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Assessment of efficacy and safety of dotinurad therapy for hyperuricemic patients with kidney dysfunction (DTN-CKD study)

A study of DoTiNurad aiming to treat hyperuricemia with CKD (DTN-CKD study)

104

Gender, age, BMI, and comorbidities of the patients included in the per protocol set (PPS) are shown below for the entire PPS and by group [G1/G2 and G3/G4 groups]. - Gender: male; 87.8% [94.0, 81.3%]: female; [6.0,18.7%] - Mean age: 57.7 years [50.9, 64.9 years] - Mean BMI: 26.96 kg/m2 [28.34, 25.53 kg/m2] - Diabetes mellitus: 48.0% [46.0, 50.0%] - Dyslipidemia: 61.2% [56.0, 66.7%] - Hypertension: 65.3% [54.0, 77.1%] - Cerebral cardiovascular disease: 15.3% [10.0, 20.8%]

Of the 104 patients who gave consent and participated in the study, 100 (50 in the G1/G2 group and 50 in the G3/G4 group), excluding 4 patients who withdrew consent or did not receive the study drug, were included in the safety/full analysis set (FAS) population. Of the patients included in the safety/FAS population, 98 patients (50 in the G1/G2 group and 48 in the G3/G4 group) were included in the PPS population, excluding 2 patients who could not adhere to the dosing protocol.

Incidences of adverse events were as follows: - G1/G2 group: 18.0% - G3/G4 group: 22.0% Incidences (and details) of serious adverse events were as follows: - G1/G2 group: 4.0% (broken hand, humerus fracture, rib fracture, wound) - G3/G4 group: 6.0% (myelodysplastic syndrome, hepatocellular carcinoma, diverticulosis of colon with hemorrhage) Incidences (and details) of adverse drug reactions were as follows: - G1/G2 group: 6.0% (arthralgia, gouty arthritis, wound) - G3/G4 group: 2.0% (gout) No. of patients (and details) of <disease or the like> were as follows in total of 4 cases: - G1/G2 group: 2 cases (arthralgia, gouty arthritis) - G3/G4 group: 1 case (gout) - Other: 1 case (arthralgia. Occurred after consent was obtained, but before the study treatment was initiated, and consent was withdrawn) The adverse event <wound>(occurred in one case), because the patient was hospitalized and treated at another hospital due to injury.

Primary Outcome Percent change in serum uric acid levels at 24 weeks (least-squares mean (LS mean)) in the PPS was 47.3 % in the G1/G2 group and 43.0 % in the G3/G4 group, with an intergroup difference of -4.3 (95% CI: -9.5-0.9, p = 0.0321 for non-inferiority), indicating non-inferiority of the G3/G4 group over G1/G2 group was verified. Secondary Outcomes 1) Change and percent change in serum uric acid levels and proportion of patients reaching the target level at 4, 8, 12, 24 weeks in G1/G2 and G3/G4 groups. - Percent change in serum uric acid level from baseline at 24 weeks (LS mean): G1/G2 group; 47.2 %: G3/G4 group; 42.8 %. - Proportion of patients reaching the target level at 24 weeks: G1/G2 group; 93.9 %: G3/G4 group; 72.3 %. 2) Change and percent change in eGFR at 24 weeks in G1/G2 and G3/G4 groups. - Change in eGFR at 24 weeks (LS mean): G1/G2 group; 1.01 mL/min/1.73m2: G3/G4 group; 3.21 mL/min/1.73m2. - Percent change in eGFR at 24 weeks (LS mean): G1/G2 group; 3.03 %: G3/G4 group; 5.01 %. 3) Change and percent change in serum uric acid levels and proportion of patients reaching the target level at 4, 8, 12, 24 weeks in eGFR-based 5 subgroups. - Percent change in serum uric acid level at 24 weeks (LS mean): G1 group; 48.9 %: G2 group; 46.8 %: G3a group; 45.4 %: G3b group; 45.5 %: G4 group; 35.7 %. - Proportion of patients reaching the target level at 24 weeks. G1 group; 100 %: G2 group; 92.3 %: G3a group; 68.8 %: G3b group; 88.9 %: G4 group; 53.8 %. 4) Change and percent change in eGFR at 24 weeks in eGFR classification-based 5 subgroups. - Change in eGFR at 24 weeks (LS mean): G1 group; 5.75mL/min/1.73m2: G2 group; 0.57 mL/min/1.73m2: G3a group; 0.68 mL/min/1.73m2: G3b group; 3.52 mL/min/1.73m2: G4 group; 3.54 mL/min/1.73m2. - Percent change in eGFR at 24 weeks (LS mean): G1 group; 6.2 %: G2 group; 1.3 %: G3a group; 1.1 %: G3b group; 7.5 %: G4 group; 9.3 %. 5) Change and percent change in serum uric acid levels by dose and proportion of patients reaching the target level. - Percentage change in serum uric acid level at 24 weeks (LS mean): Dotinurad 1 mg group; 41.9 %: 2 mg group; 48.1 %: 4 mg group; 36.9 %: other dose (3 mg); 38.1 %. - Proportion of patients reaching the target level at 24 weeks: Dotinurad 1 mg group; 100 %: 2 mg group; 90.1 %: 4 mg group; 66.7 %: other dose (3 mg); 57.1 %. 6) Change and percent change in serum uric acid levels by presence/absence and by cause of renal dysfunction and proportion of patients reaching the target level. - Percent change in serum uric acid level at 24 weeks (LS mean): no causative disease; 47.3 %: diabetic nephropathy; 37.7 %: nephrosclerosis; 44.5 %: IgA nephropathy; 51.5 %. - Proportion of patients reaching the target level at 24 weeks: No causative disease; 93.9 %: diabetic nephropathy; 50.0 %: nephrosclerosis; 83.3 %: IgA nephropathy 100 %. 7) Change and percent change in serum uric acid levels by age and proportion of patients reaching the target level. - Percent change in serum uric acid level at 24 weeks (LS mean): Aged 39 years or younger; 47.5 %: 40-59 years; 43.8 %: 60-79 years; 45.5 %: 80 years or older; 42.5 %. - Proportion of patients reaching the target level at 24 weeks: Aged 39 years or younger; 92.3 %: 40-59 years; 81.6 %: 60-79 years; 82.1 %: 80 years or older; 83.3 %. 8) Dynamics of uric acid clearance/creatinine clearance ratio (CUA/CCr) - CUA/CCr at baseline (mean plus/minus standard deviation (SD)): G1/G2 group; 5.06 plus/minus 2.09 %: G3/G4 group; 7.25 plus/minus 2.94 %. -Change from baseline at 24 weeks (mean plus/minus SD): G1/G2 group; 6.16 plus/minus 5.58 %: G3/G4 group; 7.71 plus/minus 5.92 %. 9) Dynamics of urine protein/creatinine ratio and urine albumin/creatinine ratio (ACR). - Urine protein/creatinine ratio at baseline (mean plus/minus SD): G1/G2 group; 0.144 plus/minus 0.303 g/gCr: G3/G4 group; 0.964 plus/minus 1.402 g/gCr. - Change from baseline in urine protein/creatinine ratio at 24 weeks (mean plus/minus SD): G1/G2 group; 0.011 plus/minus 0.128 g/gCr: G3/G4 group; -0.117 plus/minus 0.978 g/gCr. - ACR at baseline (mean plus/minus SD): G1/G2 group; 79.8 plus/minus 233.4 mg/gCr: G3/G4 group; 666.1 plus/minus 947.4 mg/gCr. - Change from baseline in ACR at 24 weeks (mean plus/minus SD): G1/G2 group; 10.2 plus/minus 89.3 mg/gCr: G3/G4 group; -75.6 plus/minus 657.9 mg/gCr.

