TWO YEAR TRIAL FAILED TO MEET PRIMARY END-POINT – BUT EXPERTS SAY STUDY MAY STILL HAVE POSITIVES
Major EU-funded Alzheimer’s trial reveals ‘mixed’ results for daily nutrition drink
The trial reports that consumption of a once-daily medical nutrition drink in people with the early, pre-dementia, stages of Alzheimer’s disease known as prodromal Alzheimer’s did not see improved results in a specific neuropsychological test battery (NTB) – which was the primary endpoint measure of the trial.
Writing in Lancet Neurology, the international team of researchers led by Professor Hilkka Soininen, from the University of Eastern Finland as part of the LipiDiDiet study noted, however, that the trial did show that the drink did result in a significant stabilisation of everyday cognitive and functional performance, as well as reduced brain shrinkage.
The nutritional combination tested in the trial came in the form of ‘Fortasyn Connect’, which is made by Nutricia. The combination of active nutrients includes omega-3 fatty acids, choline, uridine monophosphate, phospholipids, antioxidants and B vitamins in a once daily 125ml medical nutrition drink that is marketed as Souvenaid. It is a Food for Special Medical Purpose (FSMP).
Soininen said the results bring us closer to understanding the impact of nutritional interventions on prodromal Alzheimer's, “which we are now better at diagnosing but unable to treat.”
“The LipiDiDiet study illustrates that this nutritional intervention can help to conserve brain tissue and also memory and patients' ability to perform everyday tasks - possibly the most troubling aspects of the disease,” said Soininen.
However, some experts have said the failure to meet its primary end-point mean that the findings on secondary outcomes should be treated with caution.
“This study hints that a medical drink could slow the decline of thinking skills in people experiencing mild memory problems,” said Dr Doug Brown, Director of Research at Alzheimer’s Society – who noted that the trial because the trial did not meet its main success criteria that would be needed for developing new drugs, “we cannot be confident of the drink’s benefits.”
“Although there was less cognitive decline in people taking the daily drink over two years, the same number of people still went on to develop dementia as those who had a fake drink every day,” he noted. “We certainly can’t conclude that the drink slows progression of Alzheimer’s disease.”
Meanwhile, Professor Tara Spires-Jones, programme lead at the UK Dementia Research Institute and the University of Edinburgh, noted that while some of the secondary outcomes were promising, overall the study indicates that specific changes in nutrition are ‘unlikely’ to make a large differences to people with Alzheimer’s, even in the early stages.
“There is strong evidence that a healthy lifestyle including exercise and a healthy diet can help reduce risk for developing dementia, but once the brain damage starts, a dietary intervention is unlikely to stop the disease,” she said.
Nutricia said it welcomes publication of the results from the trial – noting that it is proud that Souvenaid, containing the key nutrient combination Fortasyn Connect, was selected as the intervention product on the basis of its results in an earlier EU project.
“These results in patients with MCI support and extend findings from two previous randomized controlled trials of Souvenaid in patients with mild AD. We are pleased that this adds to the body of evidence for Souvenaid and we remain committed to ongoing and further clinical research,” the company said.
Professor John Hardy of UCL added that in general positive secondary outcomes are ‘notoriously unreliable’ – and are difficult to replicate in future studies.
“The paper is clear in saying more work is needed. It is. We now need a second trial with a primary outcome defined from the apparent positives in this failed trial.”
The Alzheimer’s Burden
- 47 million people have Alzheimer's or a related dementia for which there is currently no cure.
- Alzheimer's has a long pre-dementia (or predementia) phase with first signs of cognitive decline appearing several years before the onset of dementia.
- Many patients with the early symptoms of the disease can now be diagnosed in advance of dementia fully manifesting.
- The number of people living with Alzheimer's dementia is expected to double every 20 years, reaching 74.7 million in 2030 and 131.5 million in 2050.
The ‘pioneering’ clinical trial – which is part of the larger European Union funded LipiDiDiet project – involved 311 patients across 11 sites in four countries (Finland, Germany, the Netherlands and Sweden).
It involved people prodromal Alzheimer's, which is often referred to as Mild Cognitive Impairment or MCI. Patients were randomised to receive either the nutritional intervention (Souvenaid by Nutricia) or an iso-caloric control drink which did not contain the same lend of nutrients, for 24 months.
Analysis of Alzheimer’s progression was the primary outcome of the trial and was measured through changes in a neuropsychological test battery (NTB) score – which was the performed before the start of the trial and again at the end.
In terms of NTB scores, the nutritional intervention did not appear to offer an advantage, although patients in the Souvenaid group did have slightly less brain shrinkage on scans – something that the researchers suggest is promising because shrinkage in brain regions that control memory is linked to dementia progression.
Soininen and colleagues also noted that because the decline in the NTB of the control group was less than anticipated, the overall statistical analysis of the trial may be underpowered.
Secondary endpoint results included 45% less worsening in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) – which tracks a patient's disease progression based on performance in managing everyday life like handling household emergencies and financial transactions/
Furthermore, the trial reported significant differences in brain shrinkage between the two groups, with 26% difference for the hippocampus, and 16% for the ventricular volume.
"While this nutritional intervention is not a cure for Alzheimer's, it effectively shows that the earlier in the disease process we intervene, the greater the advantage for the patient,” commented LipiDiDiet project coordinator Professor Tobias Hartmann. “Importantly, reduced atrophy in the patient's brain shows that the benefit extends beyond symptomatic effects, something never before achieved."
Source: Lancet Neurology
Published online ahead of print, doi: 10.1016/S1474-4422(17)30332-0
“24-month intervention with a specific multinutrient in people with prodromal Alzheimer's disease (LipiDiDiet): a randomised, double-blind, controlled trial”
Authors: Hilkka Soininen, et al