Dieter Häring

Relapse and disability outcomes in patients with multiple sclerosis treated with fingolimod: subgroup analyses of the double-blind, randomised, placebo-controlled FREEDOMS study

BACKGROUND Fingolimod 0·5 mg once daily is approved for treatment of relapsing multiple sclerosis (MS). In the phase 3, 2-year FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral therapy in MS) study, fingolimod significantly reduced annualised relapse rates (ARRs) and the risk of confirmed disability progression compared with placebo. We aimed to investigate whether the beneficial treatment effect reported for the overall population is consistent in subgroups of patients with different baseline characteristics. METHODS We did subgroup analyses of ARRs (primary outcome) and confirmed disability progression (a secondary outcome) over 24 months in the FREEDOMS study, a randomised, double-blind study that included 1272 patients with relapsing-remitting MS who were assigned 1:1:1 to fingolimod (0·5 mg or 1·25 mg) or placebo once daily for 24 months. Subgroups were predefined, predefined and slightly modified, or defined post hoc, by demographic factors (including sex and age), disease characteristics (including baseline disability scores, relapse rates, and lesion parameters), and response to previous therapy (including analyses in patients eligible for fingolimod treatment according to the European label). Data were analysed by intention to treat. The FREEDOMS study is registered with ClinicalTrials.gov, number NCT00289978. FINDINGS Treatment with fingolimod 0·5 mg was associated with significantly lower ARRs versus placebo across all subgroups except for patients aged over 40 years. ARR ratios ranged from 0·76 (95% CI 0·54-1·09; p=0·13) in patients aged over 40 years to 0·29 (0·16-0·52; p<0·0001) in patients who had relapse activity despite receiving interferon beta during the year before study enrolment. Hazard ratios for confirmed disability progression over 24 months with fingolimod 0·5 mg versus placebo ranged from 0·85 (95% CI 0·53-1·36; p=0·50) in patients with a T2 lesion volume of 3300 mm(3) or less to 0·32 (0·14-0·73; p=0·0066) in patients with an EDSS over 3·5. In patients who relapsed and had lesion activity despite treatment with interferon beta in the previous year, the ARR ratio for fingolimod 0·5 mg versus placebo was 0·38 (95% CI 0·21-0·68, p=0·0011), and for treatment-naive patients with rapidly evolving severe disease it was 0·33 (0·18-0·62, p=0·0006). Hazard ratios for confirmed disability progression over 24 months were 0·68 (0·29-1·62; p=0·39) and 0·73 (0·25-2·07; p=0·55), respectively, in these groups. INTERPRETATION Patients with relapsing-remitting MS with a wide spectrum of clinical and MRI features including subgroups specified by the European label can potentially benefit from treatment with 0·5 mg fingolimod. FUNDING Novartis.

Inclusion of brain volume loss in a revised measure of ‘no evidence of disease activity’ (NEDA-4) in relapsing–remitting multiple sclerosis

Background: ‘No evidence of disease activity’ (NEDA), defined as absence of magnetic resonance imaging activity (T2 and/or gadolinium-enhanced T1 lesions), relapses and disability progression (‘NEDA-3’), is used as a comprehensive measure of treatment response in relapsing multiple sclerosis (RMS), but is weighted towards inflammatory activity. Accelerated brain volume loss (BVL) occurs in RMS and is an objective measure of disease worsening and progression. Objective: To assess the contribution of individual components of NEDA-3 and the impact of adding BVL to NEDA-3 (‘NEDA-4’) Methods: We analysed data pooled from two placebo-controlled phase 3 fingolimod trials in RMS and assessed NEDA-4 using different annual BVL mean rate thresholds (0.2%–1.2%). Results: At 2 years, 31.0% (217/700) of patients receiving fingolimod 0.5 mg achieved NEDA-3 versus 9.9% (71/715) on placebo (odds ratio (OR) 4.07; p < 0.0001). Adding BVL (threshold of 0.4%), the respective proportions of patients achieving NEDA-4 were 19.7% (139/706) and 5.3% (38/721; OR 4.41; p < 0.0001). NEDA-4 status favoured fingolimod across all BVL thresholds tested (OR 4.01–4.41; p < 0.0001). Conclusion: NEDA-4 has the potential to capture the impact of therapies on both inflammation and neurodegeneration, and deserves further evaluation across different compounds and in long-term studies.

