Delaying Disability Progression Research Articles

Comparative efficacy of ofatumumab versus oral therapies for relapsing multiple sclerosis patients using propensity score analyses and simulated treatment comparisons.

Evidence from network meta-analyses (NMAs) and real-world propensity score (PS) analyses suggest monoclonal antibodies (mAbs) offer a therapeutic advantage over currently available oral therapies and, therefore, warrant consideration as a distinct group of high-efficacy disease-modifying therapies (DMTs) for patients with relapsing multiple sclerosis (RMS). This is counter to the current perception of these therapies by some stakeholders, including payers. A multifaceted indirect treatment comparison (ITC) approach was undertaken to clarify the relative efficacy of mAbs and oral therapies. Two ITC methods that use individual patient data (IPD) to adjust for between-trial differences, PS analyses and simulated treatment comparisons (STCs), were used to compare the mAb ofatumumab versus the oral therapies cladribine, fingolimod, and ozanimod. As IPD were available for trials of ofatumumab and fingolimod, PS analyses were conducted. Given summary-level data were available for cladribine, fingolimod, and ozanimod trials, STCs were conducted between ofatumumab and each of these oral therapies. Three efficacy outcomes were compared: annualized relapse rate (ARR), 3-month confirmed disability progression (3mCDP), and 6-month CDP (6mCDP). The PS analyses demonstrated ofatumumab was statistically superior to fingolimod for ARR and time to 3mCDP but not time to 6mCDP. In STCs, ofatumumab was statistically superior in reducing ARR and decreasing the proportion of patients with 3mCDP compared with cladribine, fingolimod, and ozanimod and in decreasing the proportion with 6mCP compared with fingolimod and ozanimod. These findings were largely consistent with recently published NMAs that identified mAb therapies as the most efficacious DMTs for RMS. Complementary ITC methods showed ofatumumab was superior to cladribine, fingolimod, and ozanimod in lowering relapse rates and delaying disability progression among patients with RMS. Our study supports the therapeutic superiority of mAbs over currently available oral DMTs for RMS and the delineation of mAbs as high-efficacy therapies.

A plain language summary on assessing the long-term effectiveness of cladribine tablets in people living with relapsing multiple sclerosis: The CLASSIC-MS study.

Previous studies have shown that people living with multiple sclerosis (MS) treated with cladribine tablets have fewer relapses (where new symptoms occur or existing symptoms get worse for 24hours or more) and delayed disability progression (slowing down of the disease getting worse). The CLASSIC-MS study looked at the long-term effectiveness of treatment with cladribine tablets in people living with MS who had taken part in the original CLARITY and CLARITY Extension clinical studies. Results showed that people treated with cladribine tablets maintained their mobility (the ability to move freely) for longer and experienced other positive effects long after their treatment ended, including being less likely to need further treatment for their MS. The results obtained from CLASSIC-MS show that the benefits of taking cladribine tablets carry on even when patients stop taking the treatment. Clinical Trial Registration: NCT03961204 (CLASSIC-MS) (ClinicalTrials.gov).

The socioeconomic impact of disability progression in multiple sclerosis: A retrospective cohort study of the German NeuroTransData (NTD) registry.

Multiple sclerosis (MS) is a progressively debilitating neurologic disease that poses significant costs to the healthcare system and workforce. To evaluate the impact of MS disease progression on societal costs and quality of life (QoL) using data from the German NeuroTransData (NTD) MS registry. Cross-sectional cohort study. The cost cohort included patients with MS disability assessed using Expanded Disability Status Scale (EDSS) in 2019 while the QoL cohort included patients assessed using EDSS and EuroQol-5 Dimension 5-Levels between 2009 and 2019. Direct and indirect medical, and non-medical resource use was quantified and costs derived from public sources. Within the QoL cohort (n = 9821), QoL worsened with increasing EDSS. Within the cost cohort (n = 7286), increasing resource use with increasing EDSS was observed. Societal costs per patient, excluding or including disease-modifying therapies, increased from €5694 or €19,315 at EDSS 0 to 3.5 to €25,419 or €36,499 at EDSS 4 to 6.5, and €52,883 or €58,576 at EDSS 7 to 9.5. In multivariate modeling, each 0.5-step increase in EDSS was significantly associated with increasing costs, and worsening QoL. This study confirms the major socioeconomic burden associated with MS disability progression. From a socioeconomic perspective, delaying disability progression may benefit patients and society.

