Fingolimod reduces the rate of brain volume loss in patients with relapsing multiple sclerosis (RMS), and this effect is independent of disease status and previous treatment history. |
Brain volume is clinically relevant in RMS because it tracks disease progression, and the rate of brain volume loss predicts long-term disability. |
Routine measurement of brain volume in RMS could be valuable in informing treatment decisions. |
Although reliable, longitudinal measurement of brain volume to determine rate of loss is difficult in routine clinical practice; developments in magnetic resonance imaging analysis are beginning to address the challenges faced. |
1 Introduction
2 Effect of Fingolimod on BVL in Patients with RMS
2.1 Reductions in BVL with Fingolimod: Evidence from Randomized, Double-Blind, Controlled Phase III Studies
Study name and identifier | Design | Duration | Patients | Intervention/s | Brain volume assessment |
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RMS studies
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FREEDOMS NCT00289978 [20] | Multicenter, phase III, randomized, double-blind, placebo-controlled, parallel-group | 2 years | Aged 18–55 years; RMS according to 2005 revised McDonald criteria; ≥1 confirmed relapses during the preceding year (or ≥2 during the previous 2 years); EDSS score of 0.0–5.5; treatment-naïve or previously treated; no relapse or steroid treatment within 30 days of randomization (N = 1272) | Fingolimod 1.25 mg (n = 429) Fingolimod 0.5 mg (n = 425) Placebo (n = 418) | MRI scan at screening, 6, 12, and 24 months; PBVC evaluated with SIENA |
FREEDOMS II NCT00355134 [21] | Multicenter, phase III, randomized, double-blind, placebo-controlled, double-dummy, parallel-group | 2 years | Aged 18–55 years; RMS according to 2005 revised McDonald criteria; ≥1 confirmed relapses during the preceding year (or ≥2 during the previous 2 years); EDSS score of 0.0–5.5; treatment-naïve or previously treated; no relapse or steroid treatment within 30 days of randomization (N = 1083) | Fingolimod 1.25 mg (n = 370) Fingolimod 0.5 mg (n = 358) Placebo (n = 355) | MRI scan at screening, 6, 12, and 24 months; PBVC evaluated with SIENA |
TRANSFORMS NCT00340834 [22] | Multicenter, phase III, randomized, double-blind, active-controlled, double-dummy, parallel-group | 1 year | Aged 18–55 years; RMS according to 2005 revised McDonald criteria; ≥1 confirmed relapses during the preceding year (or ≥2 during the previous 2 years); EDSS score of 0.0–5.5; treatment-naïve or previously treated with IFNβ or GA; no relapse or steroid treatment within 30 days of randomization (N = 1292) | Fingolimod 1.25 mg (n = 426) Fingolimod 0.5 mg (n = 431) IFNβ-1a IM 30 μg/week (n = 435) | MRI scan at screening and 12 months; PBVC evaluated with SIENA |
FREEDOMS extension NCT00662649 [27] | Dose-blinded, parallel-group extension | 2 years | Completed FREEDOMS; did not discontinue study owing to an AE; did not experience onset of chronic immune system disease requiring immunosuppressive treatment (N = 920) |
Continuous
Fingolimod 1.25 mg (n = 289) Fingolimod 0.5 mg (n = 331)
Switch
Fingolimod 1.25 mg (n = 145) Fingolimod 0.5 mg (n = 155) | MRI scan every 12 months; PBVC evaluated with SIENA |
Randomized, dose-blinded, then open-label extension | 2 years | Completed FREEDOMS II (N = 632) |
Continuous
Fingolimod 1.25 mg (n = 203) Fingolimod 0.5 mg (n = 217)
Switch
Fingolimod 1.25 mg (n = 105) Fingolimod 0.5 mg (n = 107) | MRI scan at baseline, month 12, month 24, and EOS; PBVC evaluated with SIENA | |
TRANSFORMS extension | Randomized, dose-blinded, double-blinded, then open-label extension | 2 years, then up to 4.5 years | Completed TRANSFORMS (N = 1027) |
Continuous
Fingolimod 1.25 mg (n = 330) Fingolimod 0.5 mg (n = 356)
Switch
Fingolimod 1.25 mg (n = 174) Fingolimod 0.5 mg (n = 167) | MRI scan at screening, month 12, and month 24, at study discontinuation and at a 3-month follow-up visit; PBVC evaluated with SIENA |
LONGTERMS | Single-arm, open-label, long-term follow-up extension | Up to 7 years | Completed phase II, III and IIIb trials or extension studies (N = 2355) |
Continuous
Fingolimod 0.5 mg (n = 783)
Switch
Placebo–fingolimod 0.5 mg (n = 773) | MRI scan at screening and at months 6, 12, 24, 36, 48, 60, and 72; PBVC evaluated with SIENA |
PPMS studies
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INFORMS NCT00731692 [31] | Multicenter, phase III, randomized, double-blind, placebo-controlled | 3–5 years | Aged 25–65 years old; PPMS according to 2005 revised McDonald criteria; at least 1 year of disease progression; two or more of the following: positive brain MRI; positive spinal cord MRI; positive cerebrospinal fluid; EDSS score of 3.5–5.6; increase in EDSS score of ≥0.5 points in the past 2 years (N = 970) |
Cohort 1
Fingolimod 1.25 mg (n = 147) Placebo (n = 133)
Cohort 2
Fingolimod 0.5 mg (n = 336) Placebo (n = 354) | MRI scan at screening and every 12 months; PBVC evaluated with SIENA |
2.1.1 Fingolimod versus Placebo: FREEDOMS and FREEDOMS II
Endpoint | Fingolimod 0.5 mg, oral | Placebo | IFNβ-1a IM 30 μg/week |