Correlation between brain volume loss and clinical and MRI outcomes in multiple sclerosis

Objective: We investigated the determinants and clinical correlations of MRI-detected brain volume loss (BVL) among patients with relapsing-remitting multiple sclerosis from the phase 3 trials of fingolimod: FREEDOMS, FREEDOMS II, and TRANSFORMS. Methods: Post hoc analyses were conducted in the intent-to-treat populations from each trial and in a combined dataset of 3,635 patients from the trials and their extensions. The relationship between brain volume changes and demographic, clinical, and MRI parameters was studied in pairwise correlations (Pearson) and in multiple regression models. The relative frequency of confirmed disability progression was evaluated in the combined dataset by strata of concurrent BVL at up to 4 years. Results: Increasing age, disease duration, T2 lesion volume, T1-hypointense lesion volume, and disability were associated with reduced brain volume (p < 0.001, all). The strongest individual baseline predictors of on-study BVL were T2 lesion volume, gadolinium-enhancing lesion count, and T1-hypointense lesion volume (p < 0.01, all). During each study, BVL correlated most strongly with cumulative gadolinium-enhancing lesion count, new/enlarged T2 lesion count (p < 0.001, both), and number of confirmed on-study relapses (p < 0.01). Over 4 years in the combined dataset (mean exposure to study drug, 2.4 years), confirmed disability progression was most frequent in patients with greatest BVL. Conclusions: Rate of BVL in patients during the fingolimod trials correlated with disease severity at baseline and new disease activity on study, and was associated with worsening disability.

Effect of fingolimod on diffuse brain tissue damage in relapsing-remitting multiple sclerosis patients

BACKGROUND Multiple sclerosis (MS) affects all areas of the brain resulting in both focal and diffuse damage. In Phase 3 clinical trials, fingolimod showed significant reductions in both focal lesions and rate of brain volume loss (BVL) in patients with relapsing-remitting MS. OBJECTIVE To investigate if the effects of fingolimod 0.5mg on BVL are mediated exclusively through its effects on focal damage or if fingolimod also acts independently in reducing diffuse damage. METHODS This was a pooled post-hoc analysis of patients from two Phase 3 studies (FREEDOMS [N=1272] and FREEDOMS II [N=1083]), with no evidence of focal disease activity as defined by absence of gadolinium-enhancing lesions at baseline and new active lesions and clinical relapses at follow-up. The percent brain volume change (PBVC), as a measure of diffuse tissue damage, was assessed at Month (M) 12 and M24 by using the Structural Image Evaluation using Normalization of Atrophy (SIENA) method. A regression analysis was performed in the pooled intent-to-treat (ITT) population to quantify the treatment effect of fingolimod on BVL vs. placebo (PBO) in the overall population (unadjusted model), and whether this effect is sustained after adjusting for new active lesions and on-study relapses (adjusted model). RESULTS Of 1088 patients, 638 (PBO, n=127; fingolimod, n=511) at M12 and 450 patients (PBO, n=68; fingolimod, n=382) at M24 showed no focal activity. Fingolimod significantly reduced PBVC by 65.5% over 12M (fingolimod vs. PBO: -0.16 vs. -0.45; p=0.001) and by 48.2% over 24M (-0.42 vs. -0.81; p=0.004). An absolute difference in PBVC of -0.27% (p<0.001) in favor of fingolimod vs. PBO over 24M was still evident in the pooled ITT population, after adjusting for active lesions and on-study relapses. The regression model suggests that 54% (-0.27%/-0.51%) of effects of fingolimod on PBVC are independent of its effects on visible focal damage. CONCLUSIONS The effect of fingolimod on diffuse damage is partly independent of its treatment effect on focal damage, suggesting that both inflammatory and neurodegenerative components of MS are affected.

