Benefits of high-caloric fatty diet for ALS vary by rate of disease progression

A high-caloric fatty diet did not result in a disease-modifying effect for the entire population of patients with amyotrophic lateral sclerosis, or ALS, according to findings published in Annals of Neurology.

However, a post hoc analysis demonstrated a significant survival benefit among a subgroup of fast-progressing patients randomly assigned to the high-caloric fatty diet, indicating that a disease-modifying effect “cannot be excluded.”

“It has been shown that high-caloric nutrition can stabilize body weight,” Albert C. Ludolph, MD, of the department of neurology at the University of Ulm and the German Center for Neurodegenerative Diseases, and colleagues wrote. “Targeting weight loss in ALS may be therapeutically useful, because increasing energy content of the diet increased survival in ALS mouse models and showed efcacy in humans in a pilot clinical trial in gastrostomized ALS patients as well as in a longitudinal register of percutaneous endoscopic gastrostomy implanted patients. However, direct evidence for a therapeutic effect of increased calorie intake is missing.”

Ludolph and colleagues examined the efficacy of a high-caloric fatty diet to determine whether it would extend the rate of survival in patients with ALS.

The researchers analyzed data from a randomized, placebo-controlled, parallel-group, double-masked trial conducted between February 2015 and September 2018. Patients with possible, probable (clinically or laboratory-supported) or confirmed ALS were eligible. Ludolph and colleagues conducted the study at 12 sites in Germany.

Participants had a disease duration of greater than 6 months and less than 3 years, with disease onset defined as the date of first muscle weakness, excluding fasciculation and cramps. They achieved a best-sitting slow vital capacity of at least 50% and were willing to fill out a diet questionnaire over the course of the study.

The researchers randomly assigned participants 1:1 to a high-caloric fatty diet (405 kcal/day, 100% fat) or placebo. All patients also received 100 mg of riluzole daily for at least 4 weeks prior to enrollment and throughout the study period.

The primary endpoint was survival time, defined as time to death or time to study cutoff date. Follow-up occurred at 3, 6, 9, 12, 15 and 18 months after randomization.

The study included 201 patients (121 men; age, 62.4±10.8 years).

At 28 months, the point in time at which the last event occurred in both groups, confirmatory analysis of the primary outcome survival demonstrated a survival probability of 0.39 (95% CI, 0.27–0.51) in the placebo group and 0.37 (95% CI, 0.25–0.49) in the high-caloric fatty diet group (HR = 0.97, 1-sided 97.5% CI, to 1.44).

In a post hoc analysis, Ludolph and colleagues stratified patients according to their initial rate of progression, as “recent studies revealed an effect of edaravone and rasagiline on the subgroup of fast-progressing patients exclusively.” In this subgroup of patients, the researchers observed “a significantly prolonged survival” after 18 months among patients in the high-caloric fatty diet arm. Survival probability was 0.38 (95% CI, 0.21–0.54) in the placebo group and 0.62 (95% CI, 0.47–0.74) in the diet group (HR = 0.50, 2-sided 95% CI, 0.27-0.92). The researchers observed no difference in regard to survival among slowly progressing patients.

“The results again highlight the importance of considering the progression rate of patients, as the effect of interventions seems to be dependent on this characteristic of the disease,” Ludolph and colleagues wrote. “We suggest that future clinical studies should feature a lead-in phase to accurately measure pre-baseline disease progression and consequently stratify according to progression rates.”