Challenges in randomized controlled trials and emerging multiple sclerosis therapeutics.
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ABSTRACT:
SUBMITTER: Huang D
PROVIDER: S-EPMC5563727 | biostudies-other | 2015 Dec
REPOSITORIES: biostudies-other
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Project description:Therapeutic approaches to multiple sclerosis (MS) are based on altering the functions of the immune system, either by using broad immunosuppressive drugs used for transplantation rejection and rheumatology, or by modulating them more discreetly with beta interferon and synthetic amino-acid copolymers. These strategies are only partially successful, have important safety and tolerability limitations, and have shown to be mostly effective in earlier stages of the disease, in which acute relapses dominate the clinical picture. For progressive phenotypes of MS there are currently no effective therapeutic options. As very specific and potent immunosuppressive agents, monoclonal antibodies (mAbs) may offer considerable advantages over other therapies for MS. During the last decade, anti-a4 integrin natalizumab became the first approved mAb for treatment of relapsing MS, after convincingly demonstrating clinically significant effects on two large Phase 3 trials. Moreover, the concept of disease remission was introduced for the first time, to describe patients that show no signs of clinical or imaging markers of disease activity during therapy with natalizumab. Of the mAbs under development for MS, alemtuzumab and rituximab have also shown promising evidence of effectiveness, and potentially expanded the therapeutic horizon to reversal of disease progression in early relapsing patients, and progressive patients who previously had not been studied. However, the appearance of progressive multifocal leukoencephalopathy (PML) in natalizumab-treated MS patients, as well as in patients with lymphoma, lupus and rheumatoid arthritis treated with rituximab, and autoimmune-type complications in alemtuzumab-treated MS patients underlines the fact that extended efficacy comes with significant clinical risks. The challenge is then how best to utilize therapies that have evidently superior efficacy in a chronic disease of young adults, to obtain the best benefit-risk ratio, and how to monitor and prevent emergent safety concerns.
| S-EPMC3011221 | biostudies-literature
Project description:Background and objectivesTo investigate the potential of plasma neurofilament light (pNfL) as a biomarker of disease progression and treatment response in progressive multiple sclerosis (PMS) with and without acute disease activity.MethodsA post hoc blinded analysis of pNfL levels in 2 placebo-controlled, phase 3 studies in secondary progressive multiple sclerosis (SPMS; EXPAND) and primary progressive multiple sclerosis (PPMS; INFORMS) using siponimod and fingolimod, respectively, as active compounds was performed. pNfL levels were quantified using a single molecule array (Homebrew Simoa) immunoassay from stored ethylenediaminetetraacetic acid (EDTA) plasma samples of all patients who consented for exploratory biomarker analysis in either study; pNfL levels were divided into high (≥30 pg/mL) and low (<30 pg/mL) at baseline. We investigated the association of pNfL levels with disability progression, cognitive decline, and brain atrophy and their sensitivity to indicate treatment response through clinical measures.ResultsWe analyzed pNfL in 4,185 samples from 1,452 patients with SPMS and 1,172 samples from 378 patients with PPMS. Baseline pNfL levels were higher in SPMS (geomean 32.1 pg/mL) than in PPMS (22.0 pg/mL; p < 0.0001). In both studies, higher baseline pNfL levels were associated with older age, higher Expanded Disability Status Scale score, more Gd+ lesions, and higher T2 lesion load (all p < 0.05). Independent of treatment, high vs low baseline pNfL levels were associated with significantly higher risks of confirmed 3-month (SPMS [32%], hazard ratio [95% CI] 1.32 [1.09-1.61]; PPMS [49%], 1.49 [1.05-2.12]) and 6-month disability progression (SPMS [26%], 1.26 [1.01-1.57]; PPMS [48%], 1.48 [1.01-2.17]), earlier wheelchair dependence (SPMS [50%], 1.50 [0.96-2.34]; PPMS [197%], 2.97 [1.44-6.10]), cognitive decline (SPMS [41%], 1.41 [1.09-1.84]), and higher rates of brain atrophy (mean change at month 24: SPMS, -0.92; PPMS, -1.39). Baseline pNfL levels were associated with future disability progression and the degree of brain atrophy regardless of presence or absence of acute disease activity (gadolinium-enhancing lesions or recent occurrence of relapses before baseline). pNfL levels were lower in patients treated with siponimod or fingolimod vs placebo-treated patients and higher in those having experienced disability progression.DiscussionpNfL was associated with future clinical and radiologic disability progression features at the group level. pNfL was reduced by treatment and may be a meaningful outcome measure in PMS studies.Trial registration informationEXPAND (ClinicalTrials.gov identifier: NCT01665144) and INFORMS (ClinicalTrials.gov identifier: NCT00731692).
