Background

Ocrelizumab (Ocre) is an anti-CD20 monoclonal antibody with a known major depleting effect on B cells and marginal on T cells. It is approved for clinical use in highly-active naïve multiple sclerosis (MS) patients and those not responder to previous treatment. In MS patients switching from other drugs prolonged dysfunction of adaptive immune system may occur after discontinuation, posing the need to carefully investigate the safety profile of treatment sequencing.

Objectives

To investigate the B and T cells subsets longitudinal dynamic during treatment with Ocre in patients with MS switching from Fingolimod (FTY) and other treatments (Dimetylfumarate, Interferon Beta, Glatiramer Acetate, Natalizumab, Teriflunomide) compared to naïve patients.

Methods

A multicenter observational 2-year study was conducted in patients starting treatment with Ocre grouped in three arms: naïve (naïve), switching from FTY (pre-FTY), switching from other treatments (other). Data about lymphocyte subtype count (CD3+, CD4+, CD8+ and CD20+) were collected at baseline and every 6 months after starting Ocre. Slope of reduction and proportion of patients with lymphocytes count below the normal lower limit was calculated.

Results

A sample of 135 patients was analysed (37 pre-FTY, 64 other, 34 naïve). At baseline pre-FTY compared to naïve showed significant decrease of CD3+ (1204.54+675.37 cells/mm3 vs 1735.53+653.56, p=0.0003), CD4+ (551.91+254.42 vs 997.03+352.79, p<0.0001), CD8+ (430.38+379.73 vs 537.75+254.34, p=0.027) and CD20+ (88.25+90.94 vs 191.32+149.62, p=0.021) cells. During Ocre the slope of reduction of CD3+ in naïve patients was 5.45 cells/mm3/week (p=0.003). Compared to naïve, the rate of decrease in CD3+ was -1.2 cells/mm3/week in pre-FTY (p=0.087) and +0.19 (p=0.012) in other. The slope of reduction of CD4+ was 2.00 cells/mm3/week in naïve (p=0.072). Compared to naïve the rate of reduction in CD4+ was +0.91 cells/mm3/week in pre-FTY (p=0.061) and +1.70 cells/mm3/week (p=0.012) in other. CD8+ and CD20+ cells decrease was similar among groups (p for interaction between time and treatment = 0.184 and 0.108, respectively). In pre-FTY group compared to baseline the proportion of patients with CD3+ and CD4+ cells lymphopenia was unchanged (16.22% versus 17.14% ; 32.35% versus 34.29%), while the proportion of CD8+ cells was increased (8.82% versus 25.71%).

Conclusions

Our study confirms that Ocre may induce depletion of T cell subsets beyond B cells. Nevertheless, in pre-FTY we also observed a prolonged T- lymphocytopenia , as carry-over effect of the previous therapy. FTY-induced immunosenescence or slow immunoreconstitution may explain this finding.

Abstract

Personalized medicine is the tailoring of treatment to the individual characteristics of patients. Once a treatment has been tested in a clinical trial and its effect overall quantified, it would be of great value to be able to use the baseline patients’ characteristics to identify patients with larger/lower benefits from treatment, for a more personalized approach to therapy.
I will show a previously published statistical method, aimed at identifying patients’ profiles associated
to larger treatment benefits applied to randomized clinical trials in multiple sclerosis, demonstrating the possibility to refine and personalize the treatment effect estimated in randomized studies by using the baseline demographic and clinical characteristics of the included patients. The
method can be applied to any randomized trial in any medical condition to create a treatment-specific score associated to different levels of response to the treatment tested in the trial. This is an easy and affordable method toward therapy personalization, indicating patient profiles related to a larger benefit from a specific drug, which may have implications for taking clinical decisions in everyday clinical practice.

