Effects of CDR132L on cardiac structure and function in heart failure with preserved ejection fraction and left ventricular hypertrophy: the 8212-Preserved trial
R A De Boer, J Bauersachs, M Cikes, M Gamborg, P S Jhund, L Kober, C S P Lam, R Schwarz, T Thum, D Vesterlev, S SolomonAbstract
Introduction
Heart failure (HF) with preserved ejection fraction (HFpEF) accounts for approximately 50% of HF cases, but treatment options are still limited. Left ventricular (LV) hypertrophy (LVH) is a precursor of HFpEF. It contributes to diastolic dysfunction, making LVH a potential treatment target for HFpEF. Cardiac microRNA-132 (miR-132) is thought to play a role in driving adverse cardiac remodelling and hypertrophy. CDR132L, a specific antisense oligonucleotide, is a first-in-class miR-132 inhibitor that has been shown to attenuate HF in preclinical models, with antihypertrophic and antifibrotic effects.
Purpose
To evaluate in a phase 2 randomised controlled trial the effects of three doses of CDR132L compared with placebo in 200 patients with HFpEF and LVH, in addition to standard of care (SoC).
Methods
In 8212-Preserved patients aged 40–84 years with symptomatic HF diagnosed ≥90 days before screening will be included if they have clinically stable symptomatic HFpEF (New York Heart Association class II–III), with a need for oral diuretic treatment, and on guideline-directed SoC HF medication (Figure). At screening, LV ejection fraction (LVEF) must be ≥50%, with proof of LVH on echocardiography (increased LV mass index [LVMi] or increased wall thickness) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels must be ≥300 pg/mL (sinus rhythm) or ≥600 pg/mL (atrial fibrillation/flutter). Major exclusion criteria are an estimated glomerular filtration rate <30 mL/min, severe valvular heart disease, and known genetic causes of increased cardiac mass. Patients will be randomised to receive intravenous infusions of CDR132L in three doses, or placebo infusions, once every 4 weeks for 24 weeks, followed by a 24-week extension phase (Figure).
Results
The primary outcome is the change in plasma miR-132 levels from baseline to 24 weeks to test target engagement of CDR132L. Secondary outcomes include the change in a composite Z-score based on three outcome measures: LVMi and left atrial volume index (LAVi; both measured with cardiac magnetic resonance imaging), and NT-proBNP. Adverse events will also be assessed.
Conclusion
The 8212-Preserved trial will investigate whether CDR132L, targeting miR-132, can reverse cardiac remodelling in patients with HFpEF and LVH. Given the central role that LVH plays in HFpEF, attenuation or reversal of LVH by CDR132L could have the potential to improve care for patients with HFpEF.8212-Preserved trial designFor image description, please refer to the figure legend and surrounding text.