Defining brain volume cutoffs to identify clinically relevant atrophy in RRMS.

Objective: To define values of normalized brain volume (NBV) that can be categorized as low, medium, or high, according to baseline characteristics of relapsing-remitting multiple sclerosis (RRMS) patients. Methods: Expected NBV (eNBV) was calculated for each patient based on age, disease duration, sex, baseline Expanded Disability Status Scale (EDSS), and T2-lesion volume, entering these variables into a multiple regression model run on 2342 RRMS patients (pooled FREEDOMS/FREEDOMS-II population). According to the difference between their observed NBV and their eNBV, patients were classified as having low NBV, medium NBV, or high NBV. We evaluated whether these NBV categories were clinically meaningful by assessing correlation with disability worsening. Results: The distribution of differences between observed NBV and eNBV was used to categorize patients as having low NBV, medium NBV or high NBV. Taking the high-NBV group as reference, the hazard ratios (HRs) for 2-year disability worsening, adjusted for treatment effect, were 1.23 (95% confidence interval (CI): 0.92–1.63, p = 0.16) for the medium NBV and 1.75 (95% CI: 1.26–2.44, p = 0.001) for the low NBV. The predictive value of NBV groups was preserved over 4 years. Treatment effect appeared more evident in low-NBV patients (HR = 0.58) than in medium-NBV (HR = 0.72) and in high-NBV (HR = 0.80) patients; however, the difference was not significant (p = 0.57). Conclusion: RRMS patients can be categorized into disability risk groups based on individual eNBV values according to baseline demographics and clinical characteristics.

Fingolimod effect on gray matter, thalamus, and white matter in patients with multiple sclerosis

Objective To study the effect of fingolimod on deep gray matter (dGM), thalamus, cortical GM (cGM), white matter (WM), and ventricular volume (VV) in patients with relapsing-remitting multiple sclerosis (RRMS). Methods Data were pooled from 2 phase III studies. A total of 2,064 of 2,355 (88%) contributed to the analysis: fingolimod 0.5 mg n = 783, fingolimod 1.25 mg n = 799, or placebo n = 773. Percentage change from baseline in dGM and thalamic volumes was evaluated with FMRIB’s Integrated Registration & Segmentation Tool; WM, cGM, and VV were evaluated with structural image evaluation using normalization of atrophy cross-sectional version (SIENAX) at months 12 and 24. Results At baseline, compound brain volume (brain volume in the z block [BVz] = cGM + dGM + WM) correlated with SIENAX-normalized brain volume (r = 0.938, p < 0.001); percentage change from baseline in BVz over 2 years correlated with structural image evaluation using normalization of atrophy percentage brain volume change (r = 0.713, p < 0.001). For placebo, volume reductions were most pronounced in cGM, and relative changes from baseline were strongest in dGM. Over 24 months, there were significant reductions with fingolimod vs placebo for dGM (0.5 mg −14.5%, p = 0.017; 1.25 mg −26.6%, p < 0.01) and thalamus (0.5 mg −26.1%, p = 0.006; 1.25 mg −49.7%, p < 0.001). Reduction of cGM volume loss was not significant. Significantly less WM loss and VV enlargement were seen with fingolimod vs placebo (all p < 0.001). A high T2 lesion volume at baseline predicted on-study cGM, dGM, and thalamic volume loss (p < 0.0001) but not WM loss. Patients taking placebo with high dGM (hazard ratio [HR] 0.54, p = 0.0323) or thalamic (HR 0.58, p = 0.0663) volume at baseline were less likely to show future disability worsening. Conclusions Fingolimod significantly reduced dGM volume loss (including thalamus) vs placebo in patients with RRMS. Reducing dGM and thalamic volume loss might improve long-term outcome.