Abstract

Personalized medicine is the tailoring of treatment to the individual characteristics of patients. Once a treatment has been tested in a clinical trial and its effect overall quantified, it would be of great value to be able to use the baseline patients’ characteristics to identify patients with larger/lower benefits from treatment, for a more personalized approach to therapy.
I will show a previously published statistical method, aimed at identifying patients’ profiles associated
to larger treatment benefits applied to randomized clinical trials in multiple sclerosis, demonstrating the possibility to refine and personalize the treatment effect estimated in randomized studies by using the baseline demographic and clinical characteristics of the included patients. The
method can be applied to any randomized trial in any medical condition to create a treatment-specific score associated to different levels of response to the treatment tested in the trial. This is an easy and affordable method toward therapy personalization, indicating patient profiles related to a larger benefit from a specific drug, which may have implications for taking clinical decisions in everyday clinical practice.

Abstract

Personalized medicine is the tailoring of treatment to the individual characteristics of patients. Once a treatment has been tested in a clinical trial and its effect overall quantified, it would be of great value to be able to use the baseline patients’ characteristics to identify patients with larger/lower benefits from treatment, for a more personalized approach to therapy.
I will show a previously published statistical method, aimed at identifying patients’ profiles associated
to larger treatment benefits applied to randomized clinical trials in multiple sclerosis, demonstrating the possibility to refine and personalize the treatment effect estimated in randomized studies by using the baseline demographic and clinical characteristics of the included patients. The
method can be applied to any randomized trial in any medical condition to create a treatment-specific score associated to different levels of response to the treatment tested in the trial. This is an easy and affordable method toward therapy personalization, indicating patient profiles related to a larger benefit from a specific drug, which may have implications for taking clinical decisions in everyday clinical practice.

Background

SARS-COV-2 pandemic poses an imminent threat to humanity and in particular in those people suffering chronic diseases. Immune-mediated disease, as NMOSD and MOGAD, could be at a higher risk of severe forms of COVID-19 both for the disease itself and for immunosuppressive treatments.

Objectives

To evaluate the prevalence and severity of COVID-19 infection in the NMOSD/MOGAD population in Italy and evaluate possibily risk factors for disease outcomes.

Methods

The MS Study Group of the Italian Neurological Society has set up a proactive programme to provide information about COVID-19 in NMOSD/MOGAD patients, using a semistructured survey.

Results

569 NMOSD/MOGAD patients from 40 Italian MS Centres have been censored for COVID-19.

68% (387/569) of the patients were treated with rituximab, 16% (91/569) with azathioprine, 4.4% (25/569) with tocilizumab, 5.4% (31/569) with other therapies and 6.2% (35/569) were untreated or without information.

8/569 patients (1.4%) were diagnosed having confirmed or highly suspected COVID-19: positive rhino-pharyngeal swabs for SARS-CoV-2 were found in 4 out of 6 tested patients.

At the time of data collection, 6 patients recovered, 1 was still hospitalised and, unfortunately, 1 died. Hospitalisation was required for 3 patients.

5/8 (68%) patients were treated with rituximab. There was no evidence of any difference of such a percentage with the one of the overall population (OR=0.78, 95%CI=0.18-3.31, p=0.74).

COVID-19 infection was classified mild in 5, severe in 2 and critical in 1. The main experienced symptoms were fever, cough, fatigue and shortness of breath. 5/8 patients experienced CNS symptoms as headache (3), dizziness (1), anosmia (1) and delirium (1).

Conclusions

1) the prevalence of COVID-19 infection appears low in NMOSD/MOGAD patients (1.9%) with a mortality rate similar to that of the general italian population (12.5% vs 14.3%);

2) no other risk factors for severe course of COVID-19 than those already known emerge;

3) the baseline use of biologics, and in particular anti-CD20 monoclonal antibodies, is not associated with a higher risk of COVID-19 infection and apparently not with worse COVID-19 outcomes

Even if preliminary, these findings suggest a cautious optimism in the care of these autoimmune conditions during the pandemic phase.