Non-inferiority of changes in serum uric acid level was verified in G3/G4 group compared to G1/G2 group. The change in serum uric acid levels was approximately the same in the G1, G2, G3a, and G3b groups, but was slightly smaller in the G4 group. Adverse drug reactions observed were known events except for a 'wound', and no new safety concerns were raised. The results suggest that dotinurad may be an option for the management of uric acid levels in patients with decreased renal function up to G3/G4.

Oct. 31, 2024

No

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https://jrct.mhlw.go.jp/latest-detail/jRCTs061210079

Wada Jun

Okayama University Hospital

2-5-1 Shikata-cho, Kita-ku, Okayama

junwada@okayama-u.ac.jp

Tanabe Katsuyuki

Okayama University Hospital

2-5-1 Shikata-cho, Kita-ku, Okayama

+81-86-235-7234

tanabek@okayama-u.ac.jp

Complete

Feb. 22, 2022

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

1) Patients with hyperuricemia aged 20 years or older at the time of providing informed consent
2) Patients who have not received treatment with uricosuric drugs within 2 weeks prior to the observation start date
3) Patients with a serum uric acid level (untreated level) 8.0 mg/dL or higher within 6 weeks prior to the observation start date
4) Patients with an estimated GFR (eGFR) 15 mL/min/1.73m2 or higher within 6 weeks prior to the observation start date

1) Patients with acute gouty arthritis that has not subsided
2) Patients diagnosed with urolithiasis
3) Patients with secondary hyperuricemia (tumor lysis syndrome, etc.)
4) Patients with an AST or ALT of 100 IU/L or higher
5) Patients who are pregnant, likely to be pregnant, or breastfeeding
6) Patients with a history of hypersensitivity to the ingredients contained in dotinurad preparations
7) Patients who are judged as inappropriate for this study by the principal investigator or subinvestigator

Both

Patients with hyperuricemia whose renal function is in the GFR range of G1 to G4

The starting dose of dotinurad is 0.5 mg/day, once daily, and is titrated to a final dose of 2 mg/day up to a maximum of 4 mg/day.

Percent change in serum uric acid levels at 24 weeks in G1/G2 and G3/G4 groups (non-inferiority)

1) Change and percent change in serum uric acid levels and proportion of patients reaching the target level at 4, 8, 12, 24 weeks in G1/G2 and G3/G4 groups
2) Change and percent change in eGFR at 24 weeks in G1/G2 and G3/G4 groups
3) Change and percent change in serum uric acid levels and proportion of patients reaching the target level at 4, 8, 12, 24 weeks in eGFR classification-based 5 subgroups
4) Change and percent change in eGFR at 24 weeks in eGFR classification-based 5 subgroups
5) Change and percent change in serum uric acid levels by dose and proportion of patients reaching the target level
6) Change and percent change in serum uric acid levels by presence/absence and by cause of renal dysfunction and proportion of patients reaching the target level
7) Change and percent change in serum uric acid levels by age and proportion of patients reaching the target level
8) Dynamics of uric acid clearance/creatinine clearance ratio (CUA/CCr)
9) Dynamics of urine protein/creatinine ratio and urine albumin/creatinine ratio

Safety Outcomes
1) Adverse events
2) Liver function test results (AST, ALT, gamma-GT)
3) Urinary pH
4) Casual blood glucose level, HbA1c

Exploratory Outcomes
1) Investigation on the differences in patient backgrounds (at week 0) between patients who have reached the target level of serum uric acid control and those who have not
2) Investigation on the differences in information during the observation period, such as the dose of dotinurad and the incidence of gout, between patients who have reached the target level of serum uric acid control and those who have not

+81-86-235-7133

Jan. 25, 2022

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