The Use of Disease-Modifying Therapy (DMT) to Prevent Disability Progression in Patients with Multiple Sclerosis (MS) in Thailand

Background: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that leads to significant disability and economic burden for patients, families, the health system, and society. Objective: To describe the demographics, natural history, and effectiveness of disease-modifying therapies (DMTs) in MS patients. Materials and Methods: The present study was a retrospective cohort study of patients diagnosed with MS at the Prasat Neurological Institute, a tertiary referral neurological center in Bangkok, Thailand, between June 1, 2010 and June 30, 2020. Demographic data, clinical characteristics, and disease course of MS patients were explored. The primary outcome of the present study was a comparison of time to events of clinical relapse, new magnetic resonance image (MRI) T2W activity, new MRI T1W with gadolinium (Gd) enhancement, and time to disability progression between patients who received DMT and patients without DMT. Results: There were 102 patients diagnosed with MS. The female-to-male ratio was 2.4-to-1. The mean age at onset was 29.61±11.62 years. The phenotypic features of these patients were classified as RRMS 80.4%, SPMS 8.8%, PPMS 3.9%, and tumefactive demyelination 6.9%. Forty-eight patients (47.1%) received DMT, 28 (58.3%) received IFN-beta, 11 (22.9%) received fingolimod, seven (14.6%) received teriflunomide, and two (4.2%) received rituximab. Results demonstrated that patients who did not received DMT had significantly more clinical disability compared to patients who received DMT (HR 2.97; 95% CI 1.01 to 8.73; p=0.048). However, the times to clinical relapse and MRI activity, including new T2W and new T1W Gd enhancing lesion, were not significantly different between the two groups. Conclusion: Patients with a relapsing-remitting phenotype tended to progress to severe disability within ten years. Treatment with DMT may delay disability progression in patients with MS. Keywords: Multiple sclerosis (MS); Disease-modifying therapy (DMT)

Orchestrating a New Path for Multiple Sclerosis: Achieving Physical, Cognitive, and Emotional Rehabilitation Goals Through Physical and Music Therapy.

Interdisciplinary therapies for the management of people with multiple sclerosis (MS) are underappreciated. There is an urgent need to introduce music therapy (MT), either alone or in combination with physical therapy (PT), into clinical practice to achieve synergy with disease-modifying therapies. A holistic approach to rehabilitation for people with MS may mitigate symptoms and reduce polypharmacy, potentially lowering health care costs. As MS progresses, patients experience a range of worsening symptoms, and many develop psychosocial comorbidities. As disease-modifying therapies delay disability progression, nonpharmacologic treatments become increasingly important. The main aim of PT is to improve or maintain patients' functional mobility, strength, and flexibility. Because it targets multiple functions, MT can help improve functional and psychosocial domains and may be a valuable intervention to help patients achieve the physical, cognitive, and emotional goals of PT. Exploratory studies showed that MT, alone or in combination with PT, can lead to functional improvements in mobility, balance, gait, and fatigue. Similar to PT, MT also has benefits in improving fine motor skills, cognition, learning, and memory and in providing emotional support. Both MT and PT have the potential to improve overall well-being and health-related quality of life in physically active patients with MS, and MT can provide added emotional support for those who are less able to engage in physical activity. However, MT is not typically a part of standard of care, and PT visits are limited. Nevertheless, interdisciplinary therapies should be incorporated into clinical practice.

Measuring Treatment Response in Progressive Multiple Sclerosis-Considerations for Adapting to an Era of Multiple Treatment Options.

Disability in multiple sclerosis accrues predominantly in the progressive forms of the disease. While disease-modifying treatment of relapsing MS has drastically evolved over the last quarter-century, the development of efficient drugs for preventing or at least delaying disability in progressive MS has proven more challenging. In that way, many drugs (especially disease-modifying treatments) have been researched in the aspect of delaying disability progression in patients with a progressive course of the disease. While there are some disease-modifying treatments approved for progressive multiple sclerosis, their effect is moderate and limited mostly to patients with clinical and/or radiological signs of disease activity. Several phase III trials have used different primary outcomes with different time frames to define disease progression and to evaluate the efficacy of a disease-modifying treatment. The lack of sufficiently sensitive outcome measures could be a possible explanation for the negative clinical trials in progressive multiple sclerosis. On the other hand, even with a potential outcome measure that would be sensitive enough to determine disease progression and, thus, the efficacy or failure of a disease-modifying treatment, the question of clinical relevance remains unanswered. In this systematic review, we analyzed outcome measures and definitions of disease progression in phase III clinical trials in primary and secondary progressive multiple sclerosis. We discuss advantages and disadvantages of clinical and paraclinical outcome measures aiming for practical ways of combining them to detect disability progression more sensitively both in future clinical trials and current clinical routine.

