Rationale and design of the EMPA-ELDERLY trial: a randomised, double-blind, placebo-controlled, 52-week clinical trial of the efficacy and safety of the sodium-glucose cotransporter-2 inhibitor empagliflozin in elderly Japanese patients with type 2 diabetes.

INTRODUCTION: Elderly people (≥65 years) with type 2 diabetes mellitus (T2DM) are becoming increasingly prevalent, notably in Japan. As cardiovascular (CV) risk increases with age and sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce CV risk, elderly patients with T2DM are increasingly likely to be prescribed these glucose-lowering drugs. There is controversy surrounding the effects of SGLT2 inhibitors on muscle mass, particularly in elderly patients for whom loss of muscle is especially undesirable; however, robust evidence on this important issue is lacking. Consequently, we have designed a clinical trial of the SGLT2 inhibitor empagliflozin in elderly Japanese patients with T2DM (Empagliflozin in Elderly T2DM Patients (EMPA-ELDERLY)) to assess its effects on body composition as well as glycaemic control. EMPA-ELDERLY will be the first randomised clinical trial of an SGLT2 inhibitor in elderly patients with T2DM to evaluate effects on skeletal muscle mass, muscle strength and physical performance concurrently. METHODS AND ANALYSIS: EMPA-ELDERLY is a randomised, double-blind, placebo-controlled, parallel-group clinical trial to be conducted in Japan. Patients with T2DM aged ≥65 years are eligible if they are Japanese with a body mass index of ≥22 kg/m2 and glycated haemoglobin (HbA1c) levels from ≥7.0% to ≤10.0% from either diet and exercise alone or treatment with oral glucose-lowering drugs. Approximately 128 participants will be randomised 1:1 to once per day, oral, double-blind treatment with empagliflozin 10 mg or matching placebo for 52 weeks. The primary endpoint is the change in HbA1c level from baseline at week 52. Secondary endpoints include changes from baseline to 52 weeks in body composition, including muscle mass and body fat, measured by bioelectrical impedance analysis, as well as skeletal muscle index, grip strength and time in the five-time chair stand test. Other endpoints include changes in patient-reported outcomes (including quality of life), cognitive function and safety. ETHICS AND DISSEMINATION: We will submit the trial results to conferences and peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04531462.

Efficacy and safety of risankizumab in Japanese patients with moderate to severe plaque psoriasis: Results from the SustaIMM phase 2/3 trial.

Risankizumab, a humanized immunoglobulin G1 monoclonal antibody, selectively inhibits interleukin-23, a key cytokine in the pathogenesis of psoriasis, by binding to its p19 subunit. In SustaIMM (ClinicalTrials.gov/NCT03000075), a phase 2/3, double-blinded, placebo-controlled study, Japanese patients with moderate to severe plaque psoriasis (n = 171) were stratified by bodyweight and concomitant psoriatic arthritis and randomized 2:2:1:1 to 75 mg risankizumab, 150 mg risankizumab, placebo with cross-over to 75 mg risankizumab and placebo with cross-over to 150 mg risankizumab. Dosing was at weeks 0, 4, 16, 28 and 40, with placebo cross-over to risankizumab at week 16. The primary end-point was 90% or more improvement from baseline in Psoriasis Area and Severity Index (PASI-90) at week 16 for risankizumab versus placebo. Missing data were imputed as non-response. All primary and psoriasis-related secondary end-points were met for both risankizumab doses (P < 0.001). At week 16, PASI-90 responses were significantly higher in patients receiving 75 mg (76%) or 150 mg (75%) risankizumab versus placebo (2%). Corresponding response rates were 86%, 93% and 10% for static Physician Global Assessment (sPGA) score of clear/almost clear; 90%, 95% and 9% for PASI-75; and 22%, 33% and 0% for PASI-100, with significantly higher responses for both risankizumab doses versus placebo. Through week 52, PASI and sPGA responses increased or were maintained and treatment-emergent adverse events were comparable across treatment groups. Both doses of risankizumab were superior to placebo in treating patients with moderate to severe plaque psoriasis. The safety profile was consistent with previous risankizumab trials, with no new or unexpected safety findings.

Empagliflozin as add-on to linagliptin in a fixed-dose combination in Japanese patients with type 2 diabetes: Glycaemic efficacy and safety profile in a 52-week, randomized, placebo-controlled trial.

