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A randomised, double-blind, placebo-controlled, parallel group, 52 weeks phase IV trial to evaluate efficacy and safety of oral, once daily empagliflozin in elderly Japanese patients with type 2 diabetes mellitus and insufficient glycaemic control

A study to test how well empagliflozin works in Japanese people with type 2 diabetes who are older than 65 years

129

The demographic data were well balanced between the 2 treatment groups. All patients were Asian (Japanese). The patient population consisted of more male (92 patients, 72.4%) than female patients (35 patients, 27.6%), with 19 female patients (30.2%) in the placebo treatment group and 16 female patients (25.0%) in the empagliflozin group. The total mean age was 74.1 years (SD 5.0), where 59 patients (46.5%) were >=75 year at screening. A total of 86 patients (67.7%) had a history of hypertension (placebo: 48 patients, 76.2%; empagliflozin: 38 patients, 59.4%) and most patients were characterised with normal renal function (37 patients, 29.1%) to mild renal impairment (83 patients, 65.4%). Mean time since diagnosis with T2DM was 12.1 years (SD 7.9) and 100 patients (78.7%) reported a history of >=1 relevant medical condition. In general, baseline HbA1c was comparable between treatment groups with 7.6% mean HbA1c (SD 0.5) reported for both treatment groups. At baseline, 98 patients (77.2%) were taking antidiabetic medication, 9 patients (14.3%) in the placebo group and no patients in the empagliflozin group took a newly introduced drug used in diabetes during the on-treatment period. One patient from each treatment group was reported with an important protocol deviation (iPD). One patient (1.6%) from the placebo group was reported with 2 iPDs of prohibited medication use, and 1 patient (1.5%) in the empagliflozin group was reported with an iPD of non-compliance with study drug intake. The mean exposure to trial medication was similar between the treatment groups. Most patients (98.4%) were compliant with treatment within the accepted compliance window of 80% to 120% tablet count.

In this trial, 174 patients were screened by 18 centres in Japan. A total of 129 patients were entered into the trial and randomised in a 1:1 ratio into 2 treatment groups (placebo: 64 patients; empagliflozin: 65 patients). Patients were stratified according to baseline HbA1c values and age. The number and characteristics of randomised patients per stratum was well balanced between the 2 treatment groups. All 129 patients were treated with >=1 dose of randomised trial medication. Overall, the proportion of patients that discontinued trial medication prematurely was low and similar between the groups (placebo: 6 patients, 9.4%; empagliflozin: 4 patients, 6.2%). The reasons for premature discontinuation of trial medication displayed a similar frequency in each treatment group; AE was the most common reason, reported for 6 patients overall (4.7%); all other discontinuations were due to withdrawal by patient (4 patients, 3.1%). Overall, 119 patients (92.2%) completed the 52-week treatment period.

Most patients in the trial reported at least 1 AE, with no marked differences between the treatment groups. The proportion of patients reported with severe AEs was lower in the empagliflozin group than in the placebo group. Drug-related adverse events as assessed by the investigator were more frequent in the empagliflozin treatment group. Adverse events leading to treatment discontinuation showed no meaningful differences within or between treatment groups. The frequency of patients with SAEs was balanced between the treatment groups, a majority of which required hospitalisation. One patient in the placebo group had a fatal AE that was not considered related to the trial medication. The most common AE at the preferred-term (PT) level was constipation; reported in 3 patients (4.7%) in the placebo group and 7 patients (10.8%) in the empagliflozin group. No other AEs were reported with a frequency >10% in either treatment group. The frequency of AESIs was very low. In total, 2 patients (3.1%) in the empagliflozin group were reported with an AESI and neither event lead to treatment discontinuation. There were no AESIs in the placebo group. The 2 events meeting AESI criteria for hepatic injury in the empagliflozin group were both adjudicated with an unlikely relationship to the trial medication. Elevated levels of ALT and/or AST >=3x upper limit of normal (ULN) were not detected in any other patients. One patient from each treatment group presented with asymptomatic ketone bodies which did not require adjudication. There were no patients reported in either treatment group with decreased renal function. There were no events leading to lower limb amputation, confirmed hypoglycaemic events, or reports of PTs associated with muscle weakness.