PND16 Socioeconomic Value of Ocrelizumab in the Treatment of Patients with Primary Progressive Multiple Sclerosis

Ocrelizumab is the first and only disease-modifying therapy (DMT) approved by Health Canada for patients with primary progressive multiple sclerosis (PPMS). In this study, we assess the socioeconomic benefits derived from using ocrelizumab in PPMS compared with best supportive care (BSC) in Canada. A Markov-state model based on one-point spaced Expanded Disability Status Scale (EDSS) states (0–9) was used to estimate costs associated with disease progression. EDSS at baseline and transition probabilities were derived from the ORATORIO trial and MSBase natural history study, respectively. Treatment effect on delaying disability progression was modeled through the hazard ratio for time to 24-week confirmed disability progression, which was derived from a counterfactual analysis of the ORATORIO double-blind and open-label extension phases. Societal benefits included savings in direct healthcare and non-healthcare costs, and indirect costs (including informal care and productivity loss, among others). Drug costs were excluded to focus on treatment benefits. Resource use and cost inputs at 2019 prices were derived from published studies in the multiple sclerosis space or from national statistics databases. Data on PPMS prevalence and proportion of patients receiving BSC in Canada were obtained by triangulating Canadian epidemiologic data, Roche PPMS market share forecast, and real world data from the Ocrevus patient support program. The socioeconomic value of ocrelizumab compared with BSC in Canada is estimated to be CAD$61.3 million over 5 years. These cost savings are driven by reduction in the utilization of healthcare resources and community services ($33.1 million), productivity loss ($13.8 million), and informal care ($10.8 million). Ocrelizumab for PPMS offers substantial socioeconomic benefits compared with BSC in Canada.

MAGNIMS score predicts long-term clinical disease activity-free status and confirmed disability progression in patients treated with subcutaneous interferon beta-1a

BackgroundSubcutaneous (sc) interferon (IFN) β-1a reduces relapse rates and delays disability progression in patients with MS. We examined the association of the year 1 Magnetic Resonance Imaging in MS (MAGNIMS) score with long-term clinical disease activity (CDA) -free status and confirmed disability progression in patients treated with sc IFN β-1a in PRISMS. MethodsPatients treated with sc IFN β-1a three-times-weekly (22 or 44 μg; pooled data) were classified by MAGNIMS score (0, n = 129; 1, n = 108; 2, n = 130) at year 1. Hazard ratios (HR; 95% confidence intervals [CI]) for risk of CDA and confirmed Expanded Disability Status Score (EDSS) progression were calculated by MAGNIMS score for up to 15 years of follow-up. ResultsThe risk of CDA was higher with a year 1 MAGNIMS score of 1 versus 0 (HR 1.82 [1.38–2.41]), 2 versus 0 (2.63 [2.01–3.45]) and 2 versus 1 (1.45 [1.11–1.89], all p < 0.0001). The same outcome was observed with the risk of confirmed EDSS progression (1 versus 0: 1.93 [1.23–3.02]; 2 versus 0: 2.95 [1.95–4.46]; 2 versus 1: 1.53 [1.05–2.23]; all p < 0.0001). ConclusionIn PRISMS, MAGNIMS score at Year 1 predicted risk of CDA and confirmed disability progression in sc IFN β-1a-treated patients over up to 15 years.PRISMS-15 clinicaltrial.gov identifier: NCT01034644

PND55 Socioeconomic Value of Ocrelizumab in the Treatment of Patients with Primary Progressive Multiple Sclerosis

