Souvenaid Trial Missed Primary, Partially Met Secondary Endpoints

Series - International Athens/Springfield Symposium on Advances in Alzheimer Therapy, 2016:

At the 14th International Athens/Springfield Symposium on Advances in Alzheimer Therapy, held March 9 to 12 in Athens, Greece, scientists presented their latest results on Souvenaid, a medical food formulated as a breakfast drink that is being marketed by the Netherlands-based food company Nutricia. A clinical trial within the LipiDiDiet project, funded by the European Union, missed its primary outcome, finding no significant benefit on a composite measure of cognition. Even so, researchers associated with the Souvenaid program highlighted positive results on secondary measures of memory, cognition, and daily function in a subset of trial participants who complied with the daily regimen of Souvenaid and were at the earliest stages of prodromal AD. Hippocampal atrophy also slowed.

“We missed the primary endpoint, but it looks like something is happening cognitively in these people,” said Tobias Hartmann, Saarland University, Homburg, Germany, who coordinates the LipiDiDiet project. A second study, funded by Nutricia, reported in Athens that Souvenaid stimulates brain phospholipid metabolism in mild AD.

Hilkka Soininen, University of Eastern Finland, Kuopio, headed the LipiDiDiet Souvenaid trial, which tested Souvenaid early in disease. Scientists at 11 sites in four countries enrolled people aged 55 to 85 with prodromal Alzheimer’s (Dubois et al., 2007). All had deficits in episodic memory and a biomarker of underlying AD pathology, but their symptoms were mild, with MMSE scores of 24 or higher. In this randomized, double-blind, placebo-controlled study, 153 people drank Souvenaid, and 158 drank placebo every day for two years. Each group had a 20 percent dropout. Volunteers were assessed at baseline, six, 12, and 24 months.

The researchers took as primary outcome a composite score on five subtests from a modified Neuropsychological Test Battery (NTB). Secondary measures included the CDR-SB, other NTB composite scores including one of episodic memory, and MRI measures of brain volume. The Pentara Corporation of Salt Lake City, Utah, led by Suzanne Hendrix, independently analyzed the data. The scientists assessed a subgroup of 119 people taking Souvenaid, and 133 on placebo, who regularly followed the protocol. The scientists also analyzed benefits in people with the highest baseline MMSE scores, meaning those who started at the earliest phases of prodromal AD.

Overall, Souvenaid made no difference on the NTB composite. The treatment group did not perform differently from the placebo group. This is the primary result of the trial. Hartmann said the placebo group declined less than expected, rendering the study underpowered.

For the CDR-SB, the researchers saw a trend toward a benefit for the treatment group, which became a statistically significant 0.55 points only in the subgroup who regularly followed the treatment protocol. Within that compliant subgroup, 68 people who started the trial with an MMSE of 26 or higher scored an average of 0.69 points above placebo; the 37 who began with an MMSE of 28 or above had a 1.3-point advantage. Soininen said these effects were statistically significant. She saw similar benefits on the episodic memory composite score of the NTB. “The gains were most pronounced with high baseline MMSE, and with regular intake. Starting earlier seems to translate to more benefit,” said Hartmann.

The drink affected hippocampal volume. After two years, this brain structure had atrophied 39 percent more in the placebo than the treatment group. Hartmann interpreted this to be a good thing, saying that AD patients have more shrinkage than age-matched controls early in disease, and this may parallel disease progression (Oct 2009 conference news; Hennemen et al., 2009; Barnes et al., 2009). He commented, however, that whether atrophy changes translate into cognitive and clinical benefit remains to be seen. Other studies are less clear about how hippocampal volume loss relates to age, disease, and treatment  (Jun 2013 news; Jul 2004 conference news). 

Several cases of serious adverse events occurred. They included infections and nervous system disorders, but Hartmann said that as in previous trials, they were considered unrelated to Souvenaid. Patrick Kamphuis heads the neuroscience division of Nutricia research; he told Alzforum that for the time being, the present results would not change the company’s labeling or marketing of Souvenaid, though the company is leaving open that possibility. This medical food is sold over the counter in 15 countries, though not the United States, for about €4 per bottle.

The study will remain double-blind and continue for another four years. During this time, the researchers will analyze blood and cerebrospinal fluid, and progression to AD dementia.

“The significant secondary endpoints seem to indicate an effect on hippocampal functioning and degeneration,” wrote Philip Scheltens, VU University Medical Center, Amsterdam, to Alzforum. Scheltens was an investigator in the current study, but was not involved in the analyses. Co-author Pieter Jelle Visser, also at VU University Medical Centre, agreed. “There is a nice convergence on memory that suggests Souvenaid could be of some benefit fairly early in the disease,” he told Alzforum. The drink may help synapses when damage is still limited, he said. However, Visser said more data and replication are needed before recommending routine treatment. Scheltens pointed out that some participants may not meet the more recent definition of prodromal AD, which requires evidence of amyloid (Dubois et al., 2014). 

