Disease-modifying Therapies In Patients Research Articles

Outcome Reporting Bias in Clinical Trials Researching Disease-Modifying Therapy in Patients With Multiple Sclerosis.

Outcome reporting bias occurs when publication of trial results is dependent on clinical significance, thereby threatening the validity of trial results. Research on immunomodulatory drugs in multiple sclerosis has thrived in recent years. We aim to comprehensively examine to what extent outcome reporting bias is present in these trials and the possible underlying factors. We identified clinical trials evaluating the efficacy and safety of immunomodulatory drugs in patients with multiple sclerosis (MS) registered in ClinicalTrials.gov after September 2007 and completed before the end of 2018. Information about study design, type of funding, and primary and secondary outcome measures was extracted from the registry. Timing of registration in relation to study initiation and subsequent amendments to the planned outcomes were reviewed. Publications related to these trials were identified in several bibliographic databases using the trial registration number. Registered primary and secondary outcomes were recorded for each trial and compared with outcomes in the publication describing the main outcomes of the trial. A search of ClinicalTrials.gov identified 535 eligible registered clinical trials; of these, 101 had a matching publication. Discrepancies between registered and published primary and secondary outcomes were found in 95% of the trials, including discrepancies between the registered and published primary outcomes in 26 publications. Forty-four percent of the published secondary outcomes were not included in the registry. A similar proportion of registered and nonregistered reported primary efficacy outcomes were positive (favoring the intervention). Nonindustry-funded and open-label trials in MS were more prone to selective primary outcome reporting, although these findings did not reach statistical significance. Only two-thirds of the trials were registered in ClinicalTrials.gov before the trial start date, and 62% of trials made amendments in registered outcomes during or after the trial period. Selective outcome reporting is prevalent in trials of disease-modifying drugs in people with MS. We propose methods to diminish the occurrence of this bias in future research.

Efficacy and safety of autologous haematopoietic stem cell transplantation versus alemtuzumab, ocrelizumab, ofatumumab or cladribine in relapsing remitting multiple sclerosis (StarMS): protocol for a randomised controlled trial

IntroductionAutologous haematopoietic stem cell transplantation (aHSCT) is increasingly used as treatment for patients with active multiple sclerosis (MS), typically after failure of disease-modifying therapies (DMTs). A recent phase III trial,...

Neuroinflammation and Mitochondrial Dysfunction in Parkinson's Disease: Connecting Neuroimaging with Pathophysiology.

There is a pressing need for disease-modifying therapies in patients suffering from neurodegenerative diseases, including Parkinson's disease (PD). However, these disorders face unique challenges in clinical trial designs to assess the neuroprotective properties of potential drug candidates. One of these challenges relates to the often unknown individual disease mechanisms that would, however, be relevant for targeted treatment strategies. Neuroinflammation and mitochondrial dysfunction are two proposed pathophysiological hallmarks and are considered to be highly interconnected in PD. Innovative neuroimaging methods can potentially help to gain deeper insights into one's predominant disease mechanisms, can facilitate patient stratification in clinical trials, and could potentially map treatment responses. This review aims to highlight the role of neuroinflammation and mitochondrial dysfunction in patients with PD (PwPD). We will specifically introduce different neuroimaging modalities, their respective technical hurdles and challenges, and their implementation into clinical practice. We will gather preliminary evidence for their potential use in PD research and discuss opportunities for future clinical trials.

Does the Multiple Sclerosis Impact Scale-29 (MSIS-29) have the range to capture the experience of fully ambulatory multiple sclerosis patients? Learnings from the ASCLEPIOS studies.

Trials of disease-modifying therapies (DMTs) for multiple sclerosis (MS) often include patients with minimal disability. Patient-reported outcome instruments used in these trials have often not captured physical and psychological treatment effects concomitant with observed clinical benefits. To examine whether the Multiple Sclerosis Impact Scale-29 (MSIS-29) captures changes in the impact of MS in a sample of patients enrolled in the Phase 3 ASCLEPIOS studies (ofatumumab vs. teriflunomide). Measurement properties (i.e. item fit, reliability, and targeting) of the MSIS-29 were analyzed using Rasch measurement theory (RMT) in data from two phase 3 ofatumumab clinical trials including patients with relapsing-remitting or secondary progressive MS (N = 1882). Targeting of the MSIS-29 items to the patient population was explored within groups categorized by Expanded Disability Status Scale (EDSS) scores. Under RMT analyses, both the Physical and Psychological Impact scales of the MSIS-29 were not appropriately targeted to the overall sample of patients. In particular, 49% and 30% of patients with an EDSS score ≤ 2.5 had fewer physical and psychological impacts, respectively, than would typically be captured by these MSIS-29 items compared to patients with EDSS scores of ≥ 3. The MSIS-29 is commonly used to evaluate the patient-reported physical and psychological impact of MS. However, it may be limited in evaluating changes associated with DMTs in patients with minimal disability.