The MS Study Group: M Inglese, A Di Sapio, D Vecchio, P Cavalla, A Protti, M Radaelli, S Malagu', A Gajofatto, D Landi, G Marfia, MP Amato, A Lugaresi, C Scandellari, S Bonavita, P Perini, F Rinaldi, D Centonze, S Di Lemme, P Immovilli, U Aguglia, M Zaffaroni, S Montepietra, L Moiola, M Filippi, MT Ferro', M Salvetti, MC Buscarinu, F Granella, M Dotta, M Mirabella, M Lucchini, G De Luca, C Tortorella, C Gasperini, G Maniscalco, D Ferraro, E Cocco, R Bergamaschi, M Ulivelli, P Valentino, M Falcini, L Brambilla, G Lus, M De Riz, M Trojano, P Ragonese, A Bertolotto

Background

Prevention of disability over the long-term is the main treatment goal in multiple sclerosis (MS), however, randomized clinical trials provide only short-term (3-6-month) treatment effect on disability.

Objectives

To externally validate the previously developed sustained progression score which established 6-month confirmed disability progression events as indicators of long-term disability worsening in randomized double-blind CLARITY (Cladribine Tablets Treating MS Orally) trials. A higher score indicates a greater probability of a progression event to be sustained over the long-term.

Methods

Data from the CLARITY and CLARITY 2-year Extension study were used. The 3-and 6-month confirmed disability progression events and the time over which progression remained sustained were identified. Patient characteristics at the time of progression previously associated with the likelihood of improvement after confirmed progression event (age, primary progressive MS, a relapse in previous month, expanded disability status scale score≥6 and its change from baseline, number of affected functional system domains, and worsening in pyramidal, brainstem and sensory domains) were used to calculate the sustained progression score for each progression event. A Cox proportional hazards model was used to validate the association of the score calculated for each 6-month confirmed disability progression event with time to improvement. To demonstrate application of the score in trial setting, the analysis of the CLARITY study were repeated estimating the effect of therapy on long-term disability outcomes. Effect of cladribine on 3-month confirmed progression events with any score and score˃1.5 was evaluated.

Results

A total of 667 6-month confirmed disability progression events were identified in the combined dataset, of which only 12 were followed by a 6-month confirmed disability improvement. The external validation of the score illustrated a trend towards a decrease in the likelihood of disability improvement in progression events with higher score (Hazard Ratio HR=0.72, 95% CI: 0.21-2.42). Results of the original trial were confirmed in addition to that oral cladribine reduced the risk of disability progression that was likely to be sustained over the long-term (only events with score˃1.5; HR: 0.64; 95% CI: 0.47-0.87).

Conclusions

The sustained progression score, estimated using the characteristics of confirmed progression events, provides important complementary information that will allow future trials to establish the effect of therapy not only on short-term but also on long-term disability accrual.

Background

In CLARITY, treatment with cladribine tablets 10 mg (cumulative dose 3.5 mg/kg over 2 years [CT3.5]) significantly reduced relapse rates and slowed disability progression versus placebo in RRMS patients. A key question is to evaluate whether and for how long cladribine tablets can improve EDSS scores.

Objectives

To evaluate post hoc long-term prevalence of disability improvement assessed by Expanded Disability Status Scale (EDSS) score in relapsing-remitting multiple sclerosis (RRMS) patients treated with cladribine tablets enrolled into CLARITY Extension.

Methods

Patients enrolled into CLARITY Extension were included and pooled by early (CT3.5 in CLARITY then CT3.5 or placebo in CLARITY Extension; n = 284), versus delayed (placebo in CLARITY then CT3.5 in CLARITY Extension; n = 244) treatment. Disability improvement was defined as a decrease in EDSS from baseline of ≥ 1 point for baseline EDSS < 5.5, or ≥ 0.5 points for baseline EDSS ≥ 5.5, confirmed at 6 months. Improvement was considered lost when EDSS returned to ≥ baseline (regression of improvement confirmed at 6 months). Prevalence of improved EDSS was estimated by a new statistical approach, accounting for not only the onset of improvement but also the duration. Prevalence was estimated as the difference between the Kaplan-Meier (KM) estimators for the probability of having an improvement before time t and the probability of returning to baseline before time t. P values were estimated using a bootstrap technique on the area under the modified KM curve.

