scholarly journals Clinical trials in multiple sclerosis: potential future trial designs

2019 ◽  
Vol 12 ◽  
pp. 175628641984709 ◽  
Author(s):  
Navid Manouchehri ◽  
Yinan Zhang ◽  
Amber Salter ◽  
Rehana Z. Hussain ◽  
Hans-Peter Hartung ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Study Groups ◽  
Response To Treatment ◽  
Disease Biomarkers ◽  
Disease Modifying Therapies ◽  
Early Validation ◽  
Response Profiles ◽  
New Treatments ◽  
Individual Disease

Clinical trials of new treatments in multiple sclerosis (MS) currently require large sample sizes and long durations in order to yield reliable results. The differential responses of an already heterogeneous population of MS patients to individual disease-modifying therapies (DMTs) will further complicate future trials. MS trials with smaller samples and faster outcomes are conceivable through the substitution of current clinical and MRI outcomes with objectively measureable genomic and proteomic biomarkers. Currently, biomarkers that could be utilized for diagnosis and monitoring of MS disease activity are in the early validation phase. The power of single biomarkers or multiple correlated biomarkers to predict prognosis and response to treatment could initially be compared with currently accepted methods. These prospectively validated disease biomarkers could then be used to subcategorize the spectrum of MS patients into a finite number of endophenotypes with demonstrable different molecular pathogeneses and DMT response profiles. Newly developed DMT could potentially be assessed within specific endophenotypes and compared with pharmacogenomically relevant active comparator DMT. This approach may increase the efficiency of MS trials through homogenization of patient population and minimization of nonresponders in study groups, providing the potential for the development of targeted therapies.

scholarly journals Disability improvement as a clinically relevant outcome in clinical trials of relapsing forms of multiple sclerosis

2021 ◽  
pp. 135245852110002
Author(s):  
Bruce AC Cree ◽  
Jeffrey A Cohen ◽  
Anthony T Reder ◽  
Davorka Tomic ◽  
Diego Silva ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Therapeutic Benefit ◽  
Disease Modifying Therapies ◽  
Long Term Follow Up ◽  
Post Hoc ◽  
Switch Group ◽  
Relevant Outcome

Background: Disease-modifying therapies (DMTs) can reduce the risk of disability worsening in patients with relapsing forms of multiple sclerosis (RMS). High-efficacy DMTs can lead to confirmed or sustained disability improvement (CDI and SDI). Objective and Methods: Post hoc analyses of data from the TRANSFORMS, FREEDOMS, and FREEDOMS II trials and their extensions assessed the effects of fingolimod (0.5–1.25 mg/day) on stabilizing or improving disability over ⩽8 years in participants with RMS. CDI and SDI rates were compared between participants initially randomized to fingolimod, interferon (IFNβ-1a), or placebo. Results: At 8 years’ follow-up in TRANSFORMS, 35.1% (95% confidence interval [CI], 28.2%–43.1%) of assessed participants in the IFNβ-1a–fingolimod switch group and 41.9% (36.6%–47.6%) on continuous fingolimod experienced CDI; disability did not worsen in approximately 70%. Similar results were seen in the combined FREEDOMS population. Proportionally fewer TRANSFORMS participants achieved SDI in the IFNβ-1a–fingolimod switch group than on continuous fingolimod (5.4% [3.0%–9.5%] vs 14.2% [10.8%–18.4%], p = 0.01). Conclusion: CDI and SDI are outcomes of interest for clinical trials and for long-term follow-up of participants with RMS. Monitoring CDI and SDI in addition to disability worsening may facilitate understanding of the therapeutic benefit of RMS treatments.

scholarly journals Predictors of adherence and persistence to disease-modifying therapies in Multiple Sclerosis