Fingolimod (FTY720) oral for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): Study design of the phase 3 FORCIDP trial

Background CIDP is an acquired immune-mediated inflammatory demyelinating disorder of the peripheral nervous system (PNS). Fingolimod (0.5 mg once daily) is an approved disease-modifying therapy for relapsing multiple sclerosis. In experimental autoimmune neuritis, a T-cell mediated disease model for human inflammatory disease of the PNS, fingolimod completely suppressed paraparesis and significantly decreased demyelination of sciatic nerves. Objective To present the design of a study to evaluate the efficacy (delaying disability progression), safety and tolerability of fingolimod 0.5 mg once daily compared with placebo in CIDP patients. Methods FORCIDP is a double-blind, randomized, multicenter, placebo-controlled, parallel-group study in ~156-200 adult patients with CIDP and a history of recent disease activity. After randomization (to either fingolimod 0.5 mg daily or placebo) and start of study drug, prior therapy will be withdrawn or tapered. The primary outcome is the time-to-first disability progression assessed by the adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale compared with placebo, in the setting of withdrawal of prior CIDP treatments (immunoglobulin or steroids). Other assessments include grip strength, Rasch-Built Linearly Weighted Overall Disability Scale, MRC Sum Score, physical examination, ECG, laboratory tests, and adverse event reporting. Treatment duration for an individual patient is flexible and will depend on patient disability status and number of disability events in the entire study population. The study will be stopped when either the minimum required number of patients meet the disability event criterion (>=1 point increase from baseline on the adjusted INCAT score) or after a maximum of 3 years after first patient enrolment, unless the study is found to be futile in an earlier interim analysis (after approx. 50 events). Conclusions This study will provide evidence for whether fingolimod can be a treatment option for patients with CIDP. This study is supported by Novartis Pharma AG, Basel, Switzerland. Disclosure: Dr. Hartung has received personal compensation for activities with Bayer Pharmaceuticals Corp., CSL Behring, Biogen Idec, Genzyme Corp., Grifols, Merck Serono, Novartis, Roche Diagnostics Corp., Teva Neuroscience, and Sanofi-Aventis Pharmaceuticals Inc. as a consultant and speaker. Dr. Sobue has received personal compensation for activities with Novartis as a committee member, and CSL Behring as a consultant. Dr. Dalakas has received personal compensation for activities with Baxter, Novartis, Grifols, CSL, Octapharma, Dysimmune Diseases Foundation, and Therapath. Dr. Dalakas has received personal compensation in an editorial capacity for Therapeutic Advances in Neurological Disorders. Dr. Dalakas has received research support from Biogen Idec, Serono, Inc., Novartis, CSL and Teva Neuroscience. Dr. Latov has received personal compensation for activities with Baxter, CSL Behring, Merck & Co. Inc., Novartis, Xenoport, and Oncogenex. Dr. Latov holds stock and/or stock options in Therapath LLC. Dr. Latov has received research support from Grifols. Dr. Leger has received personal compensation for activities with Biogen Idec, Baxter, CSL Behring, LFB Group, Novartis, Octapharma, and Pfizer Inc. as a speaker and scientific advisory board member. Dr. Leger has received personal compensation in an editorial capacity for Revue Neurologique and Presse Medicale. Dr. Leger has received research support from CSL Behring, LFB Group, Novartis, and Octapharma. Dr. Merkies has received personal compensation for activities with Talecris Pharmaceuticals as a member of the Steering Committee. Dr. Nobile-Orazio has received personal compensation for activities with CSL Behring, Baxter Laboratories, and Novartis. Dr. Agoropoulou has received personal compensation for activities with Novartis as an employee. Dr. Haering has received personal compensation for activities with Novartis as an employee. Dr. Zhang-Auberson has received personal compensation for activities with Novartis as an employee. Dr. von Rosenstiel has received personal compensation for activities with Novartis as an employee. Dr. Hughes has nothing to disclose.

