Efficacy and Safety of TRC041266 in Patients With Heart Failure, LVEF ≥40%, Diastolic Dysfunction and Type 2 Diabetes Mellitus

This study will be conducted as a randomized, multi-centre, double-blind, parallel-group, placebo-controlled study in patients receiving SoC therapy. Eligible participants will be randomized in a ratio of 1:1 to receive either test product, TRC041266 1500 mg or matching placebo twice daily for 48 weeks

HFpEF is associated with high morbidity and mortality and the prevalence is on the rise globally. Diabetics are at increased risk of developing HFpEF. There is no evidence based therapy to improve the disease condition and its associated functional incapacity. Some of the recently concluded trials, PARAGON-HF, EMPERIAL-PRESERVED, failed to demonstrate benefit and it is regarded as an area with high unmet need. Phase 2 results have demonstrated that in diabetic patients with heart failure having LVEF \>30% and receiving guideline-indicated therapy with RAS inhibitors and β-blockers, TRC4186 has the potential to improve worsening of heart failure, functional status, cardiac diastolic function and has no adverse effect on cardiac mortality. Therefore, TRC041266, the decanoic acid co-crystal of TRC4186 is an innovative product for the management of heart failure with LVEF≥40% in diabetic patients which is expected to modify the underlying disease at multiple levels and confer benefit as add-on to standard of care. The current phase 3 study has been planned based on the results of the phase 2 trial which demonstrated that the TRC4186 2000 mg/day (in two divided doses; BD) administered orally for 48 weeks resulted in significant improvement in QoL measured by PD-MLHFQ, diastolic dysfunction measured by E/e' and reduction in HF hospitalization. The dose level to be used in the present study is based on the assessment of safety, efficacy and PK data obtained from phase 1 and 2 studies. In the phase 2 study, a dose response was observed with a trend towards improvement at 500 mg/day dose of TRC4186, and clinically and statistically significant improvement was seen at 2000 mg/day (1000 mg BD). There was plateauing of the response beyond the dose of 2000 mg/day. Hence, the choice of optimal dose of TRC4186 being considered is lower than 2000 mg/day and in between 500 and 2000 mg/day, i.e., 1500 mg/day (750 mg BD). The total daily dose of TRC041266 which would be equivalent to 1500 mg/day of TRC4186, is TRC041266 3000 mg/day, to be administered in two divided doses,i.e., 1500 mg BD.