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MS-STAT

Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis

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Year of Publication: 2014

Authors: Jeremy Chataway, Nadine Schuerer, Ali Alsanousi, ..., Richard Nicholas

Journal: The Lancet

Citation: Lancet 2014;383:2213-21

Link: https://doi.org/10.1016/S0140-6736(13)62242-4

Clinical Question

Does high-dose simvastatin (80 mg daily) reduce whole-brain atrophy and disability progression in patients with secondary progressive multiple sclerosis?

Bottom Line

High-dose simvastatin reduced the annualized rate of whole-brain atrophy by 43% compared to placebo (0.288% vs 0.584% per year, p=0.003), with small but significant improvements in disability measures (EDSS and MSIS-29). The mechanism appears to be neuroprotective or vascular rather than immunomodulatory, as no effects on T-cell immune markers were observed. This positive phase 2 result supports advancement to phase 3 testing.

Major Points

  • Phase 2 double-blind RCT of 140 patients with SPMS at 3 UK neuroscience centers
  • Primary outcome: 43% reduction in annualized whole-brain atrophy rate (0.288% vs 0.584% per year, adjusted difference -0.254%, p=0.003)
  • Brain atrophy measured using validated K-means normalization brain boundary shift integral (BSI) on volumetric T1 MRI
  • Both baseline and final MRI scans done off-medication to minimize pseudoatrophy effects
  • Significant improvements in secondary clinical outcomes: EDSS (-0.254, p<0.01) and MSIS-29 total (-4.78, p<0.05)
  • No significant effect on MSFC Z score, relapse rate, or new/enlarging T2 lesions
  • No effect on T-cell immune markers (IFN-γ, IL-4, IL-10, IL-17, FoxP3) - mechanism not immunomodulatory
  • Cholesterol significantly reduced from 5.5 to 4.1 mmol/L in simvastatin group
  • Well tolerated: no increase in adverse events (77% placebo vs 70% simvastatin) or serious adverse events (20% vs 13%)
  • Placebo atrophy rate (0.584%/year) consistent with published SPMS natural history (0.64%/year)
  • First positive phase 2 trial of any agent in SPMS - supports advancement to phase 3

Design

Study Type: Investigator-led, double-blind, placebo-controlled, parallel-group, randomized, phase 2 trial

Randomization: 1

Blinding: Double-blind (patients, treating physicians, outcome assessors, MRI analysts); two-physician model with separate treating and examining neurologists

Enrollment Period: January 28, 2008 to November 4, 2011

Follow-up Duration: 25 months (24 months treatment + 1 month off-medication for final MRI)

Centers: 3

Countries: United Kingdom

Sample Size: 140

Analysis: Intention-to-treat and per-protocol; linear mixed models for repeated measures of brain atrophy; ANCOVA with bootstrap CIs for clinical outcomes; overdispersed Poisson for lesion/relapse rates; 90% power for 0.25%/year difference in atrophy; STATA 12.1

Inclusion Criteria

  • Age 18-65 years
  • Secondary progressive multiple sclerosis by Lublin-Reingold definition
  • Revised McDonald criteria for MS
  • EDSS score 4.0-6.5
  • Steady progression (rather than relapse) as major cause of increasing disability in preceding 2 years
  • Confirmed by either ≥1 point increase on EDSS or clinically documented increasing disability

Exclusion Criteria

  • Primary progressive multiple sclerosis
  • Relapse or corticosteroid treatment within 3 months of screening
  • Immunosuppressants (azathioprine, methotrexate, ciclosporin) within previous 6 months
  • Disease-modifying treatments (interferon beta, glatiramer acetate) within previous 6 months

Arms

FieldSimvastatinControl
InterventionSimvastatin 80 mg orally once daily for 24 months (after initial 1 month at 40 mg daily for dose escalation). Final MRI at 25 months (1 month off-medication).Matching placebo orally once daily for 24 months, mimicking same dose escalation schedule. Final MRI at 25 months (1 month off-medication).
Duration24 months treatment, 25 months follow-up24 months treatment, 25 months follow-up

