Brain volume loss may not reflect disability in progressive MS
Study questions use of brain atrophy as clinical endpoint in PPMS
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A brain comes apart. (Image from iStock)
- Brain volume loss in PPMS doesn't accurately reflect worsening physical disability.
- This challenges the use of brain atrophy as a primary endpoint in clinical trials.
- Walking tests may be a more reliable measures for physical disability progression.
Loss of brain volume (brain atrophy), a measure often used in clinical trials to track disease progression, may not accurately reflect worsening disability in people with primary progressive multiple sclerosis (PPMS).
That’s according to a new analysis of data from the Phase 3 PROMISE trial, in which measures of brain atrophy were only poorly associated with, and could not reliably predict, worsening physical ability in this multiple sclerosis (MS) population.
The findings challenge the common assumption that brain atrophy rate can serve as a primary endpoint in clinical trials to determine whether new disease-modifying therapies can effectively slow disability progression.
“Our findings stand in contrast to a literature of studies that show at times strong associations of MRI outcomes and disability in MS,” researchers wrote, adding that the results “question the suitability of brain volume loss” as a relevant endpoint in trials testing new therapies for PPMS.
The study, “Breaking the PROMISE: poor association between brain volume loss and clinical disability worsening over 2 years of follow-up in primary progressive multiple sclerosis,” was published in the Journal of Neurology, Neurosurgery and Psychiatry.
Brain atrophy in PPMS
MS occurs when the immune system mistakenly attacks healthy tissue in the brain and spinal cord, leading to inflammation and nerve cell damage. Over time, the loss of nerve cells leads to brain shrinkage, which occurs more rapidly in people with MS than in healthy agers.
In PPMS, a form of the disease marked by gradual disability accumulation from onset, MRI measures of brain atrophy are being increasingly used as the main outcomes in early-stage clinical trials. This is largely because changes on standard measures, such as the Expanded Disability Status Scale (EDSS), can take years to detect and would require much longer trials.
However, it remains unclear to what extent reductions in brain atrophy rates in PPMS correspond to meaningful changes in disability worsening.
To better understand this relationship, an international team of researchers examined data from the PROMISE trial, a large Phase 3 clinical study that tested glatiramer acetate in adults with PPMS. Glatiramer acetate (sold as Copaxone and generics) is approved for adults with relapsing forms of MS, but the PROMISE trial showed a lack of effect in disability worsening in PPMS patients and was terminated early.
The trial involved 943 participants who underwent disability assessments every three months, along with routine tests of physical and cognitive function and brain MRI scans. About 80% of them were followed for at least two years.
Over that period, measures of physical disability — including EDSS scores, walking function, and arm and hand dexterity — showed steady worsening, while cognitive function showed a slight improvement. MRI scans showed a decline in several measures of brain volume, indicating brain atrophy.
The researchers found no consistent or strong association between brain atrophy and worsening physical disability over the two years of follow-up. Likewise, brain volume changes during the first year of the study did not predict changes in any of the physical disability measures in the second year.
When focusing on walking performance, which the researchers described as a reliable indicator of physical disability in progressive MS, brain volume measures were not significantly associated with worsening walking ability over the two-year study period.
Further statistical analyses showed that MRI-based measures had a low ability to predict which patients would later experience worsening walking function.
“Our findings … suggest that while brain volumes do indeed decrease over the duration of a trial, there is no reason to believe that brain atrophy measures can or should stand in for physical disability measures in progressive MS trials,” the researchers wrote.
They added that relying on brain volume change as the main outcome in early trials of progressive MS carries clear risks. Potentially helpful treatments could be discarded if they do not slow brain atrophy, while drugs that appear promising on MRI might still fail to improve patients’ physical function in larger trials.
Based on their previous research showing that walking tests are more responsive and reliable measures of physical disability than EDSS scores in progressive MS, the team suggested that walking measures may be more meaningful primary outcomes in early-stage trials. Brain volume measures, they said, could still be included as secondary endpoints.
