LEVEL: Levosimendan Fails to Improve Exercise Limitations, Betters NT-proBNP and RVSP

Despite failing to reach statistical significance in improvements to 6-Minute Walk Distance (6MWD), oral levosimendan successfully improved multiple exploratory endpoints among patients with pulmonary hypertension (PH) heart failure (HF) in the LEVEL trial.¹

Presented at the European Society of Cardiology (ESC) Congress 2026 in Munich, Germany, by Sanjiv Shah, MD, director of the Heart Failure with Preserved Ejection Fraction (HFpEF) Program at Northwestern University Feinberg School of Medicine and principal investigator of the trial, these data reflect levosimendan’s safety and potential therapeutic capacity beyond 6MWD.¹

“The independent analysis of LEVEL data we presented today sharpens what the earlier topline results initially indicated: patients with the lowest baseline walking distance had the greatest improvement, on top of state-of-the-art background therapy,” Shah said in a statement. “What was particularly striking was that even patients who did not show a significant improvement in exercise capacity had the same magnitude of reduction in cardiac wall stress and pulmonary artery pressures, changes that correspond to a reduction in heart failure hospitalizations over longer follow-up.”²

LEVEL was a double-blind, randomized, placebo-controlled phase 3 trial evaluating levosimendan’s efficacy in patients with pulmonary hypertension HFpEF (PH-HFpEF). Patients were eligible for inclusion if they were 18-85 years with New York Heart Association (NYHA) Class II or III HF, as well as qualifying 6MWD and a 48-hour ambulatory cardiac rhythm monitor during the screening period. Patients with a diagnosis of PH World Health Organization groups 1, 3, 4, or 5, and patients who had undergone structural heart repair or replacement of the aortic or mitral valve, among others, were excluded.³

The trial began with a 30-day screening period, after which eligible patients continued into the 12-week treatment phase. Eligible patients were randomly assigned in a 1:1 ratio to receive either oral levosimendan or placebo. Those who completed the trial were also given the option to enter a 92-week open-label extension following the completion of all study events.³

A total of 241 patients were enrolled in the trial across 41 sites in the US and Canada. The primary endpoint of change in 6MWD did not achieve statistical significance by week 12, nor did the key secondary endpoint of change in Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS). Despite this, Shah and colleagues noted improvements in exploratory endpoints, including NT-proBNP and right ventricular systolic pressure (RVSP).²

Investigators also noted the older age of the study population, as well as most patients presenting with multiple comorbidities. Among these patients, with emphasis on atrial fibrillation and exercise tolerance, levosimendan’s benefit may increase. Additionally, the team described an inverse linear relationship between 6MWD and treatment effect, demonstrating it not to be explained by regression to the mean.²

Shah discussed these exploratory results in a prespecified group of patients with a baseline 6MWD below the trial median of 333 meters at week 12. These included a least-squares mean change of +23.7 meters on levosimendan treatment versus -2.6 meters on placebo, a change of +9.8 points in the KCCQ-TSS with levosimendan compared to +4.1 in placebo, a change of -4.4 mmHg on levosimendan and of +0.5 mmHg on placebo in RVSP, and a geometric least-squares ratio of 0.53 from baseline on levosimendan compared to a 47% reduction with placebo in NT-proBNP.²

“The magnitude of the reduction in NT-proBNP and the accompanying lowering of pulmonary pressure indicate that TNX-103 may provide clinical benefit to the majority of patients with PF-HFpEF independent of its effect on walk distance,” Shah said in a statement. “The data are compelling and consistently point toward a potential therapeutic benefit in PH-HFpEF patients.”²

References

1. Shah S. Levosimendan in patients with pulmonary hypertension due to heart failure with preserved ejection fraction: results of the LEVEL trial.

2. Tenax Therapeutics Announces Presentation of Phase 3 LEVEL Results in Late-Breaking Scientific Sessions at ESC Congress 2026. BioSpace. August 30, 2026. Accessed August 31, 2026. https://www.biospace.com/press-releases/tenax-therapeutics-announces-presentation-of-phase-3-level-results-in-late-breaking-scientific-sessions-at-esc-congress-2026

3. Tenax Therapeutics, Inc. LEVosimendan to Improve Exercise Limitation in Patients With PH-HFpEF (LEVEL). ClinicalTrials.gov Identifier: NCT05983250. Updated July 24, 2026. Accessed August 31, 2026. https://clinicaltrials.gov/study/NCT05983250