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MAGNIFY-MS

Early Reduction of MRI Activity During 6 Months of Treatment With Cladribine Tablets for Highly Active Relapsing Multiple Sclerosis

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Year of Publication: 2022

Authors: Nicola de Stefano, Frederik Barkhof, Xavier Montalban, ..., Sanjeev Roy

Journal: Neurology: Neuroimmunology & Neuroinflammation

Citation: Neurol Neuroimmunol Neuroinflamm 2022;9:e1187

Link: https://doi.org/10.1212/NXI.0000000000001187

PDF: https://www.researchgate.net/publication...mxpY2F0aW9uIn19

Clinical Question

What is the onset of action of cladribine tablets in patients with highly active relapsing multiple sclerosis, as measured by changes in MRI lesion activity?

Bottom Line

Cladribine tablets demonstrate early onset of action with significant reductions in active MRI lesion counts observable from month 1-2 onward, with increasing effect over 6 months in highly active relapsing MS patients.

Major Points

  • First study to systematically evaluate early MRI changes with cladribine tablets using frequent assessments
  • Significant reduction in CUA lesions from month 1 onward compared to baseline
  • T1 Gd+ lesions significantly decreased from month 2 onward
  • Active T2 lesions showed significant reduction from month 2
  • Proportion of lesion-free patients increased substantially over 6 months
  • Effects consistent across subgroups regardless of prior DMT use or baseline relapse activity
  • Early onset correlates with rapid B-cell depletion mechanism (90% reduction in 4-8 weeks)
  • No new safety signals observed compared to previous studies
  • Single-arm design limits comparison to placebo controls
  • Results support early treatment effect seen in CLARITY study

Design

Study Type: Phase IV, open-label, single-arm, international study

Randomization:

Blinding: Open-label (no blinding)

Enrollment Period: May 28, 2018 - April 23, 2019

Follow-up Duration: 6 months (interim analysis of 2-year study)

Centers: 50

Countries: 14

Sample Size: 270

Analysis: Mixed-effects linear model, sequential testing procedure for Type I error control

Inclusion Criteria

  • Age ≥18 years
  • Diagnosis of highly active relapsing MS
  • EDSS score ≤5
  • Highly active disease defined as: 1 relapse in previous year + ≥1 T1 Gd+ lesion OR ≥9 T2 lesions while on other DMT, OR ≥2 relapses in previous year with/without DMT

Exclusion Criteria

  • Lymphocyte count outside normal limits
  • Signs of progressive multifocal leukoencephalopathy
  • Positive HIV, hepatitis B/C, or active/latent tuberculosis
  • Active malignancy
  • Allergy/hypersensitivity to gadolinium or MRI contraindications
  • Previous exposure to alemtuzumab, fingolimod, mitoxantrone, natalizumab, or ocrelizumab

Baseline Characteristics

Control: N/A (single-arm study)

Active:

  • Sample Size: 270 patients
  • Mean Age: 37.7 ± 9.75 years
  • Female: 66.7%
  • Median EDSS: 2.0
  • Time since MS onset: 84.9 ± 85.46 months
  • Relapses in 12 months: 49.3% had 2 relapses, 38.1% had 1 relapse
  • Previous DMT use: 56.7%
  • Baseline CUA lesions: 52.2% had ≥1 lesion

Arms

FieldCladribine Tablets Group
InterventionCladribine tablets 10mg (MAVENCLAD) 3.5 mg/kg cumulative dose over 2 years, administered as 2 weeks of treatment per year (week 1 at baseline, week 2 at month 1)
Duration6 months (interim analysis)

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Difference in combined unique active (CUA) lesion counts during postbaseline periods compared to baseline periodPrimaryN/APeriod 1 (months 1-6): -1.193, Period 2 (months 2-6): -1.500, Period 3 (months 3-6): -1.692N/AAll p < 0.0001
T1 Gd+ lesion count reductionSecondaryBaseline levelsMonth 2: -0.857, Month 3: -1.355, Month 6: -1.449N/AAll p < 0.0001
Patients without CUA lesionsSecondary52.2% at baselinePeriod 1: 52.0%, Period 3: 80.5%N/AN/A
Patients without T1 Gd+ lesionsSecondary47.8% at baseline91.4% by month 6N/AN/A
Any TEAEAdverseN/A191/270 (70.7%)N/AN/A
Mild TEAEsAdverseN/A128/270 (47.4%)N/AN/A
Treatment-related TEAEsAdverseN/A89/270 (33.0%)N/AN/A
Qualifying relapsesAdverseN/A13 patients during 6-month periodN/AN/A

Subgroup Analysis

Significant CUA lesion count reductions observed across all subgroups: high vs. low relapse activity, prior DMT use vs. naive, and patients with baseline CUA lesions >0

Criticisms

  • Single-arm design without control group limits interpretation
  • Regression to mean may contribute to observed improvements
  • Relatively short 6-month follow-up period for this interim analysis
  • MRI assessments conducted at single time points with potential variability
  • Cannot directly compare to placebo as in other pivotal trials
  • Limited ability to assess dose-response relationships
  • Frequent MRI schedule may not reflect real-world monitoring

Funding

Healthcare business of Merck KGaA, Darmstadt, Germany

Based on: MAGNIFY-MS (Neurology: Neuroimmunology & Neuroinflammation, 2022)

Authors: Nicola de Stefano, Frederik Barkhof, Xavier Montalban, ..., Sanjeev Roy

Citation: Neurol Neuroimmunol Neuroinflamm 2022;9:e1187

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