| S-EPMC10263182 | biostudies-literature
Project description:BACKGROUND: Spasticity is a common and poorly controlled symptom of multiple sclerosis. Our objective was to determine the short-term effect of smoked cannabis on this symptom. METHODS: We conducted a placebo-controlled, crossover trial involving adult patients with multiple sclerosis and spasticity. We recruited participants from a regional clinic or by referral from specialists. We randomly assigned participants to either the intervention (smoked cannabis, once daily for three days) or control (identical placebo cigarettes, once daily for three days). Each participant was assessed daily before and after treatment. After a washout interval of 11 days, participants crossed over to the opposite group. Our primary outcome was change in spasticity as measured by patient score on the modified Ashworth scale. Our secondary outcomes included patients' perception of pain (as measured using a visual analogue scale), a timed walk and changes in cognitive function (as measured by patient performance on the Paced Auditory Serial Addition Test), in addition to ratings of fatigue. RESULTS: Thirty-seven participants were randomized at the start of the study, 30 of whom completed the trial. Treatment with smoked cannabis resulted in a reduction in patient scores on the modified Ashworth scale by an average of 2.74 points more than placebo (p < 0.0001). In addition, treatment reduced pain scores on a visual analogue scale by an average of 5.28 points more than placebo (p = 0.008). Scores for the timed walk did not differ significantly between treatment and placebo (p = 0.2). Scores on the Paced Auditory Serial Addition Test decreased by 8.67 points more with treatment than with placebo (p = 0.003). No serious adverse events occurred during the trial. INTERPRETATION: Smoked cannabis was superior to placebo in symptom and pain reduction in participants with treatment-resistant spasticity. Future studies should examine whether different doses can result in similar beneficial effects with less cognitive impact.
| S-EPMC3394820 | biostudies-other
Project description:BackgroundMultiple sclerosis (MS) is the most common non-traumatic disabling disease affecting young adults. A definitive curative treatment is currently unavailable. Many randomized controlled trials (RCTs) have reported the efficacy of Chinese herbal medicine (CHM) on MS. Because of the uncertain quality of these RCTs, the recommendations for routine use of CHM for MS remain inconclusive. The comprehensive evaluation of the quality of RCTs of CHM for MS is urgent.MethodsNine databases, namely, PubMed, Embase, Web of Science, Cochrane Library, EBSCO, Sinomed, Wanfang Database, China National Knowledge Infrastructure, and VIP Database, were searched from inception to September 2023. RCTs comparing CHM with placebo or pharmacological interventions for MS were considered eligible. The Consolidated Standards of Reporting Trials (CONSORT) and its extension for CHM formulas (CONSORT-CHM Formulas) checklists were used to evaluate the reporting quality of RCTs. The risk of bias was assessed using the Cochrane Risk of Bias tool. The selection criteria of high-frequency herbs for MS were those with cumulative frequency over 50% among the top-ranked herbs.ResultsA total of 25 RCTs were included. In the included RCTs, 33% of the CONSORT items and 21% of the CONSORT-CHM Formulas items were reported. Eligibility title, sample size calculation, allocation concealment, randomized implementation, and blinded description in CONSORT core items were reported by less than 5% of trials. For the CONSORT-CHM Formulas, the source and authentication method of each CHM ingredient was particularly poorly reported. Most studies classified the risk of bias as "unclear" due to insufficient information. The top five most frequently used herbs were, in order, Radix Rehmanniae Preparata, Radix Rehmanniae Recens, Herba Epimedii, Scorpio, and Poria. No serious adverse effect had been reported.ConclusionsThe low reporting of CONSORT items and the unclear risk of bias indicate the inadequate quality of RCTs in terms of reporting completeness and result validity. The CONSORT-CHM Formulas appropriately consider the unique characteristics of CHM, including principles, formulas, and Chinese medicinal substances. To improve the quality of RCTs on CHM for MS, researchers should adhere more closely to CONSORT-CHM Formulas guidelines and ensure comprehensive disclosure of all study design elements.
