Souvenir II study 2012.

Study characteristics
Methods	Randomised, double‐blind, placebo‐controlled trial Randomisation between November 2009 and May 2011. We got no information on exact trial duration from the Sponsor Nutricia
Participants	Countries: Europe (The Netherlands, Germany, Belgium, Spain, Italy, and France) Diagnosis: "drug‐naïve" patients with very mild Alzheimer’s disease (mean MMSE 25) Follow‐up: 24 weeks Inclusion criteria: diagnosis of probable Alzheimer's disease (NINCDS‐ADRA); recent MRI or CT had shown no evidence of any other potential causes of dementia; MMSE ≥ 20; age ≥ 50 years; written informed consent; and availability of a responsible caregiver Exclusion criteria: neurological disease other than Alzheimer's disease; cholinesterase inhibitor or NMDA‐receptor antagonist use within 3 months prior to baseline; Depression Scale (15‐item) score of > 6; use within 2 months prior to baseline of: Omega‐3 fatty acid containing supplements or regular consumption of oily fish (> twice/week) within 2 months prior to baseline, use of atropine, scopolamine, tolterodine, hyoscyamine, biperiden, benztropine, trihexyphenidyl, oxybutynin, antipsychotics, vitamins B, C, and/or E (> 200% of the recommended daily intake), consumption of high‐energy and/or high‐protein nutritional supplements, a change in dose of lipid‐lowering medications, antidepressants, antihypertensives, or the use of other investigational products within 1 month prior to baseline; excessive alcohol intake or drug abuse; nursing home institutionalisation; investigator uncertainty regarding the willingness or ability of the patient to comply with the protocol Setting: Community; participants recruited from Alzheimer's disease centres (The Netherlands (n = 9), Germany (n = 5), Belgium (n = 4), Spain (n = 3), Italy (n = 3), and France (n = 3)) Total number of participants: n = 259 (n = 130 Souvenaid group / n = 129 control group) Per protocol population: n = 238 (n = 118 Souvenaid group / n = 120 control group) Baseline characteristics: age, mean (SD): Souvenaid group 74.4 (6.9), control group 73.2 (8.4) women in percentage: Souvenaid group 47.7%, control group 50.4%; years of education beyond primary school, mean (SD): Souvenaid group 6.5 (4.8), control group 6.6 (4.6); MMSE, mean (SD): Souvenaid group 24.9 (2.9), placebo group 25.0 (2.8); BMI, kg/m2 (SD): Souvenaid group 26.1 (4.1), placebo group 26.7 (4.2); apolipoprotein e4 positive carrier, n (%): Souvenaid group 59 (48.8), control group 60 (50.8)
Interventions	Intervention 1: Souvenaid 125 mL drink/once daily for 24 weeks which contains Fortasyn Connect™ (DHA, EPA, phospholipids, choline, UMP, vitamin B12, B6, and folate, vitamins C and E, and selenium) (see Table 4) Intervention 2: Iso‐caloric control product 125 ml/once daily that lacked Fortasyn Connect™, but that was otherwise identical to the active product with identical taste profile and appearance
Outcomes	Primary (24 weeks): Based on NTB (Harrison 2007) memory function domain z‐score; 5 components: Rey Auditory Verbal Learning Test immediate recall, delayed recall and recognition performance, and Wechsler Memory Scale‐revised (WMS‐r) verbal paired associates immediate and delayed recall Secondary (24 weeks): NTB (Harrison 2007) executive function domain z‐score; 5 components: WMS‐r Digit Span, Trail Making Tests parts A and B (Delis Kaplan Executive Function System™ condition 2 and condition 4, respectively), Category Fluency, and the Controlled Oral Word Association Test modified NTB (Harrison 2007) total composite z‐score; 12 components: Rey Auditory Verbal Learning Test immediate recall, delayed recall and recognition performance, and Wechsler Memory Scale‐revised (WMS‐r) verbal paired associates immediate and delayed recall, WMS‐r Digit Span, Trail Making Tests parts A and B (Delis Kaplan Executive Function System™ condition 2 and condition 4, respectively), Category Fluency, and the Controlled Oral Word Association Test. Additional components: orientation task of the ADAS‐cog and the Letter Digit Substitution Test Disability Assessment for Dementia (DAD) (Gelinas 1999) Safety and tolerability parameters assessed but not explicitly named as outcomes; Electroencephalography and nutritional blood parameters not included in this review
Methods of AE Assessment	Safety parameters: examination of participant medical history, adverse events, vital signs and laboratory tests Assessment of product compliance by participant recorded; no specification for the other parameters Monitoring of the parameters over a period of 24 weeks
Notes	Funding and methods used to control bias resulting from conflict of interest: see Table 5
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Souvenir II study 2012: Quote: “Allocation to the study groups was performed using a central randomization procedure in the Electronic Data Capture system, using four different randomization codes (A, B, C, and D)” p. 228
Allocation concealment (selection bias)	Low risk	Souvenir II study 2012: Quote: “Allocation to the study groups was performed using a central randomization procedure in the Electronic Data Capture system, using four different randomization codes (A, B, C, and D)." " The investigator, study‐site staff, Danone Research staff, study staff of the Clinical Research Organisation, patients, and caregivers were all blinded to the study products.” p. 228
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Souvenir II study 2012: Quote: “The investigator, study‐site staff, Danone Research staff, study staff of the Clinical Research Organisation, patients, and caregivers were all blinded to the study products.” p. 228
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Souvenir II study 2012: Quote: “The randomization code was not broken until initial statistical modeling of the primary outcome was complete.” p. 228 Quote: "Data analysis was conducted by staff of Danone Research and an outside statistician (JWR Twisk) independently and again by staff at Rush Alzheimer’s Disease Center (S Leurgans, RC Shah, DA Bennett, W Fan) who received the whole data set and preformed a statistical analysis blinded to study treatment on the primary outcome measure" p. 234
Incomplete outcome data (attrition bias) All outcomes	Low risk	Lost to follow‐up 8.1% almost equal distributed
Selective reporting (reporting bias)	Low risk	Outcomes presented as described in published study protocol.
Other bias	Low risk

AD: Alzheimer's disease; ADAS‐Cog: Alzheimer’s Disease Assessment Scale ‐cognitive subscale; ADCS‐ADL: Alzheimer's Disease Cooperative Study Activities of Daily Living; AE: Adverse events; BMI: body mass index; CT: computer‐assisted tomography; DHA: Docosapentaenoic acid; DSM: Diagnostic and Statistical Manual of Mental Disorders; EPA: Eicosapentaenoic acid; ITT: Intention to treat; MADRS: Montgomery–Åsberg Depression Rating Scale; MMSE: Mini Mental State Examination; MRI: Magnetic resonance imaging; NTB: Neuropsychological Test Battery; NMDA: N‐methyl‐D‐aspartate. SAE: Serious adverse events; SD: Standard deviation; UMP: Uridine‐5'‐monophosphate