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Mean (SD) change in BV from 0 to 6 months, % | |||
FREEDOMS [20] | −0.22 (0.81); p = 0.006 | −0.34 (0.73) | |
FREEDOMS II [21] | −0.23 (0.87); p = 0.012 | −0.38 (0.91) | |
Mean (SD) change in BV from 0 to 12 months, % | |||
FREEDOMS [20] | −0.50 (1.05); p = 0.03 | −0.65 (1.05) | |
FREEDOMS II [21] | −0.38 (0.97); p < 0.001 | −0.63 (1.05) | |
TRANSFORMS [22] | −0.31 (0.65); p < 0.001 | −0.45 (0.73) | |
Mean (SD) change in BV from 12 to 24 months, % | |||
FREEDOMS [20] | −0.37 (0.81); p < 0.001 | −0.67 (1.07) | |
FREEDOMS II [21] | −0.49 (0.90); p = 0.013 | −0.68 (1.10) | |
Mean (SD) change in BV from 0 to 24 months, % | |||
FREEDOMS [20] | −0.84 (1.31); p < 0.001 | −1.31 (1.50) | |
FREEDOMS II [21] | −0.86 (1.22); p < 0.001 | −1.28 (1.50) |
2.1.2 Fingolimod versus IFNβ-1a IM: TRANSFORMS
2.1.3 Post Hoc Analyses of FREEDOMS, FREEDOMS II and TRANSFORMS
2.2 Sustained Effects of Fingolimod in Reducing BVL
2.3 Patient History and Disease Characteristics Can Affect BVL, But Do Not Generally Influence the Effect of Fingolimod on BVL
2.3.1 Inflammatory Disease Activity at Baseline: Gadolinium-Enhancing Lesions and Relapses
2.3.2 Disease Burden at Baseline: T2 Lesions and Disability
2.3.3 Ongoing Disease Activity: Gd+ Lesions, New or Enlarged T2 Lesions and Disability
2.3.4 Treatment History and Response to Previous Treatment
3 Fingolimod in Primary Progressive MS
3.1 Fingolimod Did Not Reduce BVL in the Placebo-Controlled Phase III INFORMS Trial
4 Correlates of BV and Its Clinical Relevance
4.1 Baseline Correlates of Baseline BV
Evaluation | BV parameter | Patient/disease parameters | Analysis methodology |
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Baseline correlation | Baseline NBV | Baseline parameters: Age Duration of MS since first symptoms Number of relapses during the year before study Number of relapses during the 2 years before study Disability, measured using EDSS score Disability, measured using MSFC score Gd-enhancing lesion number T2 lesion volume T1-hypointense lesion volume | Pairwise Pearson (or Spearman) correlation: data presented with 95% CIs and p values determined using Fisher z transformation Statistical model selection process to identify the best baseline predictors of NBV: 1. Forward model selection based on multiple regression models and AIC was conducted separately for each study 2. The order of importance was ranked in each study, and ranks were then averaged across studies to weight the studies equally. The best baseline predictors were defined as those with the lowest mean ranks across studies. Only candidate variables that were consistently selected in all studies were considered for inclusion in the final model 3. The analysis was repeated, excluding MSFC as a candidate variable 4. A multiple linear regression model was used to investigate the combined effect of more than one explanatory variable on NBV The final model was fitted to all three studies for parameter estimation |
Baseline predictors of on-study change | PBVC on-study | Baseline parameters As baseline correlation (above), plus: NBV | Pairwise Pearson or Spearman correlation as above Statistical model selection process as steps 1–3 above, then: 4. A final multiple regression model with treatment and the two best predictors was then refitted to the data from each of the three studies to quantify PBVC as a function of the best predictors. No adjustment was made for multiplicity |
Longitudinal (on-study) correlation | PBVC on-study | On-study parameters: Number of confirmed relapses EDSS score MSFC score Cumulative number of Gd-enhancing lesions T2 lesion volume Number of new or enlarged T2 lesions T1-hypointense lesion volume | Pairwise Pearson or Spearman correlation: data were presented with 95% CIs and p values determined using Fisher z transformation |
4.2 Baseline Predictors of On-Study BVL
4.3 Longitudinal Factors that Correlate with BVL on Study
4.4 Clinical Relevance of BVL and Implications for Fingolimod
4.5 Disease Activity and BVL
5 Monitoring BVL in Clinical Practice
5.1 Guideline Recommendations
5.1.1 European Guideline Recommendations
5.1.2 Canadian Guideline Recommendations
5.2 Challenges to the Adoption of Routine BV Assessment in Clinical Practice
Category | Topic |
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Age Body mass index Diurnal variation Genotype (ApoE expression) Hydration state Menstrual cycle | |
Fluid-level changes attributable to inflammation (edema) Fluid-level changes attributable to resolution of inflammation (treatment-related pseudoatrophy) | |
Alcohol consumption Cardiovascular hypertension Diabetes mellitus Obesity Smoking | |
Changes in acquisition protocols Changes in scanner type and scanner upgrades Factors influencing scan quality (head motion, distortions, inhomogeneity artifacts) Measurement error Non-standardized quantification methods Patient repositioning in the scanner | |
Reimbursement Complexity of use (e.g. PACS integration) Lack of normative data Methods dependent on real-time data Poor integration of some image formats |