Trientine in Hypertrophic Cardiomyopathy Phase 2 Trial

Key Takeaways

• Greater reduction in indexed left ventricular mass was observed with trientine than with placebo over 52 weeks.
• The reduction was stronger at higher baseline left ventricular mass and was linked to lower myocardial cellular mass.
• Adverse events were broadly similar overall, with no deaths, while gastrointestinal events plus anaemia and low copper were more common with trientine.

In adults with hypertrophic cardiomyopathy, trientine reduced cardiovascular magnetic resonance-measured indexed left ventricular mass more than placebo after 52 weeks. The between-group difference in the primary endpoint was -3.2 g/m2, with a 95% CI of -5.6 to -0.8 and P = .009. The primary endpoint was change in left ventricular mass indexed to body surface area measured by cardiovascular magnetic resonance.

TEMPEST was a multicenter, double-blind, parallel-group, randomized, placebo-controlled phase 2 trial conducted at six UK sites between 17 February 2021 and 27 April 2023. Eligible participants were 18 to 75 years old, had hypertrophic cardiomyopathy with wall thickness of at least 15 mm, and were in NYHA class I to III. No LVOT gradient threshold was required, and patients were randomized 1:1 to trientine 400 mg twice daily or placebo for 52 weeks. The trial randomized 154 patients, and 136 were included in the final efficacy analysis. Baseline features included a mean age of 53.4 years, 61.7% in NYHA class I, median wall thickness of 20.0 mm, and generally low resting outflow gradients, indicating a largely paucisymptomatic cohort.

At week 52, mean indexed left ventricular mass changed by -4.4 ± 7.7 g/m2 with trientine and -1.5 ± 6.1 g/m2 with placebo. The reduction was larger at higher starting left ventricular mass, with significance emerging in higher LVMi quartiles and an interaction P = .015. Mediation analysis linked the primary-endpoint effect to reduced myocardial cellular mass, with an average causal mediated effect of -3.9 g/m2 and a 95% CI of -6.8 to -0.9. Compared with placebo, trientine also reduced maximum wall thickness by -0.6 mm and indexed myocardial cellular mass by -3.7 g/m2. No between-group differences appeared in atrial volumes and function, exercise capacity, high-sensitivity troponin, or phosphocreatine-to-adenosine triphosphate ratio.

Overall adverse-event incidence was similar at 71.8% with trientine and 67.1% with placebo, and no deaths occurred. Serious adverse events were reported in 5.1% and 9.6%, and none were attributed to either study treatment. Gastrointestinal events were more common with trientine, while anaemia and decreased copper were also more frequent, without differences in serum caeruloplasmin or iron. Cardiovascular adverse events were infrequent, urine copper-creatinine ratio increased by week 13 and persisted, and 11 withdrawals occurred, including 8 with trientine and 3 with placebo. One trientine withdrawal followed possible medication-related nausea and dizziness. The authors described the findings as initial evidence and pointed to further study in more advanced disease and patient-centered outcomes.