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Clinical trials

Souvenaid is the first medical nutrition product clinically proven, in double-blind, randomised controlled trials, to improve memory in patients with early Alzheimer’s disease. [1,2].

Souvenaid efficacy and safety has been assessed in four double-blind, randomised controlled trials: 2 in early AD with positive results [1,2], one in a primarily moderate stage population [3], and a fourth trial, the LipiDiDiet study [4], which was independently run and funded by the EU. The LipiDiDiet study assessed Souvenaid in patients in the prodromal phase of the disease and the first results were presented earlier this year. Further analyses ongoing and optional extension phases will yield more data over the next 4 years.

Evidence for the mode of action of Souvenaid comes from biomarker investigations using EEG [5], and MRS [6] data.

References


  1. Scheltens P, et al (2010). Alz Dem ;6:1-10.e1.
  2. Scheltens P, et al (2012). JAD ;31:225–236.
  3. Shah R et al (2013). Alzheimer’s Res Ther; 5(59): 1-9
  4. Soininen H et al (2016).Neurobiology of Aging;39:S23
  5. de Waal H et al (2014). PlosOne; 9: 1-11
  6. Rijpma A et al (2016). Neurobiology of Aging;39:S7-S8.

The benefits of Souvenaid have been shown in the Souvenir I and Souvenir II trials which demonstrated memory improvement in patients with mild AD, taking Souvenaid once-daily over 12 and 24 weeks, respectively.

Souvenir I (SI)

In the Souvenir I trial, Souvenaid was found to significantly improve memory performance (assessed by Wechsler Memory Scale-revised) and was well tolerated over a 12 week period in drug-naïve patients with mild Alzheimer’s disease [1].

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Souvenir II (SII)

Souvenir II demonstrated that, over a 24-week period, Souvenaid provided significant improvements in memory performance (assessed by a Neuropsychological Test Battery) and was associated with a tolerability profile similar to a control product in drug-free patients with mild Alzheimer’s disease  [2].

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Souvenir II Open Label Extension

This open-label extension (OLE) to Souvenir II assessed safety and compliance, and explored the effect of Souvenaid on memory for a further 24 weeks. The OLE demonstrated memory improvement during Souvenaid intervention from 24 to 48 weeks in both the active-active and control-active groups.
The results also showed that 48-week use of Souvenaid was well tolerated, with intake compliance of ≥95% [4].

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EEG

Electroencephalography (EEG) can provide insights into synaptic activity, functional connectivity in the brain and functional brain network organization.

EEG measures served as secondary outcomes and markers for synaptic connectivity in the Souvenir II trial. In this study, the network measures in the beta band decreased in the control group, but remained relatively unchanged in the active group. These results suggest that Souvenaid preserves the organization of brain networks in patients with mild AD within 24 weeks, counteracting the pattern usually seen in AD. The results strengthen the hypothesis that Souvenaid affects synaptic integrity and function [5].

There are further clinical trials investigating Souvenaid in mild to moderate Alzheimer's disease (S-Connect) and in prodromal Alzheimer's disease patients (LipiDidiet).

S-Connect

S-Connect demonstrated that Souvenaid was well tolerated in mild-to-moderate Alzheimer’s disease patients, on stable doses of standard Alzheimer’s disease drug therapy (acetylcholinesterase inhibitors and/or NMD-r antagonists), and did not increase the incidence of serious adverse events associated with these therapies. No difference was observed between the Souvenaid and control groups in cognitive performance [3].

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LipiDiDiet - efficacy in patients with prodromal AD

LipiDiDiet is an EU funded trial, with the first results recently announced at the AAT/ Springfield Congress in Athens in March 2016.

This trial was designed to assess the long term effects of Souvenaid over a two-year study period, with 4 optional, blinded extension periods in a prodromal AD population [8].

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MRS – Brain phospholipid metabolism

This trial demonstrated the effects of Souvenaid on brain phospholipid metabolism and on the level of brain metabolites related to neural integrity in mild Alzheimer’s disease patients [7].

Patients with Alzheimer’s disease have specific nutritional requirements for the support of synapse formation.

Mini Mental State Examination (MMSE)

  • A widely-used and well-validated assessment of general cognitive function, often used to follow the course of cognitive changes in an individual over time. Scores range from 0 to 30 decreasing as Alzheimer’s disease progresses

Wechsler Memory Scale-revised (WMS-r)

  • A widely-used, well-validated test of different types of memory
  • Made up of several subtests: Spatial Addition, Symbol Span, Design Memory, General Cognitive Screener, Verbal Memory, Verbal Paired Associates, and Visual Reproduction
  • Performance is reported as five Index Scores: Auditory Memory, Visual Memory, Visual Working Memory, Immediate Memory and Delayed Memory

Why was WMS-r used in Souvenir I?

