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A Phase III Confirmatory Study of K-877 Extended Release Tablet-A Multicenter, Active Controlled, Randomized, Double Blind, Parallel Group Controlled Trial in Patients with dyslipidemia with high TG-

A Phase III Confirmatory Study of K-877 Extended Release Tablet

356

The mean +- standard deviation of age in the FAS was 54.9 +- 10.2 years, body weight was 76.17 +- 12.67 kg, BMI was 26.73 +- 3.65 kg/m2, the proportion of males was 86.6%, the proportion of subjects receiving postprandial administration was 82.4%, and the proportion of subjects taking concomitant statins was 13.4%. Baseline fasting serum TG was 349.3 +- 139.8 mg/dL, HDL-C (direct method) was 44.5 +- 9.8 mg/dL, LDL-C (direct method) was 136.2 +- 40.5 mg/dL, and non-HDL-C was 191.6 +- 38.9 mg/dL.

Written consent was obtained from 643 subjects, and 356 subjects who were eligible as a result of screening tests were randomized. There were 118, 119, and 119 subjects randomly assigned to the IR 0.2 mg twice daily (IR 0.2 mg/day), ER 0.2 mg once daily (ER 0.2 mg/day), and ER 0.4 mg once daily (ER 0.4 mg/day) groups, respectively. Of these, one patient assigned to the ER 0.2 mg/day did not take a single dose of the study drug, and study participation was terminated for that subject when the subject withdrew consent or requested discontinuation, resulting in 355 subjects receiving the study drug. After administration of the study drug, two subjects assigned to the IR 0.2 mg/day discontinued due to adverse events, and two subjects in the ER 0.2 mg/day and one subject in the ER 0.4 mg/day discontinued due to subject withdrawal of consent or request for discontinuation. There were 350 subjects who completed the treatment phase (116, 116, and 118 subjects in the IR 0.2 mg/day, ER 0.2 mg/day, and ER 0.4 mg/day, respectively).

In this study, 355 subjects received the study drug. The breakdown by treatment group was 118, 118, and 119 subjects in the IR 0.2 mg/day, ER 0.2 mg/day, and ER 0.4 mg/day, respectively. The mean +- standard deviation of the duration of study drug administration was 83.8 +- 9.7, 83.3 +- 5.5, and 83.7 +- 5.6 days in the IR 0.2 mg/day, ER 0.2 mg/day, and ER 0.4 mg/day, respectively. Adverse events occurred in 25.4% (30/118), 17.8% (21/118), and 26.9% (32/119) of subjects in the IR 0.2 mg/day, ER 0.2 mg/day, and ER 0.4 mg/day, respectively. Adverse drug reactions were observed in 5.9% (7/118), 2.5% (3/118), and 5.9% (7/119) of subjects in the IR 0.2 mg/day, ER 0.2 mg/day, and ER 0.4 mg/day, respectively. No statistically significant differences were observed in comparison among the groups using Fisher's exact test. In addition, there was no tendency for certain events to occur more frequently in the ER 0.2 mg/day or ER 0.4 mg/day compared with the IR 0.2 mg/day. Adverse events observed in 2% or more of subjects in any group were injection site pain in 3 subjects (2.5%) /4 cases, fatigue in 3 subjects (2.5%) /3 cases, and fever in 6 subjects (5.1%) /6 cases in the IR 0.2 mg/day, and injection site pain in 4 subjects (3.4%) /4 cases, fatigue in 5 subjects (4.2%) /6 cases, fever in 8 subjects (6.7%) /8 cases, and headache in 3 subjects (2.5%) / 4 cases in the ER 0.4 mg/day. There were no applicable events in the ER 0.2 mg/day. No deaths were observed throughout the study period. Serious adverse events occurred in 3 subjects / 3 cases, including 1 subject / 1 case (COVID-19) and 2 subjects / 2 cases (COVID-19 and COVID-19 pneumonia) in the IR 0.2 mg/day and ER 0.2 mg/day, respectively, with the subjects recovering after treatment. The investigators denied a causal relationship with the study drug. Adverse events leading to discontinuation of study drug administration (excluding deaths and serious cases) occurred in 2 subjects / 2 cases of dizziness and myalgia in the IR 0.2 mg/day, with the subjects recovering or improving after discontinuation of study drug administration. In both cases, a causal relationship with the study drug was not denied, and the subject's study participation was discontinued after the subjects withdrew consent or requested discontinuation. In the case of myalgia, the investigator judged that the subject's study participation could be continued. Although there were some laboratory parameters that showed statistically significant changes from baseline, there were no clinically problematic variations in the ER 0.2 mg/day or ER 0.4 mg/daycompared the IR 0.2 mg/day. In addition, there were no noteworthy variations in the amount of change from baseline values in the physiologic laboratory parameters.

