to receive 1200 mg or 800 mg of lanifibranor or placebo once daily for 24 weeks. The primary end point was a decrease of at least 2 points in the SAF-A score (the activity part of the Steatosis, Activity, Fibrosis [SAF] scoring system that incorporates scores for ballooning and inflammation) without worsening of fibrosis; SAF-A scores range from 0 to 4, with higher scores indicating more-severe disease activity. Secondary end points included resolution of NASH and regression of fibrosis. RESULTS: A total of 247 patients underwent randomization, of whom 103 (42%) had type 2 diabetes mellitus and 188 (76%) had significant (moderate) or advanced fibrosis. The percentage of patients who had a decrease of at least 2 points in the SAF-A score without worsening of fibrosis was significantly higher among those who received the 1200-mg dose, but not among those who received the 800-mg dose, of lanifibranor than among those who received placebo (1200-mg dose vs. placebo, 55% vs. 33%, P = 0.007; 800-mg dose vs. placebo, 48% vs. 33%, P = 0.07). The results favored both the 1200-mg and 800-mg doses of lanifibranor over placebo for resolution of NASH without worsening of fibrosis (49% and 39%, respectively, vs. 22%), improvement in fibrosis stage of at least 1 without worsening of NASH (48% and 34%, respectively, vs. 29%), and resolution of NASH plus improvement in fibrosis stage of at least 1 (35% and 25%, respectively, vs. 9%). Liver enzyme levels decreased and the levels of the majority of lipid, inflammatory, and fibrosis biomarkers improved in the lanifibranor groups. The dropout rate for adverse events was less than 5% and was similar across the trial groups. Diarrhea, nausea, peripheral edema, anemia, and weight gain occurred more frequently with lanifibranor than with placebo. CONCLUSIONS: In this phase 2b trial involving patients with active NASH, the percentage of patients who had a decrease of at least 2 points in the SAF-A score without worsening of fibrosis was significantly higher with the 1200-mg dose of lanifibranor than with placebo. These findings support further assessment of lanifibranor in phase 3 trials. (Funded by Inventiva Pharma; NATIVE ClinicalTrials.gov number, NCT03008070.).

A critical appraisal of Japan's new drug approval process: a case study of FLT3-ITD inhibitor quizartinib.

In the last two decades, simultaneous global development of novel drugs become more common by conducting multiregional clinical trials. However, regulatory authorities of different regions often make different decisions on the approvals of the same new drugs. We would like to discuss the appropriateness of Japanese regulatory approach through a case study of quizartinib, a novel anti-leukemia drug developed in Japan. The pivotal clinical trial "QuANTUM-R" conducted in 19 countries showed a modest increase in median overall survival with quizartinib than the conventional chemotherapy. However, because several critical defects in this trial were pointed out by the United States Food and Drug Administration (US FDA) and the European Medicines Agency (EMA), quizartinib has not been approved in the US and Europe to date. On the contrary, the regulatory authority of Japan gave a notice of approval to quizartinib as a "standard of care", and the country becomes the sole country that granted market authorization. In our paper, we provide more detailed discussion about the methodology for scientific evaluation of the new drug.

Comparative study of a novel selective urate reabsorption inhibitor "dotinurad" among patient groups with different stages of renal dysfunction.

BACKGROUND: Dotinurad is a selective urate reabsorption inhibitor (SURI), which selectively inhibits URAT1 to lower serum uric acid levels in patients with hyperuricemia. Herein, the effects of dotinurad were compared among patient groups with different stages of renal dysfunction. METHODS: Patient data from four clinical trials were pooled and divided into four groups according to the stage of renal dysfunction to compare the effects of dotinurad at different stages. The grouping (stages G1-G3b) was based on the estimated glomerular filtration rate (eGFR) of the patients. In addition, patient data from a long-term study (34 or 58 weeks) were evaluated in the same manner. RESULTS: In the pooled analysis, the percentage of patients achieving a serum uric acid level of ≤ 6.0 mg/dL was 64.7-100.0% at a dose of 2 or 4 mg. In the long-term analysis, the percentage of patients achieving a serum uric acid level of ≤ 6.0 mg/dL was 60.0-100.0% at a dose of 2 or 4 mg. Although the outcomes in stage G3b were worse due to higher baseline serum uric acid levels, satisfactory outcomes were observed in all stages. Even in stages G3a and G3b, when renal function declined, the eGFR remained constant throughout the dose period. CONCLUSION: The efficacy of dotinurad was confirmed in hyperuricemic patients with normal renal function (stage G1) and mild to moderate renal dysfunction (stage G2-G3b). Dotinurad was found to be effective in the treatment of hyperuricemia in patients with mild to moderate renal dysfunction.