Results

The prevalence of disability improvement (KM estimate) for the early versus delayed treatment groups at 2-years post-CLARITY baseline was 15.6% (95% confidence interval [CI]: 11.9–19.3) versus 9.3% (95% CI: 6.1–12.4), respectively and at 5-years was 12.7% (95% CI: 8.8–16.6) versus 8.6% (95% CI: 4.8–12.4), respectively (early versus delayed treatment group: P = 0.048 for 5-years difference).

Conclusions

Patients receiving early treatment with cladribine tablets had a greater prevalence of disability improvement over 5 years versus those with delayed treatment.

Background

Preventing multiple sclerosis (MS) disease progression is critical in preserving function and quality of life. Fenebrutinib is a potent, highly selective Bruton’s tyrosine kinase (BTK) inhibitor with a dual mechanism of action. Fenebrutinib targets acute and chronic aspects of MS by decreasing B-cell activation and limiting myeloid proinflammatory responses. This profile and studies of fenebrutinib in patients with other inflammatory diseases suggest a potentially favorable benefit-risk ratio, although there are no studies yet in patients with MS.

Objectives

To describe the unique design aspects of the Phase III fenebrutinib clinical trial program as they relate to understanding disease progression across the MS spectrum.

Methods

We developed a Phase III program that will assess disease progression in two identical clinical trials in relapsing MS (RMS) and one trial in primary progressive MS (PPMS).

Results

To understand the effects of fenebrutinib on disease progression, all three trials include 12-week composite Confirmed Disability Progression (cCDP12) as a primary endpoint; the RMS trials also include annualized relapse rate as a co-primary endpoint. The cCDP12 requires at least one of the following: (1) an increase in Expanded Disability Status Score (EDSS) score of ≥1.0 point from a baseline (BL) score of ≤5.5 points, or a ≥0.5 point increase from a BL score of >5.5 points; (2) a 20% increase from BL in time to complete the 9-Hole Peg Test; (3) a 20% increase from BL in the Timed 25-Foot Walk Test. The cCDP12 is a more sensitive assessment of disability than the EDSS, especially at early disease stages, as it provides a quantitative assessment of upper limb function. Comparator arms will include active disease-modifying treatments with known effects on disability progression (PPMS=ocrelizumab; RMS=teriflunomide). Treatment assignments will be 1:1, with estimated enrollment of 734 patients in each of the RMS trials and 946 in the PPMS trial. Study durations will be event driven, with the primary analysis occurring after a prespecified number of cCDP12 events (≥96 or ≥120 weeks in the RMS and PPMS trials, respectively).

Conclusions

Fenebrutinib will be investigated in RMS and PPMS and may offer a unique approach to slowing disease progression in MS. Furthermore, the use of the cCDP12 as a primary endpoint may provide a clearer, more complete picture of disability progression or improvement than the EDSS alone.

Background

Ocrelizumab (OCR) is approved for the treatment of relapsing (RMS) and primary progressive multiple sclerosis (PPMS) at a dose of 600 mg iv twice yearly and showed significant benefit on disability progression (DP). Exposure-response (ER) analyses of the pivotal OCR Phase III studies in patients with RMS or PPMS showed that those with higher exposures (based on individual mean serum concentration [Cmean] exposure quartiles) had a greater benefit on DP vs patients with lower exposure, without an increase in adverse events. While doses of OCR of 1000–2000 mg were studied in a Phase II study, doses >600 mg have not been investigated in Phase III studies in RMS or PPMS patients.

Objectives

To present the OCR higher dose selection rationale and design of two double-blind, parallel-group, randomized Phase IIIb studies (one in RMS and one in PPMS) aiming to explore if a higher dose of OCR will provide even higher benefits vs 600 mg on DP without adversely affecting the established favorable benefit-risk profile.