AIMS: This double-blind, randomized, placebo-controlled trial (ClinicalTrials.gov NCT02453555) evaluated the efficacy and safety of empagliflozin (Empa) 10 or 25 mg as add-on to linagliptin (Lina) 5 mg (fixed-dose combination, Empa/Lina 10/5 or 25/5) in insufficiently controlled Japanese type 2 diabetes patients. METHODS: The trial (40 sites; May 2015-March 2017) involved screening 433 adults (≥20 years) who were treatment-naive or were using one oral antidiabetic drug for ≥12 weeks, which was discontinued at enrolment. Patients with HbA1c 7.5%-10.0% after ≥16 weeks of using Lina (pre-enrolment or during a 16-week, open-label period) and 2 weeks of using placebo (Plc) for Empa/Lina 10/5, plus Lina, were randomized (2:1) to once-daily Empa/Lina 10/5 (n = 182) or Plc/Lina 10/5 (n = 93) for 24 weeks. Patients with HbA1c ≥ 7.0% at Week 24 received Empa/Lina up-titrated to 25/5 (n = 126) or the corresponding placebo (n = 80), per randomization, from Week 28; 172 Empa/Lina and 84 Plc/Lina patients completed 52 weeks. RESULTS: Change from baseline in HbA1c was greater (P < .0001) with Empa/Lina than with Plc/Lina at Week 24 (primary outcome, -0.93% vs 0.21%; adjusted mean difference, -1.14%) and Week 52 (-1.16% vs 0.06%; adjusted mean difference, -1.22%). More patients with HbA1c < 7.0% and greater decreases in fasting plasma glucose, body weight and systolic blood pressure were seen in the Empa/Lina group than in the Plc/Lina group. Empa/Lina was well tolerated. The adverse events that were more frequent with Empa/Lina were known empagliflozin-associated events (eg, increased urination, increased blood ketones). There were no adjudication-confirmed diabetic ketoacidosis events or lower limb amputations. CONCLUSIONS: These results support the notion that empagliflozin-linagliptin in fixed-dose combination is a therapeutic option for Japanese patients with type 2 diabetes.

Safety and efficacy of faldaprevir in combination with pegylated interferon α-2b and ribavirin in Japanese patients with genotype-1 chronic hepatitis C virus infection.

AIM: We evaluated the safety and efficacy of the hepatitis C virus (HCV) NS3/4A A protease inhibitor faldaprevir plus pegylated interferon α-2b and ribavirin (PegIFNα-2b/RBV) in Japanese patients with HCV genotype-1 infection. METHODS: Treatment-naïve patients were randomized (1:1) to faldaprevir 120 mg q.d. for 12 or 24 weeks (response-guided therapy [RGT], n = 44), or faldaprevir 240 mg q.d. for 12 weeks (n = 43), each combined with PegIFNα-2b/RBV for 24 or 48 weeks (RGT). Response-guided therapy was based on early treatment success (HCV RNA <25 IU/mL at week 4 and <25 IU/mL undetected at week 8). Treatment-experienced patients received 240 mg q.d. for 24 weeks, plus PegIFNα-2b/RBV RGT (24 or 48 weeks, prior relapsers, n = 29) or PegIFNα-2b/RBV (48 weeks, 5 prior partial responders/breakthroughs, 10 prior null responders). The primary objective was safety; sustained virologic response 12 weeks post-treatment (SVR12) was a secondary end-point. RESULTS: All except one patient experienced drug-related adverse events. Adverse events led to faldaprevir discontinuation in 1 (2%), 13 (20%), and 3 (6.8%) patients on faldaprevir 120 mg, faldaprevir 240 mg 12 weeks, and faldaprevir 240 mg 24 weeks, respectively. The SVR12 rates were: 86% with faldaprevir 120 mg and 74% with faldaprevir 240 mg among treatment-naïve patients; and 86%, 60%, and 40% among prior relapsers, partial responders/breakthroughs, and null responders, respectively. CONCLUSIONS: In treatment-naïve Japanese patients, faldaprevir 120 mg q.d. plus PegIFNα-2b/RBV was better tolerated than faldaprevir 240 mg q.d. plus PegIFNα-2b/RBV, with at least comparable efficacy. In treatment-experienced patients, most prior relapsers achieved SVR12 with 24 weeks of faldaprevir 240 mg q.d. plus PegIFNα-2b/RBV. Clinicaltrials.gov NCT01579474.