WMS-r provides a sensitive assessment of episodic memory, which is affected early in Alzheimer’s disease. It gives a measure of immediate and delayed verbal memory, and it is widely used in clinical assessment and research settings.

Neuropsychological Test Battery (NTB)

  • A collection of standardised and well-validated tests chosen to assess different areas of cognition
  • In the Souvenir II trial, the NTB used was based on one shown to be sensitive in patients with mild Alzheimer’s disease, consisting of the following cognitive tasks:

Memory domain score

  • Rey Auditory Verbal Learning Test (RAVLT): immediate, delayed and recognition
  • WMS: immediate and delayed verbal paired association

Why was the NTB used as the primary endpoint in the Souvenir II trial?

The NTB allows a detailed assessment of different areas of cognition and is sensitive to early cognitive changes. The components are standardised, well-validated, and  widely used in both clinical trials and clinical assessment.

ADAS-cog

  • The cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS), which was developed and validated for assessing cognitive functioning in patients with Alzheimer’s disease
  • The standard test includes 11 items designed measures different cognitive domains:
    • Memory and new learning (4 items)
    • Language (5 items)
    • Praxis (2 items)
  • The 13 item version also includes two tests assessing executive function: delayed verbal recall and digit cancellation
  • Scores range from 0-85 with lower scores indicating better functioning

 

Why was ADAS-cog used in Souvenir?

The ADAS-cog has been widely used in clinical trials over many years, and is generally considered to be the ‘gold-standard’ assessment of cognitive function. It was developed specifically for patients with Alzheimer’s disease and the modified version includes assessment of the key domains that are typically affected in mild- to-moderate stages of the disease.

  • Efficacy of a medical food in mild Alzheimer's disease: a randomized, controlled trial [1]

    Efficacy of a medical food in mild Alzheimer's disease: a randomized, controlled trial [1]

    An improvement in memory function has been assessed by the WMS-r test after 12 weeks of consumption of Souvenaid (green) compared to a control drink (grey) [1].

  • Efficacy of Souvenaid in mild Alzheimer’s disease: results from a randomized, controlled trial [2]

    Efficacy of Souvenaid in mild Alzheimer’s disease: results from a randomized, controlled trial [2]

    This graph shows the difference in trajectories over time between Souvenaid and control groups during the 24-week intervention period. There was a significant improvement in the memory domain of the NTB over 24 weeks of treatment with Souvenaid [2]. The OLE study indicated that the memory performance significantly increased from week 24 to week 48 in both active-active and control-active groups [4].

References

  1. Scheltens P, et al. Efficacy of a medical food in mild Alzheimer's disease: A randomized, controlled trial. Alzheimers Dement. 2010;6:1-10.e1.
  2. Scheltens P, et al. Efficacy of Souvenaid in mild Alzheimer's disease: results from a randomized, controlled trial. J Alzheimer’s Dis. 2012;31:225–236.
  3. Shah R et al (2013). The S-Connect study: results from a randomized, controlled trial of Souvenaid. Alzheimer’s Res Ther; 5(59): 1-9
  4. Olde Rikkert MG, et al. Tolerability and safety of Souvenaid in patients with mild Alzheimer's disease: results of multi-center, 24-week, open-label extension study. J Alzheimers Dis. 2015;44(2):471-80.
  5. de Waal H et al (2014). Effect of Souvenaid on functional brain network organisation: results from a randomised controlled study in mild Alzheimer’s disease. PlosOne; 9: 1-11
  6. Olde Rikkert et al (2014). Differences in nutritional status between very mild Alzheimer's disease patients and healthy controls. J Alzheimers Dis; 41(1):261-71
  7. Rijpma A et al. The effect of Souvenaid on brain phospholipid metabolism in patients with mild Alzheimer’s disease: results of a randomised controlled 31P-Magnetic Resonance Spectroscopy study. Neurobiology of Aging. 2016;39:S7-S8
  8. Soininen H, Visser P, Kivipelto M, Hartmann T. A clinical trial investigating the effects of fortasyn connect (souvenaid) in prodromal Alzheimer's disease: results of the LipiDiDiet study. Neurobiology of Aging. 2016;39:S23
  9. www.trialregister.nl, NTR3855