The primary endpoint was the change from baseline in HbA1c at Week 52, for which a clinically relevant and significant decrease was observed in the empagliflozin group. Sensitivity and subgroup analyses produced results consistent with the confirmatory analysis. Analysis of change in HbA1c over time showed a statistically significant reduction in adjusted mean HbA1c levels in the empagliflozin group compared with placebo after 4 weeks (-0.30%; 95% CIs: -0.40, -0.20; p<0.0001) with the effect approaching maximum reduction after 12 weeks (-0.52%; 95% CIs: -0.69, -0.35; p<0.0001) which was maintained to Week 52. Other measurements associated with the primary endpoint Consistent with the reduction in HbA1c, fasting plasma glucose (FPG) levels in the empagliflozin group showed a substantial reduction from baseline at Week 52 (-21.56 mg/dL [SE 2.53]) whereas FPG levels in the placebo group remained relatively unchanged (-2.17 mg/dL [SE 2.74]).

Analysis of body composition revealed a significant decrease in body weight in the empagliflozin group compared with the placebo group at Week 52 (-2.37 kg, 95% CI: -3.07, -1.68, p<0.0001). The largest decrease in weight was between baseline and Week 24 with further small decreases up to Week 52. The reduction in body weight was driven by decreases in body fat mass and total body water; body fat mass was reduced significantly in the empagliflozin group compared with the placebo group at Week 52 (-1.84 kg; 95% CIs: -2.65, -1.04; p<0.0001) and total body water was reduced -0.63 kg (95% CIs: -1.23, -0.03; p = 0.0384). There were no meaningful changes in muscle mass (-0.61 kg; 95% CIs: -1.61, 0.39; p = 0.2310) or lean body mass (-0.53 kg; 95% CIs: -1.28, 0.22; p = 0.1632) from baseline between treatment groups. No adverse events related to volume depletion were observed. Minimal numerical decreases in bone mineral content (-0.03 kg; 95% CIs: -0.07, 0.01; p = 0.1975) and skeletal muscle index (-0.081 kg/m2; 95% CIs: -0.259, 0.098; p = 0.3725) were observed in the empagliflozin group compared with placebo. Changes in grip strength (-0.3 kg; 95% CIs: -1.1, 0.5; p = 0.4208) and time in the 5-time chair stand test (0.0 s; 95% CIs: -1.0, 0.9; p = 0.9267) from baseline were highly comparable between treatment groups. None of these changes were considered clinically meaningful.

In elderly Japanese patients with T2DM and insufficient glycaemic control, treatment with empagliflozin (10 mg) as an add-on therapy to OADs and in treatment naive patients demonstrated a statistically significant and clinically meaningful improvement in the change from baseline in HbA1c after 52 weeks of treatment compared with placebo. Empagliflozin as an add-on therapy to OADs and in treatment naive patients was well tolerated and no new safety findings were observed.

Feb. 20, 2024

Yes

Researchers can refer to https://trials.boehringer-ingelheim.com/ to request access to raw data from our clinical studies.

Nippon Boehringer Ingelheim Co., Ltd

2-1-1 Osaki, Shinagawa-ku, Tokyo

medchiken.jp@boehringer-ingelheim.com

Nippon Boehringer Ingelheim Co., Ltd

2-1-1 Osaki, Shinagawa-ku, Tokyo

+81-120-189-779

medchiken.jp@boehringer-ingelheim.com

completed

Oct. 13, 2020

Interventional

Randomised, double-blind, multi-center, placebo-controlled, parallel group trial

treatment purpose

4

1.Japanese patients with diagnosis of type 2 diabetes mellitus prior to informed consent
2. Age over 65 years at informed consent
3. B+G20MI over 22 kg/m2
etc.

1. Treatment with insulin within 12 weeks prior to informed consent
2. Uncontrolled hyperglycaemia with a fasting glucose level >200 mg/dL (>11.1 mmol/L) during run-in period
etc.

Both

type 2 diabetes mellitus

investigational material(s)
Generic name etc : empagliflozin
INN of investigational material : empagliflozin
Therapeutic category code : 396 Antidiabetic agents
Dosage and Administration for Investigational material : daily oral

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

efficacy
Change from baseline in glycosylated haemoglobin A1c (HbA1c) after 52 weeks of treatment

safety
Change of body composition from baseline to Week 52
Change of grip strength from baseline to Week 52
Change of time in the 5-time chair stand test from baseline to Week 52

+81-3-5213-0028

Aug. 24, 2020