MS-SMART Trial: Evaluating Neuroprotection in Secondary Progressive Multiple Sclerosis
Secondary progressive multiple sclerosis (SPMS) remains one of the most challenging forms of MS to treat, as no effective therapies currently exist to halt disease progression. The MS-SMART trial (2020) was designed to explore whether three neuroprotective drugs—amiloride, fluoxetine, and riluzole—could slow neuroaxonal loss in SPMS. Unfortunately, the results were sobering, highlighting the complexity of SPMS and the need for innovative approaches.
Study Overview
The MS-SMART trial was a phase 2b, multiarm, double-blind, placebo-controlled trial aimed at testing the efficacy of three neuroprotective drugs in SPMS.
- Objective: To evaluate the ability of amiloride, fluoxetine, and riluzole to mitigate brain volume loss in patients with SPMS.
- Participants:
- A total of 445 patients aged 25–65 years.
- All participants had confirmed SPMS with steady progression over two years, Expanded Disability Status Scale (EDSS) scores of 4.0–6.5, and were capable of following the protocol.
- Effective contraception and negative pregnancy tests were required for female participants.
- Treatment Groups:
- Amiloride (n=111)
- Fluoxetine (n=111)
- Riluzole (n=111)
- Placebo (n=112)
Patients were monitored over 96 weeks to assess changes in brain volume and other key outcomes.
Key Outcomes
Primary Endpoint
The primary outcome of the trial was the percentage brain volume change (PBVC) over 96 weeks, measured via volumetric MRI.
- Amiloride vs. Placebo: No significant difference (PBVC = 0.0%; 95% CI -0.4 to 0.5; p=0.99).
- Fluoxetine vs. Placebo: No significant difference (PBVC = -0.1%; 95% CI -0.5 to 0.3; p=0.86).
- Riluzole vs. Placebo: No significant difference (PBVC = -0.1%; 95% CI -0.6 to 0.3; p=0.77).
Conclusion
The study concluded that none of the three neuroprotective drugs tested demonstrated a significant impact on brain volume loss in SPMS patients.
Implications of the MS-SMART Trial
1. Challenges in SPMS Treatment
This trial underscores the difficulty in treating SPMS. Unlike relapsing-remitting MS, where inflammation is the dominant mechanism, SPMS is driven by neurodegeneration and axonal loss. Traditional neuroprotective strategies may not be sufficient in halting this process.
2. Rethinking SPMS Therapy
The failure of amiloride, fluoxetine, and riluzole suggests that therapies targeting axonal pathology alone may be inadequate. Future research must consider multifactorial approaches, addressing not only neurodegeneration but also inflammation, immune modulation, and repair mechanisms.
3. Lessons in Trial Design
The MS-SMART trial utilized an innovative multiarm design, which is cost-efficient and time-saving. This approach can serve as a model for future studies investigating multiple therapies simultaneously.
Final Thoughts
The MS-SMART trial represents a significant step forward in our understanding of SPMS, despite its negative results. By rigorously testing three promising drugs, the trial provides valuable insights into the limitations of current neuroprotective strategies. While the search for effective SPMS treatments continues, the lessons learned from this study will undoubtedly shape future research.
References
Chataway J, et al. “The MS-SMART Trial: Evaluating Neuroprotection in Secondary Progressive MS.” The Lancet Neurology. 2020;19:3:214–225.