2021 ◽  
Vol 14 ◽  
pp. 175628642110310
Author(s):  
Gisela Zanga ◽  
Estefania Drzewiscki ◽  
Paula Tagliani ◽  
Maximiliano Smietniansky ◽  
Maria M. Esnaola y Rojas ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Medication Possession Ratio ◽  
Care Program ◽  
Cross Sectional Study ◽  
Response To Treatment ◽  
Cross Sectional ◽  
National Medical ◽  
Disease Modifying Therapies ◽  
Disease Modifying ◽  
Predictors Of Adherence

Background and Aims: In multiple sclerosis (MS), non-adherence/non-persistence is related to suboptimal response to treatment, including disease relapses and the need for more expensive healthcare. The aim of this study was to identify predictors related to adherence to disease modifying therapies (DMTs) in a cohort of Argentinian MS patients. Methods: We conducted a cross-sectional study at the National Medical Care Program from Argentina. MS patients with at least one claim for a DMT from 1 January 2017 to 1 October 2017 were identified. A telephone survey was performed to assess clinical and demographic factors. The medication possession ratio (MPR) was used to estimate adherence; MPR <80% defined non-adherence. Associations were studied using a logistic regression model. Results: Our database included 648 MS patients. A total of 360 patients (60% females, mean age 55.3 years) accepted to participate. Of these, 308 (85.5%) patients were receiving DMT at the time of the survey. Some 198 (63.7%) were receiving injectable therapies. Optimal adherence was 47.7%. Adherence was associated with oral medication [odds ratio (OR) 1.83 95% confidence interval (CI) 1.13–3.00, p = 0.014]. A factor related to oral drugs was higher educational level (OR 2.86 95%CI 1.41–5.81, p = 0.004). Conclusion: This real-world study showed better adherence and persistence on treatment with oral therapies in MS patients in Argentina.

scholarly journals Monoclonal Antibodies in Multiple Sclerosis: Present and Future

Biomedicines ◽  
2019 ◽  
Vol 7 (1) ◽  
pp. 20 ◽  
Author(s):  
Natalia Voge ◽  
Enrique Alvarez
Keyword(s):  
Multiple Sclerosis ◽  
Monoclonal Antibodies ◽  
Morbidity Rate ◽  
High Morbidity ◽  
Disease Modifying Therapies ◽  
High Morbidity Rate ◽  
New Treatments ◽  
Near Future ◽  
Risk Ratios

The global incidence of multiple sclerosis (MS) appears to be increasing. Although it may not be associated with a high mortality rate, this disease has a high morbidity rate which affects the quality of life of patients and reduces their ability to do their activities of daily living. Thankfully, the development of novel disease modifying therapies continues to increase. Monoclonal antibodies (MABs) have become a mainstay of MS treatment and they are likely to continue to be developed for the treatment of this disease. Specifically, MABs have proven to be some of the most efficacious treatments at reducing relapses and the inflammation in MS patients, including the first treatment for primary progressive MS and are being explored as reparative/remyelinating agents as well. These relatively new treatments will be reviewed here to help evaluate their efficacy, adverse events, immunogenicity, and benefit-risk ratios in the treatment of the diverse spectrum of MS. The focus will be on MABs that are currently approved or may be approved in the near future.

scholarly journals Aging and efficacy of disease-modifying therapies in multiple sclerosis: a meta-analysis of clinical trials

2020 ◽  
Vol 13 ◽  
pp. 175628642096901
Author(s):  
Yinan Zhang ◽  
Natalia Gonzalez Caldito ◽  
Afsaneh Shirani ◽  
Amber Salter ◽  
Gary Cutter ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Disease Activity ◽  
Meta Analysis ◽  
Group Level ◽  
T2 Lesions ◽  
Disease Modifying Therapies ◽  
Level Data ◽  
Disease Modifying ◽  
Magnetic Resonance Imaging Mri