Clinical Correlations of Brain Lesion Location in Multiple Sclerosis: Voxel-Based Analysis of a Large Clinical Trial Dataset

There is a limited correlation between white matter (WM) lesion load as determined by magnetic resonance imaging and disability in multiple sclerosis (MS). The reasons for this so-called clinico-radiological paradox are diverse and may, at least partly, relate to the fact that not just the overall lesion burden, but also the exact anatomical location of lesions predict the severity and type of disability. We aimed at studying the relationship between lesion distribution and disability using a voxel-based lesion probability mapping approach in a very large dataset of MS patients. T2-weighted lesion masks of 2348 relapsing-remitting MS patients were spatially normalized to standard stereotaxic space by non-linear registration. Relations between supratentorial WM lesion locations and disability measures were assessed using a non-parametric ANCOVA (Expanded Disability Status Scale [EDSS]; Multiple Sclerosis Functional Composite, and subscores; Modified Fatigue Impact Scale) or multinomial ordinal logistic regression (EDSS functional subscores). Data from 1907 (81%) patients were included in the analysis because of successful registration. The lesion mapping showed similar areas to be associated with the different disability scales: periventricular regions in temporal, frontal, and limbic lobes were predictive, mainly affecting the posterior thalamic radiation, the anterior, posterior, and superior parts of the corona radiata. In summary, significant associations between lesion location and clinical scores were found in periventricular areas. Such lesion clusters appear to be associated with impairment of different physical and cognitive abilities, probably because they affect commissural and long projection fibers, which are relevant WM pathways supporting many different brain functions.

Blinded continuous monitoring in clinical trials with recurrent event endpoints

In studies with recurrent event endpoints, misspecified assumptions of event rates or dispersion can lead to underpowered trials or overexposure of patients. Specification of overdispersion is often a particular problem as it is usually not reported in clinical trial publications. Changing event rates over the years have been described for some diseases, adding to the uncertainty in planning. To mitigate the risks of inadequate sample sizes, internal pilot study designs have been proposed with a preference for blinded sample size reestimation procedures, as they generally do not affect the type I error rate and maintain trial integrity. Blinded sample size reestimation procedures are available for trials with recurrent events as endpoints. However, the variance in the reestimated sample size can be considerable in particular with early sample size reviews. Motivated by a randomized controlled trial in paediatric multiple sclerosis, a rare neurological condition in children, we apply the concept of blinded continuous monitoring of information, which is known to reduce the variance in the resulting sample size. Assuming negative binomial distributions for the counts of recurrent relapses, we derive information criteria and propose blinded continuous monitoring procedures. The operating characteristics of these are assessed in Monte Carlo trial simulations demonstrating favourable properties with regard to type I error rate, power, and stopping time, ie, sample size.

Relapse Rate and MRI Activity in Young Adult Patients With Multiple Sclerosis: A Post Hoc Analysis of Phase 3 Fingolimod Trials

Background Disease activity differs in young patients with multiple sclerosis (MS) compared with the overall adult MS population. Objective The objective of this paper is to evaluate the effect of fingolimod 0.5 mg on disease activity in young adults with MS from three randomized, double-blind Phase 3 trials. Methods Annualized relapse rate (ARR), number of new/newly enlarging T2 lesions (neT2), and no evidence of disease activity (NEDA-3) were estimated in the intent-to-treat population at age 20 (youngest) and 30 (young) and compared to the overall population. Models used included a negative binomial regression (ARR/neT2) and a logistic regression (NEDA), with age at baseline as a continuous covariate. Results ARRs were higher in younger patients (all p < 0.05), and significantly reduced with fingolimod versus placebo or interferon beta-1a (IFN β-1a), with the percentage reduction inversely proportional to age. Fingolimod was significantly associated with a lower number of neT2 lesions versus placebo/IFN in all age groups except versus IFN in the youngest patients. Regardless of age, fingolimod-treated patients were more likely to achieve NEDA-3 versus placebo/IFN β-1a, with strongest benefits in the youngest patients (all p < 0.05). Conclusions Young adults show higher levels of MS disease activity, and may particularly benefit from fingolimod treatment compared with the overall study population.