Ocrelizumab is the only disease-modifying therapy (DMT) approved for patients with primary progressive multiple sclerosis (PPMS). We assessed benefits derived from the use of ocrelizumab in PPMS in the UK from a socioeconomic perspective, using best supportive care (BSC) as a comparator. A Markov-state model based on 1-point spaced Expanded Disability Status Scale (EDSS) states (0–9) was used to estimate costs associated with disease progression. EDSS at baseline and transition probabilities were derived from the ORATORIO trial and a natural history study, respectively. Treatment effect on delaying disability progression was modeled through the hazard ratio for time to 12-week confirmed disability progression, which was derived from a counterfactual analysis of the ORATORIO double-blind and open-label extension phases. Societal benefits included savings in direct healthcare and non-healthcare costs, and indirect costs (including informal care and productivity loss, among others). Drug costs were excluded to focus on treatment benefits. Resource use and cost inputs at 2019 prices were derived from a cross-sectional study of patients with multiple sclerosis that was published in 2017 or from national statistics databases. Data on PPMS prevalence and proportion of patients receiving BSC in the UK were obtained from Roche epidemiologic forecasts and a real-world study, respectively. The socioeconomic value of ocrelizumab versus BSC in the UK is estimated to be GBP77.2 million over 5 years. These cost savings are driven by informal care (GBP33.3 million), productivity loss (GBP16.5 million), community services (GBP14.8 million), and disability support pensions (GBP9.1 million). Data may be presented for additional countries. Ocrelizumab for PPMS offers substantial socioeconomic benefits versus BSC in the UK, suggesting that increasing the use of DMT could be of value to patients, caregivers, and healthcare systems.

Neuroprotection induced by dexpramipexole delays disease progression in a mouse model of progressive multiple sclerosis.

Drugs able to counteract progressive multiple sclerosis (MS) represent a largely unmet therapeutic need. Even though the pathogenesis of disease evolution is still obscure, accumulating evidence indicates that mitochondrial dysfunction plays a causative role in neurodegeneration and axonopathy in progressive MS patients. Here, we investigated the effects of dexpramipexole, a compound with a good safety profile in humans and able to sustain mitochondria functioning and energy production, in a mouse model of progressive MS. Female non-obese diabetic mice were immunized with MOG35-55 . Functional, immune and neuropathological parameters were analysed during disease evolution in animals treated or not with dexpramipexole. The compound's effects on bioenergetics and neuroprotection were also evaluated in vitro. We found that oral treatment with dexpramipexole at a dose consistent with that well tolerated in humans delayed disability progression, extended survival, counteracted reduction of spinal cord mitochondrial DNA content and reduced spinal cord axonal loss of mice. Accordingly, the drug sustained in vitro bioenergetics of mouse optic nerve and dorsal root ganglia and counteracted neurodegeneration of organotypic mouse cortical cultures exposed to the adenosine triphosphate-depleting agents oligomycin or veratridine. Dexpramipexole, however, was unable to affect the adaptive and innate immune responses both in vivo and in vitro. The present findings corroborate the hypothesis that neuroprotective agents may be of relevance to counteract MS progression and disclose the translational potential of dexpramipexole to treatment of progressive MS patients as a stand-alone or adjunctive therapy.

Fingolimod for Relapsing-Remitting Multiple Sclerosis: The Experience From Saudi Arabia.

Fingolimod (Gilenya, Novartis pharmaceuticals) is the first oral disease-modifying therapy for reducing the frequency of clinical relapses and delaying disability progression in patients with relapsing-remitting multiple sclerosis (RRMS). In this study, we aimed to evaluate the outcome of Saudi patients with active RRMS treated with fingolimod. We conducted a retrospective multicenter observational study at the King Abdulaziz Medical City in Jeddah and Riyadh, Saudi Arabia. The inclusion criteria consisted of patients 18 years and older who were diagnosed with RRMS according to the revised McDonald criteria who are currently receiving or received fingolimod treatment in the past for a minimum of 6 months. A total of 100 patients were treated with fingolimod. The mean ± SD duration of the disease was 9.23 ± 6.63 years. The mean ± SD duration of using fingolimod was 32.00 ± 24.83 months. The mean ± SD baseline expanded disability status scale (EDSS) score was 2.95 ± 2.58. The mean ± SD EDSS score at last follow-up was 2.95 ± 2.65. The mean ± SD annualized relapse rate was significantly reduced from 1.24 ± 1.39 at baseline to 0.43 ± 1.15 at the last follow-up (P = 0.001). In addition, radiological activity was significantly improved at follow-up magnetic resonance imaging studies when compared with the baseline. Our multicenter study provides further evidence for the efficacy of fingolimod in reducing clinical and radiological disease activity in patients with RRMS. The reduction in relapse rate, stabilization of the EDSS score, and improvement in magnetic resonance imaging images were similar to other observational studies conducted in different countries worldwide. Fingolimod seems to be well tolerated for our multiple sclerosis population.