Background: Disease-modifying therapies (DMTs) for multiple sclerosis (MS) are approved for the treatment of disease activity and are effective in reducing relapses and new magnetic resonance imaging (MRI) lesions. However, disease activity generally subsides with time, and age-dependent changes in DMT efficacy are not well-established. We aimed to investigate whether age impacts the efficacy of DMTs in treating disease activity in patients with relapsing–remitting MS (RRMS). Methods: DMT efficacy related to age was assessed through a meta-analysis of clinical trials that evaluated the efficacy of DMTs in RRMS patients as measured by reductions in the annualized relapse rate (ARR), new T2 lesions, and gadolinium-enhanced lesions on MRI. Using the mean baseline patient age from each trial, a weighted linear regression was fitted to determine whether age was associated with treatment efficacy on a group level. Results: Group-level data from a total of 28,082 patients from 26 trials of 14 different DMTs were included in the meta-analysis. There were no statistically significant associations between age and reductions in ARR, new T2 lesions, and gadolinium-enhanced lesions of the treatment group compared with placebo. Conclusion: DMTs for RRMS show efficacy in treating disease activity independent of age as demonstrated by group-level data from DMT clinical trials. Nevertheless, clinical trials select for patients with baseline disease activity regardless of age, thereby not representing real-world patients with RRMS, where disease activity declines with age.

scholarly journals Advancing trial design in progressive multiple sclerosis

2017 ◽  
Vol 23 (12) ◽  
pp. 1573-1578 ◽  
Author(s):  
Robert J Fox ◽  
Jeremy Chataway
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Progressive Multiple Sclerosis ◽  
Participant Selection ◽  
Funding Agencies ◽  
Disability Status ◽  
New Treatments ◽  
Clinical Measures ◽  
Development And Validation ◽  
Further Development

The failure of a majority of clinical trials in progressive multiple sclerosis (MS) has highlighted the need to reconsider how these trials are designed and conducted, and many areas deserve focus. Basic scientists are reconceptualising the pathophysiology of progressive MS into three broad areas: systemic inflammation, compartmentalized inflammation and non-inflammatory neurodegeneration, with the latter two becoming predominant as the disease progresses. This framework will guide the choice of experimental therapies. Previous clinical trials have highlighted how participant selection can have a significant impact on study outcome. Phase 2 biomarkers which are biologically stable, dynamically changing over time, and easy to assess in multi-centre studies are greatly needed. Shortcomings inherent in the Expanded Disability Status Scale are prompting the development and validation of better clinical measures. The standard two-arm, fixed-duration trial paradigm has been challenged with new, innovative approaches that can test more therapies efficiently. International collaboratives such as the Progressive MS Alliance will support increased dialogue with regulators, industry and other funding agencies. Better engagement with people living with progressive MS will transform them from simply being the recipient of MS therapies to partners in the search for new treatments. Focused, targeted action will drive further development of effective therapies for progressive MS.

scholarly journals Evolution of clinical trials in multiple sclerosis

2019 ◽  
Vol 12 ◽  
pp. 175628641982654 ◽  
Author(s):  
Yinan Zhang ◽  
Amber Salter ◽  
Erik Wallström ◽  
Gary Cutter ◽  
Olaf Stüve
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Treatment Options ◽  
Adaptive Designs ◽  
Resonance Imaging ◽  
Disease Modifying Therapies ◽  
Relapsing Remitting ◽  
Trial Efficiency ◽  
The Cost ◽  
Larger Sample

Clinical trials have advanced the treatment of multiple sclerosis (MS) by demonstrating the safety and efficacy of disease-modifying therapies (DMTs). This review discusses major changes to MS clinical trials in the era of DMTs. As treatment options for MS continue to increase, patients in modern MS trials present earlier and with milder disease compared with historic MS populations. While placebo-controlled trials for some questions may still be relevant, DMT trials in relapsing–remitting MS (RRMS) are no longer ethical. The replacement of the placebo arm by an active comparator arm in trials have raised the cost of trials by requiring larger sample sizes to detect on-study changes in treatment effects. Efforts to improve trial efficiency in RRMS have focused on exploring adaptive designs and relying on sensitive magnetic resonance imaging measures of disease activity. In trials for progressive forms of MS (PMS), the lack of sensitive outcome measures that can be used in shorter-term trials have delayed the development of effective treatments. Recent shifting of the focus to advancing trials in PMS has identified paraclinical outcome measurements with improved potential, and the testing of agents for neuroprotection and remyelination is in progress.