| S-EPMC11369894 | biostudies-literature
Project description:Intravenous glucocorticoids are recommended for multiple sclerosis (MS). However, they can be inconvenient and expensive. Due to their convenience and low cost, oral glucocorticoids may be an alternative treatment. Recently, several studies have shown that there is no difference in efficacy and safety between oral methylprednisolone (oMP) and intravenous methylprednisolone (ivMP).We sought to assess the clinical efficacy, safety and tolerability of oral methylprednisolone versus intravenous methylprednisolone for MS relapses in this meta-analysis.Randomized controlled trials (RCTs) evaluating the clinical efficacy, safety and tolerability of oral methylprednisolone versus intravenous methylprednisolone for MS relapses were searched in PubMed, Cochrane Library, Medline, EMBASE and China Biology Medicine until October 25, 2016, without language restrictions. The proportion of patients who had improved by day 28 was chosen as the efficacy outcome. We chose the risk ratio (RR) to analyze each trial with the 95% confidence interval (95% CI). We also used the fixed-effects model (Mantel-Haenszel approach) to calculate the pooled relative effect estimates.A total of 5 trials were identified, which included 369 patients. The results of our meta-analysis revealed that no significant difference existed in relapse improvement at day 28 between oMP and ivMP (RR 0.96, 95% CI 0.84 to 1.10). No evidence of heterogeneity existed among the trials (P = 0.45, I2 = 0%). Both treatments were equally safe and well tolerated except that insomnia was more likely to occur in the oMP group compared to the ivMP group.Our meta-analysis reveals strong evidence that oMP is not inferior to ivMP in increasing the proportion of patients experiencing clinical improvement at day 28. In addition, both routes of administration are equally well tolerated and safe. These findings suggest that we may be able to replace ivMP with oMP to treat MS relapses.
| S-EPMC5703548 | biostudies-literature
Project description:BACKGROUND: Pain is common in multiple sclerosis (MS). Duloxetine has a potential therapeutic role in treating MS-related pain. METHODS: Thirty-eight MS patients were randomized 1:1 to receive duloxetine (n = 18) or matched placebo (n = 20). The dosing regimen was 30 mg daily for 1 week, then 60 mg daily for 5 weeks. The primary outcome measure was change in worst pain for week 6 relative to baseline recorded on a daily pain diary. RESULTS: Of 38 randomized patients, 14 (78%) patients randomized to duloxetine and 18 (90%) randomized to placebo completed treatment per protocol. These participants had an average age of 55.5 years, 25% were male, and 66% had relapsing-remitting MS (RRMS). Baseline characteristics were similar. Discontinuations were due primarily to drug intolerance. Among those who completed treatment, worst pain at 6 weeks was reduced by 29% (±20%) for duloxetine versus 12% (±18%) for placebo (P = .016). Average daily pain at 6 weeks was reduced by 39% (±29%) in the duloxetine group compared to 10% (±18.8%) in the placebo group (P = .002). There were no significant changes (week 6 vs. baseline) or between-group differences for subject global impression, Beck Depression Inventory, 36-item Short Form Health Status Survey (SF-36), or sleep quality score. CONCLUSIONS: Fewer patients could tolerate duloxetine compared to placebo. Among patients who completed 6 weeks of treatment, there were significant reductions in average and worst daily pain scores with duloxetine compared to placebo. This study suggests that duloxetine has a direct pain-relieving effect in MS.
| S-EPMC4399771 | biostudies-other
Project description:Inflammatory demyelination of the central nervous system (CNS) is the hallmark of multiple sclerosis (MS), a chronic debilitating disease that affects more than 2.5 million individuals worldwide. It has been widely accepted, although not proven, that the major pathogenic mechanism of MS involves myelin-reactive T cell activation in the periphery and migration into the CNS, which subsequently triggers an inflammatory cascade that leads to demyelination and axonal damage. Virtually all MS medications now in use target the immune system and prevent tissue damage by modulating neuroinflammatory processes. Although current therapies such as commonly prescribed disease-modifying medications decrease the relapse rate in relapsing-remitting MS (RRMS), the prevention of long-term accumulation of deficits remains a challenge. Medications used for progressive forms of MS also have limited efficacy. The need for therapies that are effective against disease progression continues to drive the search for novel pharmacological targets. In recent years, due to a better understanding of MS immunopathogenesis, new approaches have been introduced that more specifically target autoreactive immune cells and their products, thus increasing specificity and efficacy, while reducing potential side effects such as global immunosuppression. In this review we describe several immunopharmacological targets that are currently being explored for MS therapy.