Ocrelizumab for Treating Patients with Primary Progressive Multiple Sclerosis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

Ocrelizumab is indicated for relapsing remitting and primary progressive multiple sclerosis (RRMS and PPMS, respectively). In an appraisal undertaken by the National Institute for Health and Care Excellence (NICE), the company Roche presented the evidence for ocrelizumab used in patients with PPMS, which came from one single randomised controlled trial (RCT) comparing ocrelizumab versus placebo. Based on results from this trial, the licensed indication was restricted to patients with early PPMS in terms of disease duration and level of disability, and with imaging features characteristic of inflammatory activity. Overall, the Evidence Review Group (ERG) found that the RCT had a low risk of bias. In the post-hoc defined magnetic resonance imaging (MRI) active subgroup, matching the label indication, the risk of confirmed disability progression sustained for 12weeks (CDP-12) was significantly delayed in the ocrelizumab group compared to placebo. However, considering the same risk with progression sustained for 24weeks (CDP-24), which was deemed the most clinically relevant, the benefit from ocrelizumab did not reach statistical significance. In the same MRI active subgroup, benefits from ocrelizumab on functional outcomes and on health-related quality of life were not clearly demonstrated. A de novo Markov model was used to estimate the cost-effectiveness of ocrelizumab versus best supportive care (BSC) for treating patients with PPMS. Health states were defined by the Expanded Disability Status Scale (EDSS), ranging from 0 to 9. Disability progression was based on the MSBase natural history cohort that exhibited disease progression in the absence of disease-modifying therapy. Treatment with ocrelizumab delayed disability progression, with evidence of its clinical effectiveness obtained from the RCT. The economic analysis was undertaken from the National Health Service and Personal Social Services perspective, and the outcomes were reported in terms of life years gained and quality-adjusted life years (QALYs), with the overall results reported in terms of an incremental cost-effectiveness ratio (ICER), expressed as cost per QALY gained over a 50-year time horizon. Both costs and effects were discounted at 3.5% per annum. The company undertook deterministic one-way sensitivity analyses and scenario analyses, including probabilistic sensitivity analysis (PSA). The ERG raised several concerns, which were discussed at the appraisal committee meetings, resulting in the committee's preferences being applied and a revised economic analysis from the company. Under an approved patient access scheme with appraisal committee preferences applied, analyses yielded an ICER of approximately £78,300 per QALY. Sensitivity analysis results indicated that the treatment effect on CDP-12 had the greatest impact. Results for the PSA showed that at a willingness-to-pay threshold of £30,000 per QALY gained, ocrelizumab versus BSC had a zero probability of being cost-effective. Following new analyses submitted by the company, with a revised confidential patient access scheme, NICE recommended ocrelizumab in the treatment of early PPMS in adults with imaging features characteristic of inflammatory activity.

Patient and physician preferences for multiple sclerosis treatments in Germany: A discrete-choice experiment study.

ObjectiveTo assess heterogeneity in patient and physician preferences for multiple sclerosis treatment features and outcomes via a discrete-choice experiment.MethodPatients with self-reported multiple sclerosis and treating physicians participated in an online discrete-choice experiment. Patients, each considering a better or worse reference condition, and physicians, each considering two patient profiles, chose between hypothetical treatment profiles defined by seven attributes with varying levels: years until disability progression, number of relapses in the decade, mode of administration, dosing frequency, and risks of mild, moderate, and severe side effects. Latent class analysis was used to measure respondent preferences and identify potential subgroups with distinct preferences.ResultsDistinct treatment preferences emerged among subgroups of patients (n = 301) and physicians (n = 308). Patients in class 1 (43% of sample) were most concerned about side effects; chief concerns of class 2 patients (57%) were delaying disability progression and avoiding severe side-effect risks. The most important attributes for physicians (by class) were delaying disability (class 1, 45%), avoiding severe side-effect risks and (class 2, 33%), and avoiding all side-effect risks (class 3, 22%).ConclusionPatients and physicians have diverse preferences for multiple sclerosis treatments, reflecting heterogeneity in the disease course and available therapies and the need for shared decision making.

Preliminary Clinical Experience with Ocrelizumab, a New Recombinant Humanized Monoclonal Antibody for Multiple Sclerosis