scholarly journals Long-Term Treatment Strategies of Pediatric Multiple Sclerosis, Including the use of Disease Modifying Therapies

Children ◽  
2019 ◽  
Vol 6 (6) ◽  
pp. 73 ◽  
Author(s):  
Mary Rensel
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Term Treatment ◽  
Treatment Goals ◽  
Adult Onset ◽  
Disease Modifying Therapies ◽  
New Concepts ◽  
Long Term Treatment ◽  
Disease Modifying

Multiple sclerosis (MS) presenting in the pediatric years can lead to landmark disability levels younger in life than adult onset MS and so therefore early and effective treatment remains paramount for long-term outcomes. The goals of MS therapeutics in adults have widened to address multiple mechanisms: anti-inflammatory, neuroprotective, and myelin repair, yet the optimal paradigm for MS therapies in the pediatric population is not known. Pediatric onset MS add complexities due to the ongoing development of the central nervous system and the immune system. Clinical trials have led to an increasing number of pharmaceutical therapies for adult onset MS (AOMS), one POMS randomized controlled trial is completed and other trials are ongoing, yet due to the low prevalence of POMS, the dynamic landscape and risk management of the MS disease modifying therapies (DMT) it remains more difficult to complete trials in POMS. There is consensus that controlled clinical trials leading to appropriate and safe therapies for POMS are important for a multitude of reasons that include unique pediatric pharmacokinetics, short and long-term safety, developmental issues, clinical benefits, and regulatory approval. This review will focus on new treatment goals, paradigm, strategies, monitoring, compliance, and products in the long-term treatment of POMS. The discussion will focus on these new concepts and the published data related to DMT use in POMS. This review provides significant insight into new concepts of treatment goals and current approaches to enhance the lives of the POMS patients now and in the future.

Autoinjector Improves Injection-related Tolerability Issues in Patients with Multiple Sclerosis - Exploring the New ExtaviJect™ 30G System for the Injection of Interferon Beta-1b

2010 ◽  
Vol 5 (2) ◽  
pp. 77 ◽  
Author(s):  
Wojciech Kozubski ◽  
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Interferon Beta ◽  
Adherence To Treatment ◽  
Disease Modifying Therapies ◽  
Disease Modifying ◽  
Injector System

Most of the current disease-modifying therapies available for the treatment of multiple sclerosis (MS) are administered by injection. This is a source of fear for many patients and a substantial cause of non-adherence to treatment. Autoinjectors can address this by ensuring that the injection is made at the correct depth and can markedly improve the comfort and tolerability of administration compared with manual syringes. Data from clinical trials support the use of autoinjectors showing that they improve adherence and that smaller gauge needles greatly reduce injection discomfort. As an initiative to improve the tolerability of interferon beta-1b (INFβ-1b) (Extavia®) administration in MS, a new injector system (ExtaviJect 30G™) has been developed that is simple to use and incorporates a narrower needle than is currently used in other injections. A preference survey amongst 200 patients, who had not used the new autoinjector, indicated that it would likely be well received by MS patients and would be easier to use than the currently available autoinjectors.

Relapses, Immunosuppressive and Novel Therapies

2016 ◽  
Author(s):  
Barbara S. Giesser
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Progressive Disease ◽  
Immunosuppressive Agents ◽  
Novel Therapies ◽  
Precipitating Factors ◽  
Off Label ◽  
Disease Modifying Therapies ◽  
Disease Modifying ◽  
Acute Attacks

This chapter presents information about treatment of acute attacks of multiple sclerosis and identification of precipitating factors. Additionally, it includes a detailed discussion of immunosuppressive agents that are used (largely off label) as disease-modifying therapies and data that support their use. Many clinical trials are currently focused on testing agents for use in progressive disease as well as agents that may be neuroprotective or neurorestorative. Results of recent trials of several of these various new and experimental agents are also reviewed.

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