24-month intervention with a specific multinutrient in people with prodromal Alzheimer's disease (LipiDiDiet): a randomised, double-blind, controlled trial

Abstract

Background: Nutrition is an important modifiable risk factor in Alzheimer's disease. Previous trials of the multinutrient Fortasyn Connect showed benefits in mild Alzheimer's disease dementia. LipiDiDiet investigated the effects of Fortasyn Connect on cognition and related measures in prodromal Alzheimer's disease. Here, we report the 24-month results of the trial.

Methods: LipiDiDiet was a 24-month randomised, controlled, double-blind, parallel-group, multicentre trial (11 sites in Finland, Germany, the Netherlands, and Sweden), with optional 12-month double-blind extensions. The trial enrolled individuals with prodromal Alzheimer's disease, defined according to the International Working Group (IWG)-1 criteria. Participants were randomly assigned (1:1) to active product (125 mL once-a-day drink containing Fortasyn Connect) or control product. Randomisation was computer-generated centrally in blocks of four, stratified by site. All study personnel and participants were masked to treatment assignment. The primary endpoint was change in a neuropsychological test battery (NTB) score. Analysis was by modified intention to treat. Safety analyses included all participants who consumed at least one study product dose. This trial is registered with the Dutch Trial Register, number NTR1705.

Findings: Between April 20, 2009, and July 3, 2013, 311 of 382 participants screened were randomly assigned to the active group (n=153) or control group (n=158). Mean change in NTB primary endpoint was -0·028 (SD 0·453) in the active group and -0·108 (0·528) in the control group; estimated mean treatment difference was 0·098 (95% CI -0·041 to 0·237; p=0·166). The decline in the control group was less than the prestudy estimate of -0·4 during 24 months. 66 (21%) participants dropped out of the study. Serious adverse events occurred in 34 (22%) participants in the active group and 30 (19%) in control group (p=0·487), none of which were regarded as related to the study intervention.

Interpretation: The intervention had no significant effect on the NTB primary endpoint over 2 years in prodromal Alzheimer's disease. However, cognitive decline in this population was much lower than expected, rendering the primary endpoint inadequately powered. Group differences on secondary endpoints of disease progression measuring cognition and function and hippocampal atrophy were observed. Further study of nutritional approaches with larger sample sizes, longer duration, or a primary endpoint more sensitive in this pre-dementia population, is needed.

Funding: European Commission 7th Framework Programme.

Figure 1

Trial profile *Rescue medication was defined as the use of active product or approved Alzheimer's disease medication after progression to dementia. †All randomly assigned participants, excluding visit data after the start of rescue medication. ‡Respective visits of participants were additionally excluded in cases of major protocol deviations; number based on participants with at least one follow-up visit in the per-protocol dataset.

Figure 2

Changes in main endpoints during the 24-month intervention (A) NTB primary endpoint. (B) NTB memory domain. (C) CDR-SB. (D) MRI total hippocampal volume. (E) MRI ventricular volume. (F) CDR-SB in subgroups defined by baseline MMSE. Data are observed mean change from baseline; error bars are SE. Sample size by baseline MMSE subgroup (control/active): ≥24: mITT 117/106 (PP 96/89), ≥25: 104/91 (86/75), ≥26: 95/79 (78/66), ≥27: 77/63 (66/53), ≥28: 55/43 (48/37), ≥29 29/21 (24/19). CDR-SB=clinical dementia rating-sum of boxes. mITT=modified intention-to-treat analysis. MMSE=Mini-Mental State Examination. NTB=neuropsychological test battery. PP=per-protocol analysis.