Multiple Sclerosis (MS) is a disease affecting the central nervous system with disabling consequences. Several treatments have been identified for reducing the frequency of relapses, modifying disease course and even delaying disability progression. Ocrelizumab (Ocrevus, Roche) is a recently approved Disease Modifying Drug (DMD) for MS. We report our initial experience on patient profile and safety of consecutive patients with MS who have received ocrelizumab. A retrospective study on patients with MS in a private healthcare setting, between September 2017 and 2019. Participants received an initial dose of two ocrelizumab 300mg IV infusion, followed by one 600mg every 6 months. Data was extracted from the electronic medical records and variables assessed included gender, age, disease onset, disease course, previous medications, ocrelizumab treatment duration, adherence and adverse effects. Analysis was done using the Statistical Package for Social Sciences (SPSS). The study identified 26 patients diagnosed with MS for an average duration of 4.8 years (over 0 to 12 years) (figure 1). More than half were female patients (61.5%), with overall average age of 40 years. It was identified that 22 patients (77%) had RRMS, while five (19.2%) had PPMS (figure 2). Only two patients were lost to follow up (7.7%), with the remainder being adherent to ocrelizumab treatment for an average of 9.6 months (over 6 to 18 months) (figure 3). One hospital admission was reported from symptomatic urinary tract infection (3.8%). Furthermore, six patients (23%) were naive to treatment before the initiation of ocrelizumab, 10 (38.5%) were switched from fingolimod, with 10 (38.5%) on various other disease modifying treatments. This study provides preliminary insight into the demographics of patients with MS in Dubai. Our results demonstrate good adherence to ocrelizumab with low complication rates.

Fingolimod for Relapsing-Remitting Multiple Sclerosis: The Experience from Saudi Arabia

Fingolimod (Gilenya, Novartis pharmaceuticals) is the first oral disease-modifying therapy for reducing the frequency of clinical relapses and delaying disability progression in patients diagnosed with relapsing-remitting multiple sclerosis (RRMS). In this study, we aim to evaluate the outcome of Saudi patients with active RRMS treated with fingolimod and compare the result with other studies. We conducted a retrospective multicenter observational study involving 100 patients with RRMS at King Abdulaziz Medical City in Jeddah and Riyadh, Saudi Arabia. The inclusion criteria consisted of patients above the age of 18 years, diagnosed with RRMS according to the revised McDonald criteria, and are currently receiving or received fingolimod treatment in the past for a minimum of six months. The mean baseline expanded disability status scale (EDSS) score was 2.95±2.58 (range 1-7; median 1.75). The mean EDSS score at last follow up was 2.95±2.65 (range 1-10; median 2.00). The mean annualized relapse rate (ARR) was significantly reduced from 1.24±1.39 at baseline to 0.43±1.15 at the last follow-up (P = 0.001). In addition, radiological activity was significantly improved at follow-up magnetic resonance imaging (MRI) studies when compared to the baseline. Our multi-center study provides further evidence on the efficacy of fingolimod in reducing clinical and radiological disease activity in patients with RRMS. The reduction in relapse rate, stabilization of EDSS score, and improvement in MRI images were similar to other observational studies conducted in different countries worldwide. Fingolimod appears to be a well-tolerated for our MS population.

Clinical and MRI efficacy of sc IFN \u03b2-1a tiw in patients with relapsing MS appearing to transition to secondary progressive MS: post hoc analyses of PRISMS and SPECTRIMS

This study evaluated efficacy of subcutaneous (sc) interferon beta-1a (IFN β-1a) 44 µg 3 × weekly (tiw) in patients appearing to transition from relapsing–remitting multiple sclerosis (RRMS) to secondary progressive MS (SPMS). The PRISMS study included 560 patients with RRMS (EDSS 0–5.0; ≥ 2 relapses in previous 2 years), and the SPECTRIMS study included 618 patients with SPMS (EDSS 3.0–6.5 and ≥ 1-point increase in previous 2 years [≥ 0.5 point if 6.0–6.5]) randomly assigned to sc IFN β-1a 44 or 22 µg or placebo for 2–3 years, respectively. These post hoc analyses examined five subgroups of MS patients with EDSS 4.0–6.0: PRISMS (n = 59), PRISMS/SPECTRIMS (n = 335), PRISMS/SPECTRIMS with baseline disease activity (n = 195; patients with either ≥ 1 relapse within 2 years before baseline or ≥ 1 gadolinium-enhancing lesion at baseline), PRISMS/SPECTRIMS without baseline disease activity (n = 140), and PRISMS/SPECTRIMS with disease activity during the study (n = 202). In the PRISMS and PRISMS/SPECTRIMS subgroups, sc IFN β-1a delayed disability progression, although no significant effect was observed in PRISMS/SPECTRIMS subgroups with activity at baseline or activity during the study (regardless of baseline activity). In the PRISMS/SPECTRIMS subgroup, over year 1 (0–1) and 2 (0–2), sc IFN β-1a 44 µg tiw significantly reduced annualized relapse rate (p ≤ 0.001), and relapse risk (p < 0.05) versus placebo. Similar results were seen for the PRISMS/SPECTRIMS with baseline disease activity subgroup. Subcutaneous IFN β-1a reduced T2 burden of disease and active T2 lesions in the PRISMS/SPECTRIMS subgroups overall, with and without baseline activity. In conclusion, these post hoc analyses indicate that effects of sc IFN β-1a 44 µg tiw on clinical/MRI endpoints are preserved in a patient subgroup appearing to transition between RRMS and SPMS.

