Table 2

TEMPEST trial objectives and outcome measures

Overall objective
 To evaluate the clinical efficacy and mechanism of action of trientine in hypertrophic cardiomyopathy
ObjectiveOutcome measure
Primary efficacy objective
 To determine whether trientine compared with placebo leads to regression of LV hypertrophyChange in in LV mass indexed to body surface area
Secondary efficacy objectives
 To test whether trientine compared with placebo:

  • Increases urinary copper excretion.

Cumulative urine copper excretion, measured using urinary copper

  • Improves exercise capacity.

Change in exercise capacity, measured using cardiopulmonary exercise testing

  • Reduces arrhythmia burden.

Change in number of non-sinus supraventricular heart beats, presence and amount of atrial fibrillation, number of ventricular-origin beats and presence and amount of non-sustained ventricular tachycardia, in 24 hours, measured using ambulatory heart monitoring

  • Reduces cardiomyocyte injury.

Change in circulating high sensitivity troponin.

  • Improves LV contractile function.

Change in LV global longitudinal strain and strain rate, wall thickness, mass, volumes and ejection fraction measured using CMR.

  • Improves left atrial structure and function.

Change in atrial volume and function, measured using CMR.
Mechanistic objectives
 To understand how trientine may cause a reduction in LV hypertrophy the study will determine whether:

  • Trientine, compared with placebo, leads to cellular or extracellular mass regression.

Change in LV myocardial cellular mass, myocardial extracellular mass, myocardial extracellular volume, LV late gadolinium enhancement, measured using CMR

  • Trientine, compared with placebo, leads to an improvement in myocardial energetics.

Change in PCr:ATP ratio, measured using 31P MRS (subroup)

  • LV hypertrophy regression is mediated by cellular regression, extracellular regression or improved myocardial energetics, which are in turn determined by copper excretion.

Mediation analysis, using the aforementioned outcome measurements.

  • CMR, cardiovascular magnetic resonance; LV, left ventricular; PCr:ATP, phosphocreatine to ATP; 31P MRS, phosphorus-31 magnetic resonance spectroscopy.