Methods

The higher dose of OCR in both studies is based on achieving a Cmean of at least that observed in the highest exposure quartile of the Phase III ER analyses while limiting Cmean below that observed with the highest OCR dose of 2000 mg in the Phase II study that had a similar safety profile, except for a slightly higher incidence of infusion-related reactions (pre-medication: methylprednisolone only; no mandatory antihistamine).

Results

Modeling predicts that doses of 1200 mg (patients <75kg) or 1800 mg (patients ≥75kg) twice yearly would fulfill these criteria. Based on data from the pivotal trials, the expected risk reduction vs 600 mg in 12-week composite confirmed DP (cCDP; consisting of time to progression measured by the EDSS, Timed 25-Foot Walk or 9-Hole Peg Test) would be ≥35% in RMS and ≥27% in PPMS. Patients with RMS (EDSS score 0–5.5; N=786) or PPMS (EDSS score ≥3.0–6.5; N=699) will be randomized (2:1) to either the higher dose (above) or OCR 600 mg administered every 24 weeks (first dose divided into 2 infusions separated by 14 days) for ≥120 weeks (minimum 5 doses).

The primary outcome for both trials is risk reduction on cCDP. Immunoglobulin and oligoclonal bands in the CSF will be assessed in a sub-study of up to 288 patients.

Conclusions

These studies will test if higher-dose ocrelizumab provides an even higher benefit on cCDP vs the approved 600 mg dose without adversely affecting the established favorable benefit-risk profile.

Background

It is increasingly understood that grey matter (GM) atrophy is associated with disability progression and cognitive decline in patients with multiple sclerosis (MS). Previously, we demonstrated that treatment with cladribine tablets 3.5 mg/kg bodyweight (CT3.5; cumulative dose over 2 years) in the CLARITY study (NCT00213135) decreased brain atrophy compared with placebo, which was closely associated with a lower risk of disability progression [De Stefano et al. MSJ 2018].

Objectives

Post hoc evaluation of GM and white matter (WM) volume changes in patients with relapsing MS randomized to CT3.5 or placebo in the CLARITY study.

Methods

Images from pre-gadolinium T1-weighted magnetic resonance imaging scans of patients randomized to CT3.5 or placebo for 2 years in CLARITY were evaluated using SIENA-XL software. Images from 0–6 months (CT3.5, n=267; placebo, n=265) were analyzed independently of images from 6–24 months (CT3.5, n=184; placebo, n=186) to account for the potential effects of pseudoatrophy. Annualized mean changes in percentage of GM volume (PGMV) or WM volume (PWMV) between CT3.5 and placebo for 0–6 and 6–24 months were compared using a variance model.

Results

CT3.5 reduced GM and WM volume vs placebo in the first 6 months, consistent with pseudoatrophy [PGMV change: CT3.5 -0.53 vs placebo -0.25 (p=0.045); PWMV change: CT3.5 -0.49 vs placebo -0.34 (p=0.137)]. Brain volume loss from 6–24 months was reduced in patients randomized to CT3.5 with the difference between CT3.5 and placebo significant for GM [PGMV change: CT3.5 -0.90 vs placebo -1.27 (p=0.026); PWMV change: CT3.5-0.32 vs placebo -0.40 (p=0.52)].

Conclusions

Volume loss reduction in WM and, particularly, in GM was noted from 6-24 months in CT3.5-treated patients vs placebo, after a period of pseudoatrophy (0-6 months). Such findings suggest that CT3.5 significantly reduces brain atrophy predominantly in the GM, an effect that may contribute to lower risk of disability progression.

Background

Understanding whether multiple sclerosis (MS) can have a favorable course is still challenging. However, a small group of patients who are not disabled after many years of disease can be identified. The mechanisms responsible for this ‘benign’ clinical course remain unclear, likely due to the lack of long-term studies.

