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A Double Blind Study of CS-3150 to Evaluate Efficacy and Safety Compared to Placebo in Japanese Type 2 Diabetic Patients with Microalbuminuria (ESAX-DN study)

A Double Blind Study of CS-3150 to Evaluate Efficacy and Safety Compared to Placebo in Japanese Type 2 Diabetic Patients with Microalbuminuria (ESAX-DN study)

455

449 subjects included in full analysis set (FAS). Demographic and other baseline characteristics were not significantly difference between the CS-3150 and placebo groups. Male were 76.8% (345/449), the mean (SD) age was 65.7 (9.39) years, and the mean (SD) weight was 69.99 (13.377) kg. The mean (SD) UACR was 127.07 (61.164) mg/g creatinine, the geometric mean (95% CI) eGFRcreat was 66.70 (65.07-68.37) mL/min/1.73 m2, and the mean (SD) serum K level was 4.36 (0.300) mEq/L. The results of the safety-analysis set were similar to those of FAS.

455 patients were randomized, all of whom received the study drug, 393 patients completed the study, and 62 patients (43 in CS-3150 group and 19 in the placebo group; in the same order) discontinued treatment during the study. Of the 455 randomized patients, 449 patients (222, 227) were included in FAS. Six patients (4, 2) were excluded from FAS due to a lack of efficacy data.

The population of patients with at least one treatment-emergent adverse event was similar in CS-3150 group and placebo groups (78.3% (177/226) and 77.3% (177/229)). The population of patients with at least one drug-related treatment-emergent adverse event was 19.5% (44/226) in CS-3150 group and 7.0% (16/229) in the placebo group, which was higher in CS-3150 group. The population of patients with at least one serious treatment-emergent adverse event was similar in CS-3150 group and placebo groups (8.0% (18/226) and 10.5% (24/229)). These were also considered to be unrelated to the study drug in either group. The population of patients with at least one severe treatment-emergent adverse event was similar in CS-3150 group and placebo groups (3.5% (8/226) and 2.6% (6/229)). These were also considered to be unrelated to the study drug in either group. The population of patients who discontinued from study treatment due to a treatment-emergent adverse event was 9.3% (21/226) in CS-3150 group and 3.5% (8/229) in the placebo group, which was higher in CS-3150 group.

The proportion of patients achieving remission of microalbuminuria [95% CI] was significantly higher in the CS-3150 versus placebo group (22.1% [16.8%-28.1%] vs. 4.0% [4.0%-7.4%]; P<0.001)

- Percent change in UACR at the end of treatment. The geometric mean (95% CI) percent change in UACR from baseline to the end of treatment was -58.3 (-62.5 to -53.7) % in CS-3150 group and 8.3 (-1.6 to 19.2) % in the placebo group. The geometric least squares mean ratio of the pretreatment ratio (CS-3150 group/placebo group) (95% CI) was 0.384 (0.334-0.443), and UACR reduction rate was significantly higher in CS-3150 group (P < 0.0001). - Percent change in eGFRcreat at the end of treatment. Geometric mean (95% CIs) percent change in eGFRcreat from baseline to the end of study treatment was -10.8 (-12.4 to -9.1) % in CS-3150 group and-1.2 (-3.0 to 0.5) % in the placebo group. The geometric least squares mean ratio of the pretreatment ratio (CS-3150 group/placebo group) (95% CI) was 0.903 (0.881-0.927), and eGFRcreat reduction rate was significantly higher in CS-3150 group (P < 0.0001). - Retention rate of UACR remission (The proportion of patients achieving remission with certain duration) The overall duration category ranged from 1.8% to 4.8% in the placebo group, and CS-3150 group had a higher duration of remission (13.5% to 14.4%) in the >=100-day duration category, indicating that CS-3150 group was accompanied by a long-term duration of remission than the placebo group. - Duration of UACR remission (duration from first on-treatment remission to two or more consecutive time points when UACR was <30 mg/g creatinine and >=30% decrease from baseline). There were significant differences between CS-3150 and placebo-treated groups in the distributions of remissions and durations at FAS (P < 0.0001). Median (95% CIs) duration was 15.1 (4.1-36.1) weeks in the placebo group and median was not reached in CS-3150 group. - Progression rate to overt albuminuria The proportion of patients who transitioned to overt albuminuria at the end of treatment was significantly lower with CS-3150 versus placebo (1.4% [0.3%-3.9%] vs. 7.5% [4.4%-11%], P=0.0016) in FAS. - Time course of UACR and geometric mean percent change from baseline in UACR In CS-3150 group at FAS, UACR decreased slowly until week 24 and remained stable until the end of study treatment. No apparent changes were seen in the placebo group. UACR geometric mean change in CS-3150 group was -34.5% at 4 weeks of follow-up, compared with 16.3% in the placebo group. - Time course of eGFRcreat and mean change from baseline in eGFRcreat The mean eGFRcreat at FAS decreased in CS-3150 group after administration of the investigational drug, but remained stable after 32 weeks of treatment, with no sustained decrease. The change from baseline in eGFRcreat was greater in CS-3150 group than in the placebo group throughout treatment. At the post-treatment follow-up, eGFRcreat in CS-3150 group recovered to a level similar to that of the placebo group, with a change from baseline in eGFRcreat (SD) of -4.51 (8.906) mL/min/1.73 m2 in CS-3150 group and -4.04 (8.181) mL/min/1.73 m2 in the placebo group. - Time course of blood pressure and mean change from baseline in blood pressure Systolic blood pressure (SBP) and diastolic blood pressure (DBP) in CS-3150 group at FAS decreased slowly from week 2, SBP decreased slowly up to week 32, and DBP decreased slowly up to week 16 and remained stable until the end of study treatment. No changes were seen in the placebo group. In CS-3150 group, SBP and DBP tended to return to baseline after the end of treatment, and the values after end of treatment were similar to those in the placebo group. The change (SD) in SBP at the end of treatment was -10.4 (12.00) mmHg in CS-3150 group and -2.1 (13.09) mmHg in the placebo group, which was greater in CS-3150 group. DBP changes (SDs) were -4.6 (7.78) mmHg in CS-3150 group and -1.6 (7.99) mmHg in the placebo group, which were greater in CS 3150 group.

