A double-blind randomised, multicentre clinical trial to evaluate the efficacy and safety of two doses of etomoxir in comparison with placebo in patients with moderate congestive heart failure: The ERGO (etomoxir for the recovery of glucose oxidation) study

Christian J.F. Holubarsch (1) , Martin Rohrbach , Matthias Karrasch , Erich Boehm , Lech Polonski , Piotr Ponikowski , Siegfried Rhein

1 Hospital Lazariterhof and Baden

Etomoxir is an inhibitor of mitochondrial carnitine-palmitoyl-transferase 1 (CPT1) and thereby switches the energy metabolism from fatty acids to glucose oxidation. For two reasons such a metabolic change may be beneficial in heart failure: (1) Energy production (generation of ATP molecules per oxygen consumption) is more economical in case of glucose oxidation. (2) Glucose oxidation is associated with altered gene expression of important myocardial proteins that are related to function (sarcoplasmic reticulum calcium ATPase and myosin isoenzymes). Etomoxir was planned to be tested in a dose of 80 and 40 mg versus placebo for a period of six months in patients with heart failure. As principle measures of efficacy a maximal exercise tolerance test using an exercise bicycle and a sub-maximal six minute corridor walk test were used. Secondary endpoints were echocardiographical dimensions and scores of quality of life assessments. 350 patients were planned to be screened with the expectation that endpoint data will be available for approximately 260 patients. This study had to be stopped prematurely, because unacceptably high values for liver transaminases were detected in four patients taking 40 mg or 80 mg etomoxir. At the time of the end of the study, 121 patients were randomised to placebo, 118 to 40 mg etomoxir and 108 to 80 mg etomoxir. 21 patients in the placebo group, 17 and 14 patients in the 40 mg etomoxir and the 80 mg etomoxir group respectively, had completed the study at that time. The mean increases in exercise time were 3.3 sec, 10.2 sec, and 19.4 sec for the placebo, the 40 mg Etomoxir and 80 mg Etomoxir groups , respectively (N.S.) Neither changes were obvious in the six-minute corridor walk test from baseline nor in echocardiographical parameters. Due to hepato-toxicity of etomoxir the study had to be stopped for safety reasons. The number of patients that completed the study was too small to demonstrate significant increases in exercise time. However, there was a tendency for increased exercise time. Therefore, before rejecting the hypothesis that fatty-acid-oxidationinhibition might be beneficial in congestive heart failure, similar studies have to be performed using different fatty-acid-oxidation-inhibitors targeting CPT1 and other enzymes of this metabolic pathway.

Mots clés: Medicine

Christian J.F. Holubarsch, Martin Rohrbach, Matthias Karrasch, Erich Boehm, Lech Polonski, et al.. A double-blind randomised, multicentre clinical trial to evaluate the efficacy and safety of two doses of etomoxir in comparison with placebo in patients with moderate congestive heart failure: The ERGO (etomoxir for the recovery of glucose oxidation) study. Clinical Science, 2007, 113 (4), pp.205-212. ⟨10.1042/CS20060307⟩. ⟨hal-00479353⟩