PRELIMINARY RESULTS OF A PHASE I / II STUDY WITH PERIODIC CYCLES OF A LOW-PROTEIN AND ONLY MODERATELY LOW-CALORIE DIET IN PATIENTS WITH COGNITIVE IMPAIRMENT

Aim of the study: several preclinical studies have shown that calorie restriction has a protective effect against aging, oxidative stress and neurodegenerative diseases. Moreover, cycles of a diet designed to recreate the metabolic consequences of fasting (Fasting-Miming Diet, DMD) produced neuro-regenerative effects in mouse models of Alzheimer's disease (AD). In consideration of the above results, a randomized, single-blind, multi-centric phase I / II clinical trial of low-protein and low-calorie DMD (ProlonADTM) was conducted in patients diagnosed with mild AD or with amnestic Mild Cognitive Impairment (aMCI). Methods: The clinical study involves the enrollment of 40 patients in good nutritional status at the San Martino Polyclinic Hospital in Genoa and at the Perugia Hospital. Once eligibility is ascertained, patients are randomly assigned to the experimental arm, in which 12 monthly cycles of ProlonADTM for 5 consecutive days and a series of dietary supplements known to have neuro-protective properties are administered, or to the placebo arm, which involves 12 cycles of a placebo diet. Both diets are produced and provided free of charge by L-Nutra. The feasibility of ProlonADTM is assessed by monitoring the percentage of patients able to follow the assigned diet, while the safety assessment is linked to the estimate of grade ≥ 3 adverse events according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Secondary objectives include assessing the impact of DMD on patients' cognitive and functional status, quality of life, mood, nutritional status, body composition, caregiver burden and inflammatory, oxidative stress and of neuronal damage. Results: The enrollment of 40 patients ended in July 2022. For ProlonADTM, 8 patients (40%) completed the 12 cycles, while 5 patients (25%) were on treatment. For the placebo diet, 10 patients (50%) completed the 12 cycles, while 2 patients (10%) were on treatment. The dropout results in a similar number of patients in the two groups: in particular for ProlonADTM at the moment there are 7 patients (35%), while for the placebo diet 8 (40%). Regarding the adverse events, they mainly occurred in the treatment group in 12 patients (60%), but they are all mild or moderate (G1-2). The nutritional data show a similar trend of the two groups in the first six months as regards body composition. There is a reduction in weight in the treatment group compared to placebo, but when analyzing the odds ratios adjusted for the number of assessments and sex, there are no differences attributable to the assignment group. Finally, evaluating the neuropsychological data, a worsening on the cognitive level of the placebo group is highlighted, not evident in the treatment group. Conclusions: Overall, the data collected so far indicate a fair safety and feasibility of ProlonADTM, with a possible protective effect of the latter on cognitive decline. The above data will be confirmed at the end of the study and with further phase III clinical studies.