The safety profile of FLT3 inhibitors in the treatment of newly diagnosed or relapsed/refractory acute myeloid leukemia.

INTRODUCTION: FLT3 inhibitors are important drugs in the therapy of FLT3 positive acute myeloid leukemia (AML). Midostaurin was registered in combination with chemotherapy to treat newly diagnosed AML. Gilteritinib and quizartinib demonstrate effectiveness in a randomized trial in relapsed/refractory AML. Several promising FLT3 inhibitors are being evaluated in clinical research. AREAS COVERED: This review will report the safety of FLT3 inhibitors that are registered for acute myeloid leukemia induction and rescue therapy. EXPERT OPINION: In the near future, it is possible that all the FLT3 positive non M3-AML patients will receive a FLT3 inhibitor. Therapy adherence and strategies to mitigate adverse events must be pursued. The treatment with FLT3 inhibitors may be optimized in terms of toxicities with a rational evaluation of antifungal prophylaxis and concomitant therapy, cardiology monitoring, and keeping in mind rare adverse events. Future studies on unfit patients, special populations, and maintenance settings are warranted, together with post-market studies and real-life experiences. Whenever new FLT3 inhibitors will come to the clinic, we could face a scenario in which profound knowledge of effectiveness, toxicities, and off-target effects will be relevant to choose the best drug for each patient.

Cutaneous eruption with reactive endothelial atypia due to emerging targeted cancer therapies: Report of two cases with clinico-pathologic correlation.

Targeted anticancer therapy is being used with greater frequency and dermatologic toxicities are among the most frequent adverse events of these drugs. However, histopathological features of these adverse events are not yet well characterized. We present two cases of clinically different cutaneous toxicities on two patients with hematologic neoplasia. They were treated with different drugs and in both cases medications shared inhibition of PI3K as mechanism of action. The skin biopsy specimen showed endothelial cell atypia with large nuclei and mitotic figures. To the best of our knowledge, no other cases with these striking histopathologic findings have been reported with PI3K inhibitors or other anticancer targeted therapy.

Patch Testing With a New Composition of the Mercapto Mix-A Multicenter Study from the International Contact Dermatitis Research Group.

BACKGROUND: Mercaptobenzothiazole compounds are associated with allergic contact dermatitis caused by rubber products. Several screening substances have been used for patch testing. OBJECTIVE: To compare the frequency of positive test reactions to a mercapto mix containing a higher concentration of 2-mercaptobenzothiazole with reactions to the combination of 2-mercaptobenzothiazole 2.0% and mercapto mix 2.0%. METHODS: There were 7103 dermatitis patients in 12 International Contact Dermatitis Research Group dermatology departments who were patch tested with 2-mercaptobenzothiazole 2.0% petrolatum (pet.), mercapto mix 2.0% pet., and mercapto mix 3.5% pet. RESULTS: Contact allergy to the 3 test preparations varied among the 12 centers: 2-mercaptobenzothiazole 2.0% pet. (0-2.4%), mercapto mix 2.0% pet. (0-4.9%), and mercapto mix 3.5% pet. (0-1.4%). 2-Mercaptobenzothiazole 2.0% and mercapto mix 2.0% detected a few more positive patients compared with mercapto mix 3.5%, but the difference was statistically insignificant (mercapto mix 2.0% pet., P = 1.0; 2-mercapto-benzothiazole 2.0% pet., P = 0.66). CONCLUSIONS: Mercapto mix 3.5% pet. is not better than 2-mercaptobenzothiazole 2.0% and mercapto mix 2.0% by a difference that is significant. By using only 1 test preparation (mercapto mix 3.5%), an additional hapten could be tested. No cases of suspected/proven patch test sensitization were registered.

Dilemma in Parkinson's Treatment; Levodopa Monotherapy May be the Best Choice.