The least square means of the percent changes from baseline in fasting serum TG at 4, 8, and 12 weeks of treatment as the primary endpoint were -48.00%, -43.80%, and -48.00% for the IR 0.2 mg/day, ER 0.2 mg/day, and ER 0.4 mg/day, respectively. The difference of the least square means from the IR 0.2 mg/day(95% confidence interval) was 4.20% (-0.62%, 9.02%) and 0.00% (-4.79%, 4.79%) in the ER 0.2 mg/day and ER 0.4 mg/day, respectively. Based on the above, the upper 95% confidence interval of the ER 0.4 mg/day showed a non-inferiority margin of less than 10%, indicating the non-inferiority of the ER 0.4 mg/day to the IR 0.2 mg/day. The upper 95% confidence interval for the ER 0.2 mg/day showed a margin of less than 10%, indicating the non-inferiority of the ER 0.2 mg/day to the IR 0.2 mg/day. Furthermore, the point estimate for the ER 0.4 mg/day was lower than that for the ER 0.2 mg/day.

The non-inferiority of treatment with ER 0.2 mg/day or 0.4 mg/day (once daily) for 12 weeks to IR 0.2 mg/day (twice daily) was verified for the fasting serum TG percent changes. Based on the comparison of point estimates of TG percent changes, the TG-lowering effect between the two doses of the ER formulation was expected to be greater at ER 0.4 mg/day compared to ER 0.2 mg/day.

April. 13, 2024

https://www.jstage.jst.go.jp/article/jat/advpub/0/advpub_64677/_article/-char/en

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2051200128

Tanigawa Ryohei

Kowa Company, Ltd.

4-14, Nihonbashi-honcho 3-chome, Chuo-ku, Tokyo

ctrdinfo@kowa.co.jp

- Contact for clinical trial information

Kowa Company, Ltd.

4-14, Nihonbashi-honcho 3-chome, Chuo-ku, Tokyo

+81-3-3279-7454

ctrdinfo@kowa.co.jp

Complete

Feb. 04, 2021

Interventional

randomized controlled trial

double blind

active control

parallel assignment

treatment purpose

(1) Patients with dyslipidemia had to be age 20 years or older at written informed consent
(2) Patients who have received dietary or exercise guidance from 12 weeks or more prior to Screening
(3) Patients with the fasting serum TG >= 200 mg/dL twice consecutively at Screening

(1) Patients with a fasting serum TG > 1000 mg/dL at Screening
(2) Patients who require administration of prohibited drugs during the clinical trial period after written informed consent
(3) Patients with uncontrolled thyroid disease
(4) Patients with type 1 diabetes and uncontrolled diabetes [HbA1c(NGSP) >= 8.0 % at Screening]
(5) Patients with uncontrolled hypertension (SBP >= 160 mmHg or DBP >= 100 mmHg)
(6) Patients with an AST or ALT three times the upper limit at Screening
(7) Patients with an CK five times the upper limit at Screening
(8) Patients with cirrhosis or those with biliary obstruction
(9) Patients with acute myocardial infarction within 3 months before obtaining informed consent
(10) Patients with heart failure class III or higher according to NYHA cardiac function classification

Both

Dyslipidemia

IR 0.2 mg/day group: oral doses twice daily
ER 0.2 mg/day group: oral doses once daily
ER 0.4 mg/day group: oral doses once daily

Percent change from baseline in fasting serum TG at 4, 8, and 12 weeks of treatment.

+81-6-6395-9000

Feb. 05, 2021

none