Objectives

To assess brain damage in multiple sclerosis patients with no or minimal disability after a longstanding clinical course.

Methods

We compared 13 patients with long-term benign clinical course (LT-BMS, age >55 years, disease duration >30 years, Expanded Disability Status Scale [EDSS] <3.0) and 27 non-benign MS (non-BMS) patients (age >55 years, EDSS >3.0). MRI scans were retrospectively assessed (mean follow-up: 11 years, mean scan per patient: 3). Comparisons of brain volumes (BV) and total T2-lesion volume (LV) changes between the two groups were performed using a mixed effect model. Lesion probability maps (LPMs) of both groups were compared using a nonparametric permutation test.

Results

Patients with LT-BMS showed less over-time decrease in global BV (p=0.02) and grey matter (GM) volume (p<0.001) than non-BMS. Lower atrophy was seen in LT-BMS with no or mild cognitive impairment. By contrast, there was no over-time difference between patient groups in T2-LV accumulation and lesion frequency across brain.

Conclusions

Global brain and GM atrophy changes were mild in this unique patient group with long-standing and no or minimal physical and cognitive disability. These results support the relevant role of GM atrophy in characterizing MS patients who may have favorable long-term disease evolution.

Background

To date, no studies have explored the relationship between brain atrophy and MS disability using differing MRI protocols and scanners at multiple sites.

Objectives

To assess the association between brain atrophy and MS disability, as measured by EDSS and 6-month confirmed disability progression (CDP).

Methods

In this retrospective study at 4 MS centres, a total of 1300 patients had brain MRI imaging assessed by icobrain. Relapse-onset MS patients were included if they had two clinical MRIs 12 (±3) months apart and ≥2 EDSS scores post MRI-2, the first ≤3 months from MRI-2, with ≥6 months between first and last EDSS. Volumetric data were analysed if the alignment similarity between two images was as good as that of same-scanner scan-rescan images (normalised mutual information ≥0.2). The percentage brain volume change (PBVC), percentage grey matter change (PGMC), FLAIR lesion volume change, whole brain volume, grey matter volume, FLAIR lesion volume and T1 hypointense lesion volume at MRI-2 were calculated. Ordinal mixed effect models were used to determine the association between these volumetric MRI measures and all EDSS scores post MRI-2. Cox proportional hazards models were used for the 6-month CDP outcome, using a subset of patients with ≥3 EDSS. Models were adjusted for proportion of time spent on disease-modifying therapy during MRIs ± whole brain/grey matter volume at baseline MRI.

Results

Of the 260 relapse-onset MS patients included, 204 (78%) MRI pairs were performed in the same scanner and 56 (22%) pairs were from different scanners. During the follow-up period (median 3.8 years, range 1.3-8.9), 29 of 244 (12%) patients experienced 6-month CDP. There was no evidence for association between annualised PBVC or PGMC and CDP or EDSS (p>0.05). Cross-sectional whole brain and grey matter volume (at MRI-2) tended to associate with CDP (HR 0.99, 95% CI 0.98-1.00, p=0.06). Every 1ml of whole brain or grey matter volume lost represented a 1% higher chance of reaching 6-month CDP. Only whole brain volume (at MRI-2) was associated with EDSS score (β -0.03, SE 0.01, p<0.001) and the slope of EDSS change over time (β -0.001, SE 0.0003, p=0.02). On average, every 33ml reduction of brain volume was associated with a 1 step increase in EDSS.

Conclusions

In this real-world clinical setting where a fifth of the brain atrophy analysis were performed on different scanners, we found no association between individual brain atrophy and MS disability. However, there was an association between cross-sectional whole brain volume with EDSS and slope of EDSS change.

Background

Extending the natalizumab interval after the 24th administration could reduce the risk of progressive multifocal leukoencephalopathy (PML) without efficacy reduction.

Objectives

To evaluate the non-inferiority of the efficacy of an extended interval dosing (EID) regimen compared with the standard interval dosing (SID) of natalizumab regarding the multiple sclerosis (MS) MRI activity.