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Annualized rate of whole-brain atrophy measured as relative change in brain volume by K-means normalization brain boundary shift integral (BSI) on serial volumetric T1 MRI scans between baseline, 12 months, and 25 monthsPrimary0.584% per year (SD 0.498); n=64 assessed0.288% per year (SD 0.521); n=66 assessed0.30%/yr0.003
EDSS at 24 months (adjusted for baseline)Secondary6.35 (SD 0.83); n=615.93 (SD 1.11); n=67Difference -0.254 (95% CI -0.464 to -0.069)<0.01
MSIS-29 total at 24 months (adjusted for baseline)Secondary76.1 (SD 16.3); n=5770.1 (SD 15.6); n=66Difference -4.78 (95% CI -9.39 to -0.02)<0.05
MSIS-29 physical at 24 monthsSecondary56.3 (SD 11.8); n=5751.7 (SD 11.4); n=66Difference -3.73 (95% CI -7.18 to -0.28)<0.05
MSIS-29 psychological at 24 monthsSecondary19.8 (SD 6.0); n=5718.3 (SD 5.8); n=66Difference -1.09 (95% CI -2.83 to 0.84)>0.10
MSFC Z score at 24 monthsSecondary-1.21 (SD 2.59); n=49-0.78 (SD 2.06); n=58Difference 0.289 (95% CI -0.333 to 0.961)>0.10
New and enlarging T2 lesions (rate per person-year)Secondary2.19 (283 events); n=631.50 (205 events); n=65IRR 0.72 (95% CI 0.45-1.16)0.176
Relapse rate (per person-year)Secondary0.16 (22 events); n=700.20 (28 events); n=70IRR 1.29 (95% CI 0.64-2.60)0.473
Total cholesterol change baseline to 24 months (mmol/L)Secondary5.6 → 5.6 (no change, p=0.93)5.5 → 4.1 (p<0.0001)
Any adverse eventAdverse54/70 (77%)49/70 (70%)0.831 (one-sided)
Serious adverse eventAdverse14/70 (20%)9/70 (13%)0.873 (one-sided)
Drug-related adverse eventAdverse13/70 (19%)16/70 (23%)
Relapse (as AE)Adverse17/70 (24%)17/70 (24%)
CrampAdverse10/70 (14%)12/70 (17%)
HeadacheAdverse10/70 (14%)3/70 (4%)
PainAdverse13/70 (19%)7/70 (10%)
Increased spasticityAdverse7/70 (10%)0/70 (0%)
UTIAdverse8/70 (11%)9/70 (13%)

Subgroup Analysis

Not reported. Immunological marker analysis showed no significant differences between groups for inducible levels of IFN-γ, IL-4, IL-10, IL-17 on T cells or FoxP3 expression on CD4+ T cells at 6, 12, or 24 months.

Criticisms

  • Phase 2 trial with small sample size (n=140) - not powered to detect clinically confirmed EDSS progression
  • Single country (UK) limits generalizability
  • Imbalance at baseline: simvastatin group had fewer recent relapses (10% vs 17% in past 12 months) and was more ethnically homogeneous (99% vs 90% White)
  • Loss to follow-up higher in placebo group (6 vs 3) potentially biasing results
  • MRI outcome (brain atrophy) may not translate to clinical benefit - authors appropriately caution against overinterpretation
  • No effect on relapse rate or T2 lesion accumulation suggests mechanism is not anti-inflammatory/immunomodulatory
  • Mechanism of benefit unclear - could be neuroprotective, vascular, or simply cholesterol-lowering effect on vascular comorbidities
  • Compliance was <90% in ~23% of both groups
  • Study design did not assess whether benefit persists after stopping treatment
  • Lacks comparison to or combination with established MS DMTs

Funding

The Moulton Foundation (charity number 1109891), Berkeley Foundation (268369), Multiple Sclerosis Trials Collaboration (1113598), Rosetrees Trust (298582), personal contribution from A Pidgley, UK National Institute of Health Research (NIHR) University College London Hospitals/UCL Biomedical Research Centres funding scheme. No pharmaceutical company involvement.

Based on: MS-STAT (The Lancet, 2014)

Authors: Jeremy Chataway, Nadine Schuerer, Ali Alsanousi, ..., Richard Nicholas

Citation: Lancet 2014;383:2213-21

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