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A Phase III Long Term Study of K-877 Extended Release Tablet-A Multicenter, Randomized, Open Label, Parallel Group Trial in Patients with dyslipidemia with high TG-

A Phase III Long Term Study of K-877 Extended Release Tablet

121

The mean +- standard deviations in age, weight, and BMI for all subjects (FAS) were 58.5 +- 11.1 years, 76.78 +- 15.60 kg, and 27.67 +- 4.34 kg/m2, respectively; the proportion of males was 71.1% (86/121), the proportion of subjects receiving postprandial administration was 90.1% (109/121), and the proportion of subjects taking concomitant statins was 47.1% (57/121). Baseline fasting TG was 264.0 +- 109.2 mg/dL, HDL-C (direct method) was 48.5 +- 10.0 mg/dL, LDL-C (direct method) was 125.2 +- 36.3 mg/dL, and non-HDL-C was 171.4 +- 37.3 mg/dL.

Written consent was obtained from 163 subjects, and 121 subjects who were eligible after screening were randomly assigned. The randomization consisted of 61 and 60 subjects in the morning and evening dose groups, respectively, and all subjects received the study drug. Of the subjects who received the study drug, 7 discontinued the study due to adverse events (2 and 5 in the morning and evening dose groups, respectively). A total of 114 subjects completed the study (59 and 55 in the morning and evening dose groups, respectively).

In this study, 121 subjects were administered the study drug. The breakdown by dosing group was 61 and 60 subjects in the morning and evening dose groups, respectively. The mean +- standard deviation of the duration of study drug administration was 354.7 +- 51.7 days for all subjects, and 362.9 +- 13.5 days and 346.4 +- 71.5 days for the morning and evening dose groups, respectively. Adverse events occurred in 83.5%(101/121)of all subjects, and 86.9%(53/61) and 80.0%(48/60) of subjects in the morning and evening dose groups, respectively. Adverse drug reactions were observed in 19.0%(23/121) of all subjects, and 18.0%(11/61) and 20.0%(12/60) in the morning and evening dose groups, respectively.The adverse events that occurred in 5% or more of all subjects were fatigue [5.8%(7/121)], fever [21.5%(26/121)], vaccination site pain [5.8%(7/121)], nasopharyngitis [5.0%(6/121)], COVID-19 [5.0%(6/121)], arthralgia [9.9%(12/121)], back pain [5.8%(7/121)] and hypertension [5.0%(6/121)]. Among the adverse drug reactions, the event that occurred in more than 2% of all subjects was myalgia [2.5%(3/121)]. The incidence of adverse events and adverse drug reactions (SOC and PT) by time period did not differ significantly between the two time points, and there was no tendency for specific events to occur more frequently in any one time period. Similarly, the incidence of adverse events and adverse reactions by magnitude and severity did not differ significantly at either time point. Severe adverse events occurred in 3.3%(4/121) of all subjects, including 4.9%(3/61) and 1.7%(1/60) in the morning and evening dose groups, respectively. Arrhythmia, bladder cancer, and colon cancer were observed in the morning dose group, and myocardial infarction was observed in the evening dose group. Severe adverse drug reactions occurred in 0.8%(1/121) of all subjects, and arrhythmia was observed in the morning dose group. Moderate adverse events occurred in 18.2%(22/121) of all subjects, including 18.0%(11/61) and 18.3%(11/60) in the morning and evening dose groups, respectively. In the morning dose group, cranial rotatory vertigo, retinal hemorrhage, enteritis, nausea, fatigue, fever, gastroenteritis, COVID-19, gout, back pain, spondylolisthesis, and sciatica were observed; in the evening group, aortic valve stenosis, periodontal disease, toothache, asthenia, abnormal feeling, peripheral swelling, bacterial pharyngitis, COVID-19 (2 cases), spinal compression fracture, contusion , myalgia, positional vertigo, migraine, olfactory confusion, tension headache, taste disorder, depression, depressive symptoms, and sleep apnea were observed. Moderate adverse drug reactions occurred in 0.8%(1/121) in all subjects, and asthenia, abnormal feeling, and myalgia were observed in the evening dose group. All other adverse events and adverse drug reactions were mild. Death (myocardial infarction) was observed in 1 subject/1 case in the evening dose group, but the investigators denied a causal relationship with the investigational drug because it was considered to be due to complications (hypertension, fatty liver, left lower extremity pain) Other serious adverse events (excluding death) occurred in 7 subjects/7 cases, 5 subjects/5 cases (carotid artery stenosis, retinal hemorrhage, colon cancer, arrhythmia, bladder cancer) and 2 subjects/2 cases (COVID-19, contusion) in the morning and evening dose groups, respectively. Subjects with carotid artery stenosis, bladder cancer, retinal hemorrhage, COVID-19, and contusion all continued to receive the investigational drug and completed the study. Although the colon cancer and arrhythmia symptoms became less severe after the treatment, the investigators decided to discontinue the investigational drug in order to prioritize the treatment of the adverse events. Other events (retinal hemorrhage, COVID-19, and contusion) recovered after treatment. The investigators did not deny a causal relationship with the investigational drug, because it was an event that occurred after administration of the investigational drug, although it could have been caused by complications (first-degree atrioventricular block and right bundle branch block). The number of serious adverse events that occurred after 12 weeks (85 days of treatment) was 6 subjects/6 cases (retinal hemorrhage, colon cancer, arrhythmia, bladder cancer, COVID-19, contusion). Adverse events (excluding death and serious adverse events) that led to the discontinuation of study drug administration were observed in 4 subjects/7 cases in the evening dose group. One subject/1 case (myalgia) recovered without treatment after discontinuation of the investigational drug, and the investigators did not deny a causal relationship with the investigational drug, because it occurred after administration, although it was considered to be partly due to exercise. For 1 subject/4 cases (aortic stenosis, asthenia, myalgia, and abnormal sensation), the aortic stenosis had not resolved by the time the administration of the study drug was discontinued, but the investigators judged that further follow-up was unnecessary and terminated study observation without treatment. Three other cases (asthenia, myalgia, and abnormal sensation) recovered without treatment. For aortic valve stenosis, the investigators denied a causal relationship with the investigational drug, because it was thought to be caused by arteriosclerosis due to aging, but did not deny a causal relationship for the other three cases, because they occurred after the dosage of the study drug was increased. For 1 subject/1 case (eczema), the investigator treated the subject after the onset of eczema and judged that the study drug could be continued. However, the subject became aware of the appearance of eczema on the back, and administration of the investigational drug was discontinued. The subject recovered promptly after discontinuation of administration of the investigational drug. The investigators did not deny a causal relationship, because the onset of the disease occurred after the administration of the investigational drug. For 1 subject/1 case (increase in creatine phosphokinase in blood), the investigators judged that the study drug could be continued after the onset of the disease, but ordered the suspension of the administration of the investigational drug due to the onset of the adverse event "leg muscle pain." The "leg muscle pain" adverse event subsequently resolved, but the increase in creatine phosphokinase in the blood had not resolved, and the investigators decided that the administration of the investigational drug should not be continued, and discontinued the administration of the investigational drug. The investigators suspected an association with exercise but did not deny a causal relationship, because it occurred after administration of the study drug. Although there were some statistically significant changes in the change from baseline values in the indicators evaluated by the clinical tests, there were no clinically problematic changes in the indices. The changes from baseline values of the physiological parameters did not show any clinically problematic changes.

