Regulatory Decision Summary for Jardiance

This Supplement to a New Drug Submission was filed to expand the conditions of use of Jardiance (empagliflozin) by enabling its initiation in-hospital after a heart failure decompensation, expand the target population by allowing initiation immediately after a diagnosis of heart failure, and to add safety and efficacy information related to these new uses in the Product Monograph.

The efficacy and safety of Jardiance in participants hospitalised for acute heart failure (decompensated chronic heart failure or newly diagnosed heart failure, irrespective of ejection fraction) was evaluated in one randomized, double-blind, placebo-controlled, parallel-group, international multicenter phase III study: EMPULSE. In this trial, 530 participants were randomized to Jardiance (number of participants [n] = 265) or matching placebo (n = 265) while still in hospital, but after their decompensation had been stabilised. The primary efficacy endpoint was composed of death, incidence of heart failure events, time to the first heart failure event, and heart failure-specific quality of life improvement, assessed through a stratified hierarchical win ratio.

Patients were required to be adults hospitalized for acute heart failure predominantly caused by volume overload and be clinically stable at the time of randomization. Patients were excluded if they experienced recent major cardiovascular event or surgery or received any inhibitor of the sodium-glucose co-transporter 2. Baseline characteristics were balanced between groups and similar to the profiles of previous participants for heart failure empagliflozin trials (EMPEROR-Reduced and EMPEROR-Preserved). The study included 34% women, 78% whites; 32% of participants were younger than 65 years; 32% had heart failure with preserved ejection fraction; and 33% were included after a new diagnosis of heart failure.

Trial treatment was initiated in-hospital in addition to standard of care for heart failure. Physicians were encouraged to optimize standard of care as per local guidelines before randomization and continuously throughout the trial. Treatment was a fixed dose of 10 milligram (mg) of empagliflozin or placebo once daily for 90 days. The trial ended with a follow-up visit 7 days after treatment discontinuation.

Jardiance demonstrated superiority to placebo on the primary efficacy composite outcome consisting of death, incidence of heart failure events, time to the first subsequent heart failure event, and clinically significant variation in heart failure-specific quality of life. The primary efficacy analysis was a stratified hierarchical win ratio, which indicated that participants taking Jardiance were 36% more likely to experience a clinical benefit compared to placebo (win ratio: 1.36, 95% confidence interval [CI], 1.09, 1.68; p-value [p] = 0.003). When looking at each component of the composite outcome, incidence of mortality or heart failure events was lower in the Jardiance group and the quality-of-life component was superior compared to placebo. The component of time to the first heart failure event was not favorable but was negligible (<1% of total decisions). Superiority of Jardiance against placebo was consistent across subgroups, including in the new target population of patients with newly diagnosed heart failure. The treatment effect was also generally consistent across secondary efficacy endpoints in favour of Jardiance.

The safety profile was similar to that observed in the placebo group and to the profiles observed in previous empagliflozin trials, overall and across subgroups of interest. No new safety event was observed, including in the new target population of patients with newly diagnosed heart failure. Due to the substantial overlap between the characteristics of participants in EMPULSE and those in previous trials for heart failure (e.g., EMPEROR-Preserved, EMPEROR-Reduced), the known safety profile from previous trials was expected to apply to the new target population. The Product Monograph was updated with relevant information to enable the safe and effective use of Jardiance under the new conditions tested in this trial. No update to the risk management plan was required.

Overall, the benefit-harm-uncertainty profile is favourable for Jardiance for the recommended indication. A Notice of Compliance (NOC) was issued.

Following review and requested revisions, the final labelling and Product Monograph were considered to be acceptable.

For further details about Jardiance, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.