When CS-3150 was administered for 52 weeks to patients with type 2 diabetes and microalbuminuria taking ARB or ACE inhibitors, the superiority of CS-3150 over placebo was demonstrated in achieving and remission rate of UACR and UACR reduction. Also, progression rate to overt albuminuria in CS-3150 group was significantly lower than that in the placebo group. There were no apparent differences in the incidence of SAEs between CS-3150 and placebo groups.

Nov. 25, 2020

https://pubmed.ncbi.nlm.nih.gov/33239409/

Yes

Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/ Supporting Documents: - Study Protocol - Statistical Analysis Plan - Clinical Study Report Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication. Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent. URL: https://vivli.org/ourmember/daiichi-sankyo/

DAIICHI SANKYO Co.,Ltd.

dsclinicaltrial@daiichisankyo.co.jp

DAIICHI SANKYO Co.,Ltd.

dsclinicaltrial@daiichisankyo.co.jp

completed

Sept. 22, 2017

Interventional

Multi-center, randomized, double-blind, placebo control, 2- arm, parallel group, comparison study

treatment purpose

3

1) Patients aged 20 years or older at the time obtaining informed consent
2) Patients diagnosed to have type 2 diabetes mellitus
3) Patients who meet any of the following in the laboratory tests (central measurement) at run in period.
i. Patients with UACR >= 45 mg/g creatinine and < 300 mg/g creatinine in the early morning first urine at least twice.
ii. Patients with eGFRcreat >= 30 mL/min/1.73 m2
4) Hypertensive patients who have been taking an ARB or an ACE inhibitor for at least 12 weeks prior to the study drug administration without changing the dosage and administration.

1) Patients with type 1 diabetes mellitus
2) Patients with secondary glucose tolerance impairment
3) Patients diagnosed to have non-diabetic nephropathy
4) Patients with secondary hypertension
5) Patients who were hospitalized for hyperkalemia within 1 year before informed consent

Both

Type 2 Diabetic Patients with Microalbuminuria

investigational material(s)
Generic name etc : CS-3150
INN of investigational material : Esaxerenone (r-INN)
Therapeutic category code : 214 Antihypertensives
Dosage and Administration for Investigational material : Each subject will orally take study drug once daily

control material(s)
Generic name etc : -
INN of investigational material : -
Therapeutic category code :
Dosage and Administration for Investigational material : -

efficacy
UACR remission rate at the end of the treatment

efficacy
1. Change rate in UACR and eGFRcreat from baseline to the end of the treatment
2. Retention rate and duration of UACR remission
3. Progression rate to overt albuminuria
4. Time course of changes in UACR, eGFR, and blood pressure

Aug. 18, 2017