Effects of baseline age and disease duration on the efficacy and safety of siponimod in patients with active SPMS: Post hoc analyses from the EXPAND study.

Older age and longer disease duration (DD) may impact the effectiveness of disease-modifying therapies in patients with multiple sclerosis (MS). Siponimod is a sphingosine 1-phosphate receptor modulator approved for the treatment of active secondary progressive MS (SPMS) in many countries. The pivotal phase 3 EXPAND study examined siponimod versus placebo in a broad SPMS population with both active and non-active disease. In this population, siponimod demonstrated significant efficacy, including a reduction in the risk of 3-month confirmed disability progression (3mCDP) and 6-month confirmed disability progression (6mCDP). Benefits of siponimod were also observed across age and DD subgroups in the overall EXPAND population. Herein we sought to assess the clinical impact of siponimod across age and disease duration subgroups, specifically in participants with active SPMS. This study is a post hoc analysis of a subgroup of EXPAND participants with active SPMS (≥1 relapse in the 2 years before the study and/or ≥1 T1 gadolinium-enhancing magnetic resonance imaging lesion at baseline) receiving oral siponimod (2mg/day) or placebo during EXPAND. Data were analyzed for participant subgroups stratified by age at baseline (primary cut-off: <45 year ≥45 years; and secondary cut-off: <50 years or ≥50 years) and by DD at baseline (<16 years or ≥16 years). Efficacy endpoints were 3mCDP and 6mCDP. Safety assessments included adverse events (AEs), serious AEs, and AEs leading to treatment discontinuation. Data from 779 participants with active SPMS were analyzed. All age and DD subgroups had 31-38% (3mCDP) and 27-43% (6mCDP) risk reductions with siponimod versus placebo. Compared with placebo, siponimod significantly reduced the risk of 3mCDP in participants aged ≥45 years (hazard ratio [HR]: 0.68; 95% confidence interval [CI]: 0.48-0.97), <50 years (HR: 0.69; 95% CI: 0.49-0.98), ≥50 years (HR: 0.62; 95% CI: 0.40-0.96), and in participants with <16 years DD (HR: 0.68; 95% CI: 0.47-0.98). The risk of 6mCDP was significantly reduced with siponimod versus placebo for participants aged <45 years (HR: 0.60; 95% CI: 0.38-0.96), ≥45 years (HR: 0.67; 95% CI: 0.45-0.99), <50 years (HR: 0.62; 95% CI: 0.43-0.90), and in participants with <16 years DD (HR: 0.57; 95% CI: 0.38-0.87). Increasing age or longer MS duration did not appear to increase the risk of AEs, with an observed safety profile that remained consistent with the overall active SPMS and overall SPMS populations in EXPAND. In participants with active SPMS, treatment with siponimod demonstrated a statistically significant reduction in the risk of 3mCDP and 6mCDP compared with placebo. Although not every outcome reached statistical significance in the subgroup analyses (possibly a consequence of small sample sizes), benefits of siponimod were seen across a spectrum of ages and DD. Siponimod was generally well tolerated by participants with active SPMS, regardless of baseline age and DD, and AE profiles were broadly similar to those observed in the overall EXPAND population.

Adherence and persistence to self-administered disease-modifying therapies in patients with multiple sclerosis: A multisite analysis.

