Efficacy, safety and tolerability of ultra-high-caloric, fatty diet (UFD) in amyotrophic lateral sclerosis (LIPCAL-ALS II)

• Applicant: Professor Dr. Johannes Dorst
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 525828281

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease, leading to progressive paralysis of voluntarily innervated muscles and to death caused by respiratory failure after a mean disease duration of 3 years. Despite decades of intensive research, the pathogenesis of ALS remains largely unknown. To date, riluzole, a glutamate antagonist, is the only approved drug for ALS in Europe, extending survival by 3 months. Therefore, more effective treatments for ALS are desperately needed. In this context, weight loss has been identified as a promising therapeutic target. ALS patients feature hypermetabolism, including an increased resting energy expenditure, which causes progressive weight loss and cachexia. The extent of weight loss is an independent prognostic factor for survival in ALS, and it has been shown that survival of ALS mice can be prolonged by applying a high-caloric nutrition. Furthermore, ALS patients feature distinct alterations of lipid metabolism, and various studies suggest a protective effect of high cholesterol and triglyceride serum levels. In 2018, this applicant group completed the LIPCAL-ALS I study, a randomized, placebo-controlled, multicenter trial which tested the effects of a high-caloric fatty diet (HCFD) in ALS, containing 405 kcal (45g fat) in addition to normal food intake. Although the primary endpoint survival was missed by a narrow margin, we were able to demonstrate various extremely promising effects, including a prolonged survival in fast-progressing patients, a slower disease progression, a stabilization of body weight, and a decrease of neurofilaments a surrogate marker of the disease. Encouraged by these positive signals, we hypothesize that the beneficial effects can be enlarged, including a life-prolonging effect for the whole ALS population, by administering the 1.5-fold dosage (630 kcal and 70g fat = ultra-high-caloric fatty diet, UFD), which shall be tested in this placebo-controlled, multicenter follow-up study (LIPCAL-ALS II). To assure that such a diet will be well tolerated, we performed the TOLCAL study (clinicaltrials.gov identifier NCT02306590), which yielded excellent results with regard to tolerability and compliance. Furthermore, we gained valuable insights from the LIPCAL-ALS I study which will be fully utilized with regard to study design. This includes exclusion of atypical, slow-progressing patients, an optimized power calculation to compensate for potentially higher drop-out rates compared to studies with drugs, innovative secondary outcome parameters, and a vastly improved concept to assure study adherence and compliance based on TOLCAL. The study will be conducted within our highly specialized German network for ALS, which has previously successfully conducted a large number of clinical trials in ALS.

• DFG Programme: Clinical Trials
• Co-Investigator: Professor Dr. Albert Christian Ludolph