| S-EPMC5215047 | biostudies-literature
Project description:Background: The efficacy and safety of fingolimod for relapsing-remitting multiple sclerosis (RRMS) had been well verified in several large randomized controlled trials (RCTs) during the past decade. However, there are fewer systematic comparisons of different doses of fingolimod and whether the dose of 0.5 mg/d is the optimal one still remains to be solved. Objective: The objective of this systematic review was to evaluate the efficacy and safety of the four existing doses of fingolimod in the treatment of RRMS, especially the dose of 0.5 mg/d. Methods: MEDLINE, EMBASE, Cochrane Library, and clinicaltrials.gov were searched for RCTs which were performed to evaluate different doses of fingolimod and the corresponding control (placebo or DMTs) up to October 2020. Review Manager 5.3 software was used to assess the data. The risk ratio (RR) and mean difference (MD) was analyzed and calculated with a random effect model. Results: We pooled 7184 patients from 11 RCTs. Fingolimod 0.5 mg/d was superior to control group in all eight efficacy outcomes including annualized relapse rate (ARR) (MD -0.22, 95%CI -0.29 to -0.14, p < 0.00001) but surprisingly showed a higher risk of basal-cell carcinoma (RR 4.40, 95%CI 1.58 to 12.24, p = 0.004). Although 1.25 mg/d is more than twice the dose of 0.5 mg/d, the effect size was almost similar between them. Dose of 5 mg/d obtained an unsatisfactory efficacy while showing a greater risk of adverse events than other three doses (RR 1.17, 95%CI 1.05 to 1.30, p = 0.003). Additionally, fingolimod 0.25 mg/d not only showed a better performance in delaying the disease progress of magnetic resonance imaging (MRI), but also achieved a certain degree of patient treatment satisfaction. Conclusion: At present, 0.5 mg/d remains to be the optimal dose of fingolimod for RRMS patients but trials of a lower dose are still of great clinical significance and should be paid more attentions.
| S-EPMC8165387 | biostudies-literature
Project description:Multiple sclerosis (MS) is a chronic autoimmune disease, where T-cells attack the myelin sheath in the central nervous system (CNS), characterized by relapsing-remitting episodes, or gradually increasing severity of symptoms and disability that accumulate over time. While current MS therapies have been proven in clinical trials to provide significant benefits, they cater only to subsets of patients. Moreover, there is an acute need to identify the most effective and safe treatment appropriate for each patient prospectively, since early intervention has been proven to prevent accumulation of irreversible dysfunction. In this review we discuss the current state-of-the-art in pharmacogenetic research as applied to the common marketed and in-development MS treatments, with respect to both efficacy and safety aspects. We conclude by discussing the relevance of pharmacogenetics and other biomarkers to the prediction, prevention and personalization of MS medications in the horizon.
| S-EPMC3405323 | biostudies-literature
Project description:Myelination by oligodendrocytes (OLs) is an important biological process essential for central nervous system (CNS) development and functions. Oligodendroglial lineage cells undergo several morphological and molecular changes at different stages of their lineage progression into myelinating OLs. The transition steps of the oligodendrocyte progenitor cells (OPCs) to myelinating oligodendrocytes are defined by a specific pattern of regulated gene expression, which is under the control of coordinated signaling pathways. Any abnormal development, loss or failure of oligodendrocytes to myelinate axons can lead to several neurodegenerative diseases like multiple sclerosis (MS). MS is characterized by inflammation and demyelination, and current treatments target only the immune component of the disease, but have little impact on remyelination. Recently, several pharmacological compounds enhancing remyelination have been identified and some of them are in clinical trials. Here, we will review the current knowledge on oligodendrocyte differentiation, myelination and remyelination. We will focus on MS as a pathological condition, the most common chronic inflammatory demyelinating disease of the CNS in young adults.
| S-EPMC8069894 | biostudies-literature