INTRODUCTION: Several treatment strategies have been claimed for Parkinson's disease (PD) so far. However, there remains controversies over the best possible treatment. The aim of this study is to compare Levodopa monotherapy versus Pramipexole in combination with Levodopa L in patients with PD with regards to the efficacy and side effects. METHODS: Patients being treated with levodopa alone and Pramipexole add-on therapy to Levodopa were enrolled in the study. Factors regarding efficacy and side effects were assessed and analyzed between both groups by appropriate tests. RESULTS: 176 Patients were enrolled in the study. Results showed significant higher total MDS-UPDRS (worse total disease severity score) among patients being treated with Pramipexole add-on therapy which was particularly higher in parts 1 (Mentation, behavior and mood), 2 (Activity of daily living) and 3 (Motor examination) (P-values < 0.05). Psychosis global score with significantly higher frequency of hallucination and depression, statistically higher in combination therapy group compared to Levodopa monotherapy group (P-value < 0.05). Patients in the Pramipexole add-on group reported lower scores of Health-related quality of life (HRQoL) (P-value < 0.05). Significant correlation was between disease duration and psychosis score among Levodopa monotherapy group (P-value < 0.05). CONCLUSIONS: Compared to Levodopa monotherapy, Add-on therapy with Pramipexole shows less efficiency yet more side effects. This indicates that single administration of Levodopa still remains the best available treatment for Parkinson's disease.

Quizartinib for the treatment of acute myeloid leukemia.

INTRODUCTION: . Up to 30% of patients with acute myeloid leukemia (AML) have a mutation in the FLT3 receptor. Molecular targets have acquired a significant interest in the treatment of AML and are changing patient outcomes, including improvement of overall survival (OS) and remission rates. FLT3 inhibitors have obtained a central role in how we treat AML. AREAS COVERED: . This article reviews the mechanism of action, pharmacology, clinical efficacy, and safety of quizartinib, a FLT3 inhibitor, for the treatment of acute myeloid leukemia. EXPERT OPINION: . Quizartinib yielded an improvement in OS and complete remission (CR) rates in a phase 3 trial for relapsed/refractory FLT3-mutated AML. The toxicities are manageable; however, it is associated with significant QTc prolongation and myelosuppression. The FDA and EMA did not grant drug approval to quizartinib in the relapsed/refractory setting due to the lack of a significant benefit - to-risk ratio, safety concerns and concerns with credibility and generalizability of the trial data. Results from the frontline phase 3 study evaluating quizartinib with intensive chemotherapy are eagerly awaited. Ongoing studies are investigating its toxicity and efficacy with other therapeutic agents and will help to clarify its role in the treatment of FLT3-ITD-mutated AML.

A drug-drug interaction study of a novel, selective urate reabsorption inhibitor dotinurad and the non-steroidal anti-inflammatory drug oxaprozin in healthy adult males.

BACKGROUND: Dotinurad is a novel, selective urate reabsorption inhibitor, which reduces serum uric acid levels by inhibiting the urate transporter 1. The results of nonclinical studies indicated the possibility that the concomitant use of the non-steroidal anti-inflammatory drug oxaprozin affects the pharmacokinetics of dotinurad. We evaluated drug-drug interactions with respect to the pharmacokinetics and safety of dotinurad when co-administered with oxaprozin. METHODS: This was an open-label, two-period, add-on study in healthy adult males. For a single dose of 4 mg of dotinurad with and without oxaprozin, we compared its pharmacokinetic parameters and evaluated safety. RESULTS: This study enrolled 12 subjects, 11 of whom completed the study. The geometric mean ratio (90% confidence interval [CI]) of the urinary excretion rate of glucuronate conjugates of dotinurad after co-administration with oxaprozin compared to administration of dotinurad alone was 0.657 (0.624-0.692), while the geometric mean ratios (90% CIs) of the maximum plasma concentration and area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) were 0.982 (0.945-1.021) and 1.165 (1.114-1.219), respectively. During the study, two adverse events occurred after administration of dotinurad alone and one occurred after administration of oxaprozin alone. CONCLUSIONS: In comparison with administration of dotinurad alone, co-administration with oxaprozin was associated with a 34.3% decrease in the urinary excretion rate of the glucuronate conjugates of dotinurad, and a 16.5% increase in AUC0-inf of dotinurad. However, no clinically meaningful drug-drug interactions were observed. Administration of dotinurad alone was similar safety to co-administration with oxaprozin. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03350386.

A clinical pharmacology study of the novel, selective urate reabsorption inhibitor dotinurad in outpatients.

