Selective inhibition of microRNA-132 with CDR132L in patients with heart failure with reduced/mildly reduced ejection fraction and left ventricular hypertrophy: the 8282-Reduced trial
J Bauersachs, R A De Boer, M Cikes, M Gamborg, P S Jhund, C S P Lam, L Lind Plesner, R Schwarz, S Solomon, T Thum, L KoberAbstract
Introduction
Left ventricular (LV) hypertrophy (LVH) is linked to disease progression and poor prognosis in heart failure (HF) with reduced/mildly reduced ejection fraction (HFrEF/HFmrEF). MicroRNA-132 (miR-132) is a small, non-coding RNA that regulates the expression of important cardiac proteins and transcription factors involved in adverse cardiac remodelling. CDR132L, an antisense oligonucleotide that selectively inhibits miR-132, has demonstrated dose-dependent target engagement (reduction of plasma miR-132 levels) and good tolerability in a phase 1B study. We hypothesise that targeting cardiac remodelling with CDR132L may be beneficial for patients with HFrEF/HFmrEF and LVH.
Purpose
To describe the design of a phase 2 randomised controlled trial investigating the efficacy and safety of CDR132L in patients with HFrEF/HFmrEF and LVH, in addition to standard of care (SoC).
Methods
8282-Reduced is a multinational, multicentre, randomised, parallel, double-blind, placebo-controlled trial assessing the efficacy and safety of CDR132L in patients with HFrEF/HFmrEF and LVH (Figure). Patients aged 40–84 years with symptomatic HF diagnosed ≥180 days before screening will be included if they have New York Heart Association class II–III HF, an LV ejection fraction <50% and LVH on echocardiography at screening. Patients will be randomised 1:1 to receive CDR132L or placebo intravenously every 4 weeks for 48 weeks, in addition to SoC. The primary efficacy endpoint is change in plasma miR-132 levels from baseline to week 24 (indicating target engagement). The secondary efficacy endpoint is change from baseline to week 24 in a composite Z-score based on LV end-diastolic volume index, LV end-systolic volume index and N-terminal pro-B-type natriuretic peptide (indicating reverse modelling). The secondary safety endpoints are the number of adverse events from baseline to week 24 and week 60. Exploratory endpoints include the effect of CDR132L compared with placebo on change from baseline to week 24 and week 48 in individual Z-score components, structural and functional markers of HF, and physical function and symptoms.
Results
The 8282-Reduced trial will recruit 200 patients in total for randomisation. As of 29 December 2025, 37 patients have been randomised. Recruitment is ongoing across 72 locations in Asia, Europe and Oceania.
Conclusion
This is the first phase 2 randomised controlled trial to study the inhibition of miR-132, a key regulator of cardiac remodelling, in HFrEF/HFmrEF. Results will determine the efficacy and safety of CDR132L in reducing miR-132 levels and reversing cardiac remodelling in patients with HFrEF/HFmrEF and LVH.8282-Reduced trial designFor image description, please refer to the figure legend and surrounding text.