The mean (arithmetic mean) percent change from baseline in fasting serum TG at and immediately before the last evaluation, the primary endpoint, was -45.71% for all subjects, and -44.82% and -46.61% for the morning and evening treatment groups, respectively, all showing statistically significant reductions (one-sample t-test; p < 0.001). In addition, analysis of covariance showed that the difference (95% confidence interval) of the least squares means in the morning dose group compared to the evening dose group was 3.03%(-3.55, 9.62), which was not statistically significant (t-test; p = 0.363).

As a result, the efficacy of long-term, once-daily administration of an ER formulation in dyslipidemic patients with high TG levels was demonstrated. Excellent TG-lowering effect was demonstrated regardless of the timing of drug administration (morning or evening), and the dose was increased in cases of inadequate effect. The safety profile of long-term administration was excellent when the starting dose was 0.2 mg/day and the dose was increased to 0.4 mg/day.

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2031200343

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. 10, 2021

Interventional

randomized controlled trial

open(masking not used)

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 >= 150 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) >= 10.0 % 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

ER 0.2 mg/day morning administration group: oral doses once daily in the morning (If the efficacy is insufficient, increase the dose to 0.4 mg/day)
ER 0.4 mg/day evening administration group: oral doses once daily in the evening (If the efficacy is insufficient, increase the dose to 0.4 mg/day)

Mean of % change from baseline in fasting serum TG at the time of final evaluation* and immediately before it
* : Week 52 or at discontinuation

+81-42-648-5551

Feb. 12, 2021

none