Though there are several disease-modifying therapy (DMT) options for patients with multiple sclerosis (MS), treatment outcomes rely on patient adherence and persistence. Previous studies have demonstrated suboptimal adherence rates and high rates of early treatment discontinuation. Health-system specialty pharmacies (HSPPs) are a growing practice model that have demonstrated adherence and persistence benefits through single site evaluations. Research is needed across multiple HSSPs to understand and validate the outcomes of this practice model. A multisite prospective cohort study was performed including patients with at least three fills of a DMT between January 2020 and June 2021 at an HSSP. Patients were excluded due to pregnancy or death. Enrollment occurred for 6 months followed by 12 months of follow-up. Adherence was measured using pharmacy claims to calculate proportion of days covered (PDC) during the follow-up period. Time to non-persistence was calculated as the time from an index DMT fill to the first date of a gap of >60 days between medication exhaust and fulfillment dates. Adherence and persistence calculations were assessed at the therapeutic class level (any self-administered DMT dispensed by the HSSPs). The Kaplan-Meier method was used to present the probability of being persistent, and Cox proportional hazards regression analysis was used to estimate hazard ratios of factors associated with non-persistence, which included age, sex, study site, insurance type, and whether the patient switched medication as potential factors. The most common self-administered DMTs filled among 968 patients were glatiramer acetate (32%), fingolimod (18%), and dimethyl fumarate (18%). Most patients (96%) did not switch DMT during the study period. The median PDC was 0.97 (interquartile range 0.90-0.99), which was similar across all sites. Patients who had at least one DMT switch were 76% less likely to have a higher PDC than those who did not have any switch after adjusting for other covariates (Odds ratio: 0.24, 95% confidence interval [CI]: 0.14-0.40, p<0.001). Most patients (86%) were persistent to DMT over the 12-month study period. Among those non-persistent, median time to non-persistence was 231 (IQR 177-301) days. Patients who switched medications were 2.4 times more likely to be non-persistent (95% CI: 1.3 - 4.5, p=0.005). The most common reasons for non-persistence were discontinuation/medication held for an extended period (30%), often due to patient or prescriber decision (75%). High rates of DMT adherence and persistence were seen among patients serviced by HSSPs, indicating potential benefits of this model for patients with MS. Switching DMTs was associated with lower adherence and persistence and may be an opportunity for added care coordination or resources to optimize therapy transitions.

Immunoablative therapy followed by autologous hematopoietic stem cell transplantation as the first-line disease-modifying therapy in patients with multiple sclerosis.

Immunoablative therapy followed by autologous hematopoietic stem cell transplantation (AHSCT) is one of the possible disease-modifying therapies (DMTs) for patients with multiple sclerosis (MS). In this case series, we would like to present six patients with MS, who underwent AHSCT as the first-line DMT. Six MS patients with a rapid progression of disability with or without relapses underwent AHSCT as the first-line DMT at the University Hospital Ostrava between 2018 and 2021. The conditioning regimens for AHSCT used were a medium-intensity regime BEAM (Carmustine, Etoposid, Cytarabin, Melphalan) and low-intensity regime based on Cyclophosphamide. Four out of six patients showed some disability progression after AHSCT, so the rapid progression of MS was just slowed down by AHSCT. One patient developed activity on magnetic resonance imaging three months after AHSCT, and two experienced mild relapses during the follow-up period. None of our patients developed grade 4 non-hematological toxicity; all infections were mild. In one patient, an allergic reaction probably to dimethyl sulfoxide was observed. Our case series of 6 patients shows that AHSCT is a promising therapeutic approach to slow down the rapid progression of clinical disability in MS patients with a good safety profile.

Assessing the Health Economic Outcomes from Commercially Insured Relapsing Multiple Sclerosis Patients Who Switched from Other Disease-Modifying Therapies to Teriflunomide, in the United States.

Assess patient characteristics, healthcare resource utilization (HCRU), and relapses in patients with multiple sclerosis (MS) who switched to teriflunomide from other disease-modifying therapies (DMTs). Retrospective study of US Merative™ MarketScan® claims database (Jan 1, 2012-July 31, 2020,) including HIPAA-compliant, deidentified data. Patients ≥18 years with MS diagnosis (based on ICD-9/ICD-10 codes), receiving ≥1 DMT prior to teriflunomide and ≥12 months continuous enrollment pre and post index (date of teriflunomide initiation). Outcomes included inpatient and emergency room claims coinciding with MS diagnosis, MS-related healthcare costs, and annualized relapse rates (ARRs) (indirectly assessed using hospitalization/outpatient claims and steroid use coinciding with MS diagnosis). The analyzed cohort (N=2016) was primarily female (79%); age (mean ± standard deviation) 51.4 ± 9.3 years; MS duration 4.7±2.8 years (at index). The majority (89.2%) were treated with one DMT before switching to teriflunomide. Use of outpatient services (event rate/100 person-years) increased post vs pre index; however, MRI visits significantly reduced over the same period (both P<0.0001). Costs for MS-specific outpatient visits decreased by $371 per patient per year (PPPY) after switching to teriflunomide. Despite an increase in use post index (0.024 to 0.033 rate/100 person-years; P<0.0001), costs for MS-specific laboratory services reduced (pre-index: $271 vs $248 PPPY post-index; P=0.02). Fewer patients had relapses after switching (pre-index: n=417 [20.7%]; post-index: n=333 [16.5%]). ARR was significantly lower after switching (pre-index: 0.269 vs post-index: 0.205; P=0.000). Switching to teriflunomide from existing DMTs in patients with relapsing MS resulted in a reduction in outpatient HCRU in this analysis of US claims data. The real-world effectiveness of teriflunomide was generally consistent with efficacy reported in clinical trials, showing a reduction in relapse following a switch to teriflunomide.

