36-month LipiDiDiet multinutrient clinical trial in prodromal Alzheimer's disease

Abstract

Introduction: The LipiDiDiet trial investigates the effects of the specific multinutrient combination Fortasyn Connect on cognition and related measures in prodromal Alzheimer's disease (AD). Based on previous results we hypothesized that benefits increase with long-term intervention.

Methods: In this randomized, double-blind, placebo-controlled trial, 311 people with prodromal AD were recruited using the International Working Group-1 criteria and assigned to active product (125 mL once-a-day drink) or an isocaloric, same tasting, placebo control drink. Main outcome was change in cognition (Neuropsychological Test Battery [NTB] 5-item composite). Analyses were by modified intention-to-treat, excluding (ie, censoring) data collected after the start of open-label active product and/or AD medication.

Results: Of the 382 assessed for eligibility, 311 were randomized, of those 162 participants completed the 36-month study, including 81 with 36-month data eligible for efficacy analysis. Over 36 months, significant reductions in decline were observed for the NTB 5-item composite (-60%; between-group difference 0.212 [95% confidence interval: 0.044 to 0.380]; P = 0.014), Clinical Dementia Rating-Sum of Boxes (-45%; P = 0.014), memory (-76%; P = 0.008), and brain atrophy measures; small to medium Cohen's d effect size (0.25-0.31) similar to established clinically relevant AD treatment.

Discussion: This multinutrient intervention slowed decline on clinical and other measures related to cognition, function, brain atrophy, and disease progression. These results indicate that intervention benefits increased with long-term use.

Keywords: Alzheimer's disease; atrophy; cognition; dietary intervention; function; hippocampus; mild cognitive impairment; nutrition; omega 3; prodromal; randomized controlled clinical trial; therapy.

FIGURE 1

Trial profile *Open‐label medication was defined as the use of active study product and/or Alzheimer's disease medication after dementia diagnosis. Data collected after the start of open‐label medication were excluded (ie, censored) from the efficacy analyses. Note that although participants who started open‐label medication remained in the study for at least one additional visit, some have discontinued the study at a later stage. †All randomly assigned participants, excluding visit data after the start of open‐label medication and visit data in violation of the predefined visit window. Numbers with visit data available for the efficacy analysis (modified intention‐to‐treat) are based on the data available for the Neuropsychological Test Battery 5‐item composite. ‡Respective visits of participants were excluded in case of major protocol deviations; number based on participants with at least one follow‐up visit in the per‐protocol dataset. §All randomly assigned participants, excluding participants that discontinued at baseline and did not receive allocated intervention. Abbrevation: AD, Alzheimer's disease

FIGURE 2

Changes in main endpoints during the 36‐month intervention (mITT). A, NTB 5‐item. B, NTB memory domain. C, CDR‐SB. D, CDR‐SB in subgroups defined by baseline MMSE. E, MRI total hippocampal volume. F, MRI whole brain volume. G, MRI ventricular volume. Data are mean change from baseline as estimated by the mixed model; error bars are standard error. For (A–C) and (E–G), n is the number of participants with change from baseline data in the mixed model; for (D), n is the number of participants with at least one post‐baseline value in the mixed model. Abbreviations: CDR‐SB, Clinical Dementia Rating‐Sum of Boxes; mITT, modified intention‐to‐treat; MMSE, Mini‐Mental State Examination; MRI, magnetic resonance imaging; NTB, Neuropsychological Test Battery