Methods

It is an observational, multicenter (14 Italian centers), retrospective cohort study, starting from the 24th natalizumab infusion to the loss of follow-up or 2 years after baseline. Patients were grouped in 2 categories according to the mean number of weeks between doses: < 5 weeks, SID; ≥ 5 weeks, EID. Three hundred and eight patients were enrolled. Median dose interval (MDI) following 24th infusion was 5 weeks, with a bimodal distribution (modes at 4 and 6 weeks).

Results

Two hundred and sixteen patients were in the SID group (MDI = 4.4 weeks) and 144 in the EID group (MDI 6 weeks). The risk to develop active lesions on MRI is similar in SID and EID groups during the 6 and 12 months after the 24th natalizumab infusion, respectively 2.98% (95% CI: 0.56-5.40) vs 3.32% (95% CI: 0.00-6.65%) [p=0.88] and 6.65% (95% CI: 3.02-10.29) vs 5.67% (95% CI: 1.76-9.58%) [p=0.73]. The EID regimen does not increase the occurrence of MRI activity after 6 and 12 months.

Conclusions

There is no evidence of a reduced efficacy of natalizumab in an EID setting regarding the MRI activity. This observation confirms previous clinical results and together with the increasing evidence of a reduced risk of PML associated to an EID regimen, supports the need of a bigger randomized study to assess the need to change the standard of the natalizumab dosing schedule, in order to better manage JCV-positive patients after 24 doses of natalizumab.

Abstract

I will present how to analyse improvement in MS studies and the maning of univariate and multivariate analysis in MS studies.

Background

In CLARITY, treatment with cladribine tablets 10 mg (cumulative dose 3.5 mg/kg over 2 years [CT3.5]) significantly reduced relapse rates and slowed disability progression versus placebo in RRMS patients. A key question is to evaluate whether and for how long cladribine tablets can improve EDSS scores.

Objectives

To evaluate post hoc long-term prevalence of disability improvement assessed by Expanded Disability Status Scale (EDSS) score in relapsing-remitting multiple sclerosis (RRMS) patients treated with cladribine tablets enrolled into CLARITY Extension.

Methods

Patients enrolled into CLARITY Extension were included and pooled by early (CT3.5 in CLARITY then CT3.5 or placebo in CLARITY Extension; n = 284), versus delayed (placebo in CLARITY then CT3.5 in CLARITY Extension; n = 244) treatment. Disability improvement was defined as a decrease in EDSS from baseline of ≥ 1 point for baseline EDSS < 5.5, or ≥ 0.5 points for baseline EDSS ≥ 5.5, confirmed at 6 months. Improvement was considered lost when EDSS returned to ≥ baseline (regression of improvement confirmed at 6 months). Prevalence of improved EDSS was estimated by a new statistical approach, accounting for not only the onset of improvement but also the duration. Prevalence was estimated as the difference between the Kaplan-Meier (KM) estimators for the probability of having an improvement before time t and the probability of returning to baseline before time t. P values were estimated using a bootstrap technique on the area under the modified KM curve.

Results

The prevalence of disability improvement (KM estimate) for the early versus delayed treatment groups at 2-years post-CLARITY baseline was 15.6% (95% confidence interval [CI]: 11.9–19.3) versus 9.3% (95% CI: 6.1–12.4), respectively and at 5-years was 12.7% (95% CI: 8.8–16.6) versus 8.6% (95% CI: 4.8–12.4), respectively (early versus delayed treatment group: P = 0.048 for 5-years difference).

Conclusions

Patients receiving early treatment with cladribine tablets had a greater prevalence of disability improvement over 5 years versus those with delayed treatment.

Abstract

I will present how to analyse improvement in MS studies and the maning of univariate and multivariate analysis in MS studies.

Abstract

I will present how to analyse improvement in MS studies and the maning of univariate and multivariate analysis in MS studies.