The LipiDiDiet trial: what does it add to the current evidence for Fortasyn Connect in early Alzheimer’s disease?

Figures & data

Figure 1 Kennedy Cycle: the biochemical pathway for synthesizing new neuronal membranes. Developed from Kennedy et al, 1956¹ and adapted with permission of Annual Reviews, from Use of phosphatide precursors to promote synaptogenesis, Wurtman RJ, Cansev M, Sakamoto T, Ulus IH, 29, 2009; permission conveyed through Copyright Clearance Center, Inc.²

Table 1 Overview of primary and main secondary endpoints at 24 months in the LipiDiDiet trial. Adapted from Soininen H, Solomon A, Visser PJ, et al. LipiDiDiet clinical study group. 24-month intervention with a specific multinutrient in people with prodromal Alzheimer’s disease (LipiDiDiet): a randomised, double blind, controlled trial. Lancet Neurol. 2017;16(12):965–975. Creative commons license and disclaimer from: http://creativecommons.org/licenses/by/4.0/legalcode⁹

	Control (n=158)^a		Active (n=153)^a		p-Value mixed model^b	p-Value sensitivity model^c
NTB Primary endpoint	Mean (SD)	n	Mean (SD)	n
MITT	−0.108 (0.528)	141	−0.028 (0.453)	134	0.166	0.214
Per-protocol	−0.122 (0.570)	123	0.045 (0.414)	116	0.080	0.043
NTB Memory domain
MITT	−0.130 (0.619)	140	0.003 (0.569)	134	0.101	0.112
Per-protocol	−0.151 (0.663)	122	0.083 (0.532)	116	0.057	0.026
CDR-SB^d
MITT	1.12 (1.72)	119	0.56 (1.32)	111	0.005	0.004
Per-protocol	1.07 (1.82)	98	0.40 (1.13)	94	0.002	0.002
MRI total hippocampal volume (cm^3)
MITT	−0.43 (0.33)	104	−0.30 (0.27)	96	0.005	0.005
Per-protocol	−0.42 (0.32)	90	−0.28 (0.28)	86	0.010	0.008
MRI whole brain volume (cm^3)
MITT	−24.24 (20.93)	90	−20.27 (17.79)	83	0.265	0.284
Per-protocol	−23.88 (19.90)	77	−17.89 (16.88)	73	0.160	0.137
MRI ventricular volume (cm^3)
MITT	7.80 (5.53)	106	5.96 (4.66)	94	0.046	0.042
Per-protocol	7.40 (4.79)	92	5.39 (4.50)	83	0.046	0.042

Notes: n= number of participants with at least one post-baseline value in the mixed model. p-values are for effect of intervention over 24 months. ^aData for active and control groups are presented as observed mean change from baseline at Month 24 (SD). ^bMixed model: linear mixed model for longitudinal data, with change from baseline as outcome, baseline score, and baseline MMSE as covariates, and real measurement time as a continuous variable. ^cSensitivity analysis: mixed model for repeated measures, with change from baseline as outcome, baseline score, and baseline MMSE as covariates, and planned visit time as a categorical variable. ^dHigher scores indicate worse performance; for all other endpoints, higher scores indicate better performance.

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; SD, standard deviation.