Another presentation in Athens detailed Souvenaid’s effect on phospholipids in the brain. In a four-week, randomized, placebo-controlled trial funded by Nutricia, Anne Rijpma, a Ph.D. student in the lab of Marcel Olde Rikkert, Radboud University Medical Center, Nijmegen, Netherlands, tested whether the drink stimulated production of phospholipids, the principal component of neural membranes. Thirty-three patients with mild Alzheimer’s, on average 74 years old, took either Souvenaid or a placebo daily. At baseline and at the end of the trial, patients underwent magnetic resonance spectroscopy to measure phospholipid metabolites in the brain.

After a month, the ratio of phospholipid precursors to breakdown products had risen in the hippocampus, anterior cingulate, and retrosplenial cortex of treated patients. This suggests a shift toward more phospholipid formation than breakdown, Rijpma wrote to Alzforum in an email. “The exact effect on neuronal membrane formation requires further research,” she wrote.

“Her results strengthen the existing mechanistic evidence base for Souvenaid,” Hartmann said, adding that further studies will be needed to establish a direct link with results from the LipiDiDiet trial.

Scientists not involved with the Souvenaid trial program were unavailable for independent comment to this report.—Gwyneth Dickey Zakaib

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References

Therapeutics Citations

  1. Souvenaid

News Citations

  1. St. Louis: Imaging Preclinical AD—Can You See it Coming in the Brain?
  2. Brain Changes Speak Volumes About Normal Aging and Dementia
  3. Philadelphia: Can a Shrinking Brain Be Good for You?

Paper Citations

  1. Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O'brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P. Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007 Aug;6(8):734-46. PubMed.
  2. Henneman WJ, Sluimer JD, Barnes J, van der Flier WM, Sluimer IC, Fox NC, Scheltens P, Vrenken H, Barkhof F. Hippocampal atrophy rates in Alzheimer disease: added value over whole brain volume measures. Neurology. 2009 Mar 17;72(11):999-1007. PubMed.
  3. Barnes J, Bartlett JW, van de Pol LA, Loy CT, Scahill RI, Frost C, Thompson P, Fox NC. A meta-analysis of hippocampal atrophy rates in Alzheimer's disease. Neurobiol Aging. 2009 Nov;30(11):1711-23. PubMed.
  4. Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL, Blennow K, DeKosky ST, Gauthier S, Selkoe D, Bateman R, Cappa S, Crutch S, Engelborghs S, Frisoni GB, Fox NC, Galasko D, Habert MO, Jicha GA, Nordberg A, Pasquier F, Rabinovici G, Robert P, Rowe C, Salloway S, Sarazin M, Epelbaum S, de Souza LC, Vellas B, Visser PJ, Schneider L, Stern Y, Scheltens P, Cummings JL. Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. Lancet Neurol. 2014 Jun;13(6):614-29. PubMed.

External Citations

  1. LipiDiDiet Souvenaid trial

Further Reading

Papers

  1. Onakpoya IJ, Heneghan CJ. The efficacy of supplementation with the novel medical food, Souvenaid, in patients with Alzheimer's disease: A systematic review and meta-analysis of randomized clinical trials. Nutr Neurosci. 2015 Dec 7; PubMed.
  2. Olde Rikkert MG, Verhey FR, Blesa R, von Arnim CA, Bongers A, Harrison J, Sijben J, Scarpini E, Vandewoude MF, Vellas B, Witkamp R, Kamphuis PJ, Scheltens P. 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. PubMed.
  3. Pardini M, Serrati C, Guida S, Mattei C, Abate L, Massucco D, Sassos D, Amore M, Krueger F, Cocito L, Emberti Gialloreti L. Souvenaid reduces behavioral deficits and improves social cognition skills in frontotemporal dementia: a proof-of-concept study. Neurodegener Dis. 2015;15(1):58-62. Epub 2015 Jan 15 PubMed.
  4. de Waal H, Stam CJ, Lansbergen MM, Wieggers RL, Kamphuis PJ, Scheltens P, Maestú F, van Straaten EC. The effect of souvenaid on functional brain network organisation in patients with mild Alzheimer's disease: a randomised controlled study. PLoS One. 2014;9(1):e86558. Epub 2014 Jan 27 PubMed.
  5. Scheltens P, Kamphuis PJ, Verhey FR, Olde Rikkert MG, Wurtman RJ, Wilkinson D, Twisk JW, Kurz A. Efficacy of a medical food in mild Alzheimer's disease: A randomized, controlled trial. Alzheimers Dement. 2010 Jan;6(1):1-10.e1. PubMed.

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