Bayesian inference for a principal stratum estimand to assess the treatment effect in a subgroup characterized by postrandomization event occurrence.

The treatment effect in subgroups of patients is often of interest in randomized controlled clinical trials, as this may provide useful information on how to treat which patients best. When a specific subgroup is characterized by the absence of certain events that happen postrandomization, a naive analysis on the subset of patients without these events may be misleading. The principal stratification framework allows one to define an appropriate causal estimand in such settings. Statistical inference for the principal stratum estimand hinges on scientifically justified assumptions, which can be included with Bayesian methods through prior distributions. Our motivating example is a large randomized placebo-controlled trial of siponimod in patients with secondary progressive multiple sclerosis. The primary objective of this trial was to demonstrate the efficacy of siponimod relative to placebo in delaying disability progression for the whole study population. However, the treatment effect in the subgroup of patients who would not relapse during the trial is relevant from both a scientific and patient perspective. Assessing this subgroup treatment effect is challenging as there is strong evidence that siponimod reduces relapses. We describe in detail the scientific question of interest, the principal stratum estimand, the corresponding analysis method for binary endpoints, and sensitivity analyses. Although our work is motivated by a randomized clinical trial, the approach has broader appeal and could be adapted for observational studies.

Cladribine Tablets for the First-Line Treatment of Relapsing-Remitting Multiple Sclerosis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the single technology appraisal process, the National Institute for Health and Care Excellence invited Merck to submit evidence for the clinical and cost effectiveness of cladribine tablets (cladribine) for the treatment of relapsing-remitting multiple sclerosis (RRMS). Rapidly evolving severe (RES) and sub-optimally treated (SOT) RRMS were specified by the National Institute for Health and Care Excellence as subgroups of interest. The Liverpool Reviews and Implementation Group at the University of Liverpool was the Evidence Review Group. This article summarises the Evidence Review Group’s review of the company’s evidence submission for cladribine and the Appraisal Committee’s final decision. The final scope issued by the National Institute for Health and Care Excellence listed the following disease-modifying treatments as comparators: alemtuzumab, daclizumab, fingolimod and natalizumab. At the time of the company submission, a licence was anticipated for low-dose cladribine. The main clinical evidence (the CLARITY trial) in the company submission focused on the efficacy of low-dose cladribine vs. placebo. The CLARITY trial showed a statistically significant reduction in relapse rate for cladribine in the RES-RRMS subgroup (n = 50) but not in the SOT-RRMS subgroup (n = 19). Cladribine showed a numerical, but not a statistically significant, advantage in delaying disability progression at 6 months in the RES-RRMS subgroup. Disability progression benefits could not be estimated for those in the SOT-RRMS subgroup because of few events. The Evidence Review Group’s main concern regarding the clinical evidence was the small sample size of the subgroups. To compare the effectiveness of cladribine to other disease-modifying treatments, the company conducted network meta-analyses, which showed cladribine and its comparators to be equally effective. The Evidence Review Group considered the results of the disease-modifying treatments to be unreliable because few trials were in the network. The company’s cost-effectiveness evidence showed cladribine to be cheaper and more effective than other disease-modifying treatments in the RES-RRMS arm and the SOT-RRMS arm. The results were most sensitive to treatment effect on disability progression at 6 months. The Evidence Review Group was concerned that there was insufficient evidence to conclude that cladribine was superior to placebo in delaying disability progression. The Evidence Review Group amended the company’s economic model to allow alternative estimates for the treatment effect of cladribine and its comparators on relapse rate and disability progression at 6 months. The Evidence Review Group made other changes to the company model. After implementing all the amendments, cladribine remained cost effective in the RES-RRMS and SOT-RRMS subgroups. The Appraisal Committee recognised the uncertainty in the available data but concluded that cladribine could be considered a cost-effective use of National Health Service resources.