BACKGROUND: Dotinurad is a novel, selective urate reabsorption inhibitor (SURI), which reduces serum uric acid levels by selective inhibition of the urate transporter 1 (URAT1). The Japanese guideline for the management of hyperuricemia and gout recommends that drug selection should be based on classification of hyperuricemia as a fundamental principle. However, there may be some cases where this principle is not observed. We investigated the pharmacodynamics and safety of dotinurad in outpatients with uric acid overproduction or uric acid underexcretion type. METHODS: This was a multicenter, open-label, forced titration study. Patients were classified as uric acid overproduction or underexcretion type. Study treatment was initiated at 0.5 mg/day, followed by dose titration to the estimated maximum dose of 4 mg/day over 14 weeks. The primary endpoint was urinary uric acid excretion at each 24-h urine collection. RESULTS: A total of 26 hyperuricemic patients with or without gout were enrolled in the study and assigned to the uric acid overproduction group (overproduction group) or the uric acid underexcretion group (underexcretion group). Although urinary uric acid excretion, the primary endpoint, tended to be slightly greater in the overproduction group, no notable difference was noted between the two hyperuricemic types. Neither type had noteworthy safety concerns associated with dotinurad. CONCLUSION: The results of the study demonstrated no relevant differences between the hyperuricemic types in terms of pharmacodynamic action and safety of dotinurad.

A non-inferiority study of the novel selective urate reabsorption inhibitor dotinurad versus febuxostat in hyperuricemic patients with or without gout.

BACKGROUND: Dotinurad is a novel, selective urate reabsorption inhibitor, which reduces serum uric acid levels by selective inhibition of the urate transporter 1. We evaluated the efficacy and safety of dotinurad versus febuxostat, a widely used drug in Japan, in hyperuricemic Japanese patients with or without gout. METHODS: This was a multicenter, randomized, double-blind, active-controlled, parallel-group, forced-titration study in hyperuricemic patients. Study treatment in the dotinurad and febuxostat groups was initiated at 0.5 and 10 mg/day, followed by dose titration to 2 and 40 mg/day, respectively, over 14 weeks. The primary endpoint was the percent change in serum uric acid level from the baseline to the final visit. RESULTS: A total of 203 hyperuricemic patients with or without gout were enrolled in the study and randomized to receive dotinurad or febuxostat. The percent change in serum uric acid level from the baseline to the final visit was 41.82% in the dotinurad group and 44.00% in the febuxostat group. The mean difference was - 2.17% (two-sided 95% confidence interval - 5.26% to 0.92%). The lower limit of the interval was above the non-inferiority margin (- 10%), demonstrating the non-inferiority of dotinurad to febuxostat. The profiles of adverse events and adverse drug reactions raised no noteworthy safety concerns in either group. CONCLUSION: The non-inferiority of dotinurad to febuxostat in terms of serum uric acid lowering effect was confirmed. No noteworthy safety concerns arose.

Dotinurad versus benzbromarone in Japanese hyperuricemic patient with or without gout: a randomized, double-blind, parallel-group, phase 3 study.

BACKGROUND: Dotinurad is a novel selective urate reabsorption inhibitor that reduces serum urate levels in hyperuricemic patients with or without gout by selectively inhibiting urate transporter 1. This study was conducted to compare the efficacy and safety of dotinurad with those of benzbromarone. METHODS: In this 14-week, randomized, multicenter, double-blind, parallel-group, dose escalation, benzbromarone-controlled, phase 3 study, hyperuricemic patients with or without gout were randomized to two groups that received either dotinurad 2 mg or benzbromarone 50 mg. Dotinurad or benzbromarone was administered once a day for 14 weeks. The primary endpoint was the percent change in serum uric acid level from the baseline to the final visit. RESULTS: A total of 201 Japanese hyperuricemic patients with or without gout (dotinurad: 102, benzbromarone: 99) received at least one dose of the study drug. The mean percent change in serum uric acid level from the baseline to the final visit in the dotinurad and benzbromarone groups was 45.9% and 43.8%, respectively. Non-inferiority of dotinurad 2 mg to benzbromarone 50 mg in lowering serum uric acid was verified by the predefined non-inferiority margin (95% CI - 1.27 to 5.37%). The incidence of adverse events and adverse drug reactions was comparable between the two groups. CONCLUSION: Dotinurad 2 mg was verified to have a non-inferior serum uric acid lowering effect compared with benzbromarone 50 mg, in Japanese hyperuricemic patients with or without gout. CLINICALTRIALS. GOV IDENTIFIER: NCT03100318.