Table 2 Overview of clinical trial design and results for Fortasyn Connect

Study	Design	Key efficacy outcomes	Results
Souvenir I^Citation18	12-week, double-blind, randomized, multicenter trial of Fortasyn Connect or control product in drug-naïve patients with mild AD (MMSE 20–26), followed by optional 12-week exploratory extension	Co-primary outcomes: Change from baseline to Week 12 in delayed verbal recall task of the WMS-r; 13-item modified ADAS-Cog Secondary Outcomes: ADCS-ADL, CIBIC-plus, MMSE, NPI, QoL-AD Nutritional measures: DHA percentage of fatty acids in erythrocyte membrane, plasma homocysteine levels	Primary outcome: ADAS-cog: no change WMS-r delayed verbal recall: mean change was comparable between active and control groups Secondary outcomes: No difference between active and control group on ADCS-ADL, CIBIC-plus, NPI, QoL-AD WMS-r delayed verbal recall: 40% of patients in the active group showed an improvement compared with 24% in the control group Nutritional measures: a significant uptake of DHA and EPA into erythrocyte membranes was observed Plasma homocysteine level in the active group was 23% lower than at baseline, and 19% lower than in the control group (p≤0.001) Pre-specified mild AD analysis (MMSE 24–26): WMS-r delayed verbal recall and immediate verbal recall in the active group showed a significant improvement compared with control Post hoc analysis treatment responders^a: After 12 weeks, the percentage of patients defined as responders was significantly greater in the active group vs control group (18.2% vs 7.2%; p=0.031, Fisher exact test)
Souvenir II^Citation19	24-week, double-blind, randomized, controlled, parallel-group, multi-country trial to assess the efficacy and tolerability of Fortasyn Connect in drug-naïve patients with mild AD (MMSE score ≥20)	Primary outcomes: NTB memory function domain score (z-score), including Rey Auditory Verbal Learning Test immediate recall, delayed recall and recognition performance, and WMS-r verbal paired associates immediate and delayed recall Secondary outcomes: NTB executive function domain score (z-score), based on the WMS-r Digit Span, Trail-Making Test parts A and B (Delis Kaplan Executive Function System™ condition 2 and condition 4, respectively), Category Fluency, and the Controlled Oral Word Association Test NTB included the orientation task of the ADAS-cog and the Letter Digit Substitution Test NTB composite score (based on all 12 NTB components), individual item scores from the NTB DAD Nutritional blood parameters (plasma vitamin E, erythrocyte DHA and EPA, and homocysteine) EEG to assess eyes-closed resting-state oscillatory brain activity and functional brain connectivity	Primary outcome: NTB memory domain: memory domain z-score showed significant differences between the active and control groups Secondary outcomes: NTB total composite trend (p=0.053) No significant intervention effect on the NTB executive function domain NTB individual items: significant intervention effects on Rey Auditory Verbal Learning Test recognition performance score, Trail-Making Test part B, and Controlled Oral Word Association Test score EEG: Functional connectivity analysis (phase lag index) for the delta band revealed a significant difference in trajectory over 24 weeks between groups in favor of the active group Nutritional blood parameters: Significant biochemical changes: increased erythrocyte DHA and EPA (Mann–Whitney U test, p<0.001), plasma vitamin E, and decreased plasma homocysteine
Souvenir OLE^Citation20	24-week, open-label continuation of Souvenir II	NTB memory domain composite score (Rey Auditory Verbal Learning Test immediate recall, delayed recall and recognition performance and WMS-r verbal paired associates immediate and delayed recall) DAD Nutritional measures: plasma vitamin E, erythrocyte DHA and EPA, and plasma homocysteine	At 48 weeks: NTB memory domain score: Active-active group: continued improvement (48-week vs 24-week scores; significant 48 weeks compared to baseline) Control-active group: statistically significant increase after switching to the active product DAD: no effect Nutritional measures: clinically relevant benefit on plasma vitamin E (increase) and homocysteine (decrease) in both active–active and control–active groups
S-Connect^Citation21	24-month randomized, controlled, double-blind, parallel-group, multicenter trial of Fortasyn Connect or control product in patients with mild-to-moderate AD taking dementia medications	Primary outcome: Mean change from baseline in 11-item ADAS-cog total score Secondary outcomes: Cognitive test battery (Digit Span from the Wechsler Memory Scale 3rd Edition, Concept Shifting Test, Letter Digit Substitution Test, Category Fluency Test) ADCS-ADL CDR-SB	No differences between study groups were observed over 24 weeks in performance on the ADAS-cog, cognitive test battery, ADCS-ADL, or CDR-SB
LipiDiDiet^Citation9	24-month randomized, controlled, double-blind, parallel-group, multicenter trial of Fortasyn Connect or control product in patients with prodromal AD	Primary outcome: Change from baseline in: NTB total composite score (10 items) Secondary outcomes: NTB total composite score (16 items) NTB memory and executive function domains CDR-SB MRI: total hippocampal, whole-brain, ventricular volumes	NTB composite scores (10 or 16-item): No statistically significant differences CDR-SB, MRI hippocampal, and ventricular volume: Significant differences from placebo in favor of Fortasyn Connect Predefined Subgroup analyses: mITT: CDR-SB and hippocampal volume significant difference from placebo in favor of Fortasyn Connect Per protocol: NTB 10-item, Memory domain, CDR-SB, MRI hippocampal volume and ventricular volume significant difference from placebo in favor of Fortasyn Connect
bvFTD^Citation22	Proof of concept, double-blind, placebo-controlled, randomized, cross-over study (12 weeks each period) to explore the effects of Fortasyn Connect on symptomatological treatment of bvFTD	NPI total score Frontal Assessment Battery total score Reading the Mind in the Eyes Test total score Clinical Global Impression Severity scale	Compared with placebo, Fortasyn Connect showed significant improvements in: NPI total, CGI-S, and RMET (Social Cognition Skills)

Notes: ^aTreatment responders defined by combining scores on the modified ADAS-cog scale (cognition), ADCS-ADL scale (function), and CIBIC-plus (behavior). A patient was classified as a responder when they fulfilled at least two of the following three criteria relative to baseline scores: Modified ADAS-cog R4 point decline (clinical improvement) ADCS-ADL total score ≥4 point increase, CIBIC-plus ‘‘improvement”.

Abbreviations: AD, Alzheimer’s disease; ADAS-Cog, Alzheimer’s Disease Assessment Scale-cognitive subscale; ADCS-ADL, Alzheimer’s Disease Cooperative Study-Activities of Daily Living; bvFTD, behavioral variant of frontotemporal dementia; CDR-SB, Clinical Dementia Rating-Sum of Boxes; CIBIC-plus, Clinician Interview-Based Impression of Change plus caregiver input; DAD, Disability Assessment for Dementia scale; DHA, docosahexaenoic acid; EEG, electroencephalography; EPA, eicosapentaenoic acid; MMSE, Mini-Mental State Examination; MRI, magnetic resonance imaging; NPI, Neuropsychiatric Inventory; NTB, Neuropsychological Test Battery; QoL-AD, Quality of Life in Alzheimer’s Disease; WMS-r, Wechsler Memory Scale-revised.

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