To the Editor We read with interest the Original Investigation by Trepanowski et al1 published in a recent issue of JAMA Internal Medicine; to the authors’ knowledge, it was the longest and largest randomized trial evaluating alternate-day fasting diet against calorie restriction diet and placebo. Trepanowski et al1 concluded the investigational intervention’s lack of superiority in terms of weight loss or metabolic outcomes against the comparators. We found this publication provocative and interesting; however, we want to highlight some design characteristics that may have impacted the trial outcomes and, thus, limited the power and external validity of the results.