Souvenaid Study Problematic

Last week, various mainstream news sources reported the positive results of a randomized, double-blind, placebo-controlled, multicenter study of Souvenaid, a proprietary nutritional drink, in people with mild Alzheimer disease. The objective of the trial, printed in the latest issue of Alzheimer's and Dementia, was to restore neuronal synapses by providing "rate-limiting precursors for membrane phosphatide synthesis, such as...uridine, omega-3 polyunsaturated fatty acids, and choline," which Souvenaid contains. Citing rodent studies, the authors claimed, "These nutrients synergistically increase brain levels of phosphatide molecules that comprise the bulk of synaptic membranes, and brain levels of specific synaptic proteins, suggesting that they also increase synapse formation" [emphasis added].

Yes, it'd be nice to have a boosted smoothie that wards off cognitive decline, but...

To the credit of at least one news source, mainstream coverage of the Souvenaid study was tempered by reports of AD experts' "disdain" for the trial and its results.

Among the criticism:

• The relatively short length of the study, 12 weeks. The generally accepted minimum duration of an AD trial is 26 weeks; most extend to 1 year or longer.*
• The lack of benefit when measuring cognition with standard tests, like the ADAS-cog.
• The potential conflicts of interest among the authors, given their intimate connections to the company that makes Souvenaid. Notably coauthor Richard J. Wurtman, of MIT, owns patents on "uridine, omega-3 fatty acids, and choline to treat brain diseases by enhancing synapses," according to the study disclosures.

A review of the study article reveals additional problems.

• Because one unnamed study site failed to comply with ICH-GCP guidelines, data from 13 individuals (~6% of the study population) were excluded from the efficacy analysis.
• At baseline, approximately 40% of enrollees scored 0, the lowest score, on the delayed verbal-recall test (Wechsler Memory Scale-revised), one of the 2 primary outcome measures. This skew in the study population required the authors to use a nonparametric analysis (eg, use general categories of better, worse, and unchanged), instead of the planned parametric assessment (that is, use mean score changes in the study arms). Furthermore it's not clarified that the percentages of 0 scorers at baseline were similar in the 2 treatment groups. If they were not, then the potential for enrollees to decline on the basis of assigned treatment would certainly be affected.

Finally, although the authors claim synergistic effects of Souvenaid's active ingredients on synapse restoration, many of the individual ingredients in the formula have been shown to be ineffective (or only marginally effective) in AD. Watch for upcoming posts at the Pathophilia blog that review these AD studies.

* A 12-week blinded extension phase was conducted (n = 161). No benefit was seen with respect to the 2 primary outcome measures, but immediate verbal recall was significantly better in the group receiving Souvenaid.

ADAS-cog = Alzheimer's Disease Assessment Scale, cognitive subscale; GCP = good clinical practice; ICH = International Conference on Harmonisation; MMSE = Mini-Mental State Examination.

Photograph: Atrophied brain of person with AD from National Institute on Alcohol Abuse and Alcoholism.

Addendum: On the basis of the 12-week proof-of-concept study, the makers of Souvenaid are recruiting enrollees for a multicenter US study, called S-Connect. The trial, however, is not registered in the NIH database. The 40 US trial sites, 3 of which appear to be university affiliated, are listed here.