Phase 2 study of palmitoylethanolamide combined with luteoline in frontotemporal dementia patients

Frontotemporal dementia is a devastating neurodegenerative disorder for which no pharmacological treatments have been approved. Neuroinflammation plays a central role in driving the pathogenic mechanisms underlying frontotemporal dementia. In the last few years, co-ultramicronized palmitoylethanolamide combined with luteoline has emerged as a potential therapeutic molecule in neurodegenerative disorders pathogenically related to frontotemporal dementia, for its demonstrated strong anti-inflammatory and neuroprotective properties. Here we wanted to determine whether treatment with co-ultramicronized palmitoylethanolamide combined with luteoline may have a clinical impact in frontotemporal dementia patients. We performed a Phase 2, monocentric, randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of co-ultramicronized palmitoylethanolamide combined with luteoline in frontotemporal dementia patients. Forty eight patients with a diagnosis of probable frontotemporal dementia were randomly assign in a 1:1 ratio to receive co-ultramicronized palmitoylethanolamide combined with luteoline oral suspension at the dosage of 700 mg + 70 mg twice/day (n = 25) or placebo twice/day (n = 23) for 24 weeks. The primary efficacy outcome measure was the change at 24-weeks in the Clinical Dementia Rating Dementia Staging Instrument from the National Alzheimer's Coordinating Center and frontotemporal lobar degeneration modules-sum of boxes (CDR plus NACC FTLD-SoB). Secondary outcome measures included the Frontal Assessment Battery, Screening for Aphasia in Neurodegeneration, Alzheimer's Disease Cooperative Study-Activities of Daily Living, Neuropsychiatric Inventory, Mini-Mental State Examination and Addenbrooke's Cognitive Examination Revised. Among 48 patients randomized [mean (SD) age 63.2 (8.4), 23 (47.9%) female], 45 (93%) completed the study. Patients in the co-ultramicronized palmitoylethanolamide combined with luteoline group showed less decline for the primary outcome measure (CDR plus NACC FTLD) as compared with patients treated with placebo. The estimated mean change (W0-W24) in CDR plus NACC FTLD score was 0.53 for the co-ultramicronized palmitoylethanolamide combined with luteoline group [95% confidence interval (0.12-0.94)] and 1.39 for the placebo group [95% confidence interval (0.96-1.82)], with an estimated mean difference between of 0.86 [95% confidence interval (0.28-1.45), P = 0.005]. Estimated mean change in Alzheimer's Disease Cooperative Study-Activities of Daily Living score was -1.8 for co-ultramicronized palmitoylethanolamide combined with luteoline (95% confidence interval, -3.67 to 0.06) and -7.39 for placebo (95% confidence interval -9.34 to -5.45). Estimated mean change in screening for Aphasia in neurodegeneration scores was -3.987 for co-ultramicronized palmitoylethanolamide combined with luteoline (95% confidence interval, -7.75 to -0.22) and -10.35 for placebo (95% confidence interval, -14.33 to -6.37). No effect of treatment was found on other secondary outcome measures. Our results demonstrate that co-ultramicronized palmitoylethanolamide combined with luteoline shows promising efficacy in slowing down the progression of cognitive and functional symptoms in frontotemporal dementia patients. These findings warrant further investigation and offer potential for the development of effective therapeutic strategies for frontotemporal dementia.