Efficacy and Tolerability of Beta Hydroxybutyrate Ester in Patients With Amyotrophic Lateral Sclerosis (ALS)

Weight loss is a known negative prognostic factor in amyotrophic lateral sclerosis (ALS). One potential mechanism of weight loss in ALS is a disturbance of the mitochondrial complex I which causes an energy deficit in affected cells. Over the last years, various interventional studies targeting the energy deficit in ALS yielded promising results; however,it is still unclear which kind of nutrition or nutritional supplement is most beneficial. Ketone bodies represent a logical therapeutic option in ALS as ketone bodies are an extremely high-energetic substrate which yields the double amount of adenosine triphosphate (ATP) per mole compared to glucose. The human liver is able to synthesize ketone bodies (beta-hydroxybutyrate, acetone, and aceto-acetate) from fat in times of glucose shortage, for example after a prolonged period of fasting. This metabolic shift is the underlying principle of the ketogenic diet, a carbohydrate-free, fat-rich diet which has been successfully tested in other neurodegenerative diseases such as Alzheimer's and Parkinson's disease. In the ALS mouse model, a ketogenic diet was associated with a slower decline of motor function. However, a ketogenic diet is difficult to implement in ALS as it requires a long-term change of eating habits, which is difficult to achieve due to progressive dysphagia, fast worsening of general condition, and limited survival. Therefore, the direct administration of ketone bodies yields a more realistic alternative in ALS as it is easy to apply and allows to maintain the usual eating habits. In this study, we hypothesize that the administration of 3 x 10 g beta hydroxybutyrate ester per day (in addition to normal food intake and the standard medication of 2 x 50 mg riluzole) slows down disease progression as measured by neurofilament light chains (NfL) in serum after 6 months compared to placebo. Power calculation relies on the results of the lipids and calories for ALS (LIPCAL-ALS) study which tested the effect of