Oral fingolimod for chronic inflammatory demyelinating polyradiculoneuropathy (FORCIDP Trial): a double-blind, multicentre, randomised controlled trial

Fingolimod is approved for the treatment of relapsing-remitting multiple sclerosis and was effective in experimental autoimmune neuritis in rats, a possible model for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We aimed to evaluate the efficacy of fingolimod in delaying disability progression in patients with CIDP who withdrew from currently effective treatments (intravenous immunoglobulin [IVIg] or corticosteroids). This double-blind, multicentre, randomised, placebo-controlled, parallel-group, event-driven study was done at 48 neurology centres in Australia, Canada, Israel, Japan, the USA, and nine countries in Europe. Participants with CIDP who were receiving IVIg or corticosteroids were randomly assigned (1:1) to once-daily oral fingolimod 0·5 mg or placebo. Owing to the event-driven design, treatment duration was flexible and could be up to 4·5 years. Randomisation was done with an automated interactive voice response-web response system and was stratified by Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale scores. Previous IVIg treatment was discontinued after one final course ending the day before the first dose of fingolimod or placebo was given, whereas corticosteroids were tapered off over 8 weeks after randomisation. The primary endpoint was time to first confirmed worsening (≥1 point increase on the adjusted INCAT disability scale score versus baseline) and was assessed in the full analysis set, which consisted of all patients who underwent randomisation and had at least one efficacy assessment for the primary analysis. The survival distribution functions of time to first worsening were estimated within each treatment group according to the Kaplan-Meier survival distribution function and compared with a stratified log-rank test. The trial is registered with ClinicalTrials.gov, number NCT01625182. Of 106 participants randomly assigned between Jan 24, 2013, and March 10, 2016, 54 received fingolimod (41 who had been receiving IVIg and 13 who had been receiving corticosteroids) and 52 received placebo (41 who had been receiving IVIg and 11 who had been receiving corticosteroids). The trial ended for futility as recommended by an independent data monitoring committee after an interim analysis when 44 confirmed worsening events had occurred. At the end of the study, the survival estimate of the proportion of participants free from confirmed worsening was not significantly different between the fingolimod group (42%, 95% CI 23-60) and the placebo group (43%, 28-59; p=0·91). Adverse events occurred in 41 (76%) participants receiving fingolimod and 44 (85%) on placebo, and serious adverse events occurred in nine (17%) and four (8%) patients, respectively. The most common adverse events with fingolimod were headache (12 [22%] patients), hypertension (ten [19%]), and extremity pain (seven [13%]). Adverse events leading to study discontinuation occurred in seven (13%) participants on fingolimod and none on placebo. Fingolimod 0·5 mg once-daily was not better than placebo for the treatment of CIDP. Future trial designs should take account of the possibility that if IVIg is stopped abruptly, some patients might relapse soon afterwards whereas others might remain in remission. Novartis Pharma.

PND40 - Assessment of the Burden of Multiple Sclerosis On Family Caregivers By Patient Disability Severity

Multiple sclerosis (MS) is a disabling disease that may require caregiving. The objective of this study is to assess the burden of MS on family caregivers by patient disability severity. This study used data from Adelphi Multiple Sclerosis Disease Specific Programme, a cross-sectional survey with caregiver-reported data in the United States and Europe between 2013 and 2016. Patient disability was categorized by the expanded disability status scale (EDSS) score as no disability (0-1.5), mild (2-3.5), moderate (4-5.5) and severe disability (>=6). The impact of MS on caregiver’s quality of life (measured by CAREQOL-MS), self-rated health, time spent on caregiving, and employment status was compared across disability severity using trend test. Approximately 35% of MS patients reported having caregivers and 76% of the caregivers were family members. A total of 2,463 family caregivers of MS patients were included: 769 (31%) for patients of no disability, 651 (26%) for mild, 537 (22%) for moderate, and 506 (21%) for severe disability. The total CAREQOL-MS scores (higher means worse) in no disability, mild, moderate, and severe disability groups were 47, 56, 65, and 71, respectively (p<0.01). Caregivers of higher patient disability level were more likely to report moderate to severe impact of providing MS care on their own health (14%, 22%, 35%, 42%, p<0.01). As the patient disability increased, caregivers spent more hours per day providing care (1.9, 3.1, 4.2, 5.9, p<0.01) and more employed caregivers reported work productivity as impacted(29%, 45%, 63%, 71%, p<0.01). The majority of reported caregivers were family members. Caregivers of MS patients with more severe disability had poorer quality of life, self-rated health, and productivity. Controlling or delaying disability progression in MS patients is essential to reduce the family caregiver burden.