The potential value of disease-modifying therapy in patients with spinocerebellar ataxia type 1: an early health economic modeling study

ObjectiveThere currently is no disease-modifying therapy for spinocerebellar ataxia type 1 (SCA1). Genetic interventions, such as RNA-based therapies, are being developed but those currently available are very expensive. Early evaluation of costs and benefits is, therefore, crucial. By developing a health economic model, we aimed to provide first insights into the potential cost-effectiveness of RNA-based therapies for SCA1 in the Netherlands.MethodsWe simulated disease progression of individuals with SCA1 using a patient-level state-transition model. Five hypothetical treatment strategies with different start and endpoints and level of effectiveness (5–50% reduction in disease progression) were evaluated. Consequences of each strategy were measured in terms of quality-adjusted life years (QALYs), survival, healthcare costs, and maximum costs to be cost effective.ResultsMost QALYs (6.68) are gained when therapy starts during the pre-ataxic stage and continues during the entire disease course. Incremental costs are lowest (− €14,048) if therapy is stopped when the severe ataxia stage is reached. The maximum costs per year to be cost-effective are €19,630 in the “stop after moderate ataxia stage” strategy at 50% effectiveness.DiscussionOur model indicates that the maximum price for a hypothetical therapy to be cost-effective is considerably lower than currently available RNA-based therapies. Most value for money can be gained by slowing progression in the early and moderate stages of SCA1 and by stopping therapy upon entering the severe ataxia stage. To allow for such a strategy, it is crucial to identify individuals in early stages of disease, preferably just before symptom onset.

Selective Activation of the Wnt-Signaling Pathway as a Novel Therapy for the Treatment of Diabetic Retinopathy and Other Retinal Vascular Diseases.

Retinal ischemia, often associated with various disorders such as diabetic retinopathy (DR), retinal vein occlusion, glaucoma, optic neuropathies, stroke, and other retinopathies, is a major cause of visual impairment and blindness worldwide. As proper blood supply to the retina is critical to maintain its high metabolic demand, any impediment to blood flow can lead to a decrease in oxygen supply, resulting in retinal ischemia. In the pathogenesis of DR, including diabetic macular edema (DME), elevated blood glucose leads to blood-retina barrier (BRB) disruptions, vascular leakage, and capillary occlusion and dropouts, causing insufficient delivery of oxygen to the retina, and ultimately resulting in visual impairment. Other potential causes of DR include neuronal dysfunction in the absence of vascular defect, genetic, and environmental factors. The exact disease progression remains unclear and varies from patient to patient. Vascular leakage leading to edema clearly links to visual impairment and remains an important target for therapy. Despite recent advances in the treatment of DME and DR with anti-VEGFs, effective therapies with new mechanisms of action to address current treatment limitations regarding vessel regeneration and reperfusion of ischemic retinal areas are still needed. The Wnt signaling pathway plays a critical role in proper vascular development and maintenance in the retina, and thus provides a novel therapeutic approach for the treatment of diabetic and other retinopathies. In this review, we summarize the potential of this pathway to address treatment gaps with current therapies, its promise as a novel and potentially disease modifying therapy for patients with DR and opportunities in other retinal vascular diseases.

Understanding Hydroxyurea Utilization in Sickle Cell Disease: Exploring Patient and Provider Attitudes and Beliefs

Introduction Hydroxyurea (HU), a first line sickle cell disease (SCD) modifying drug, has a 22%-48% utilization rate, according to national estimates (Lanzkron 2006, Stettler 2015, Knisely 2020). There are numerous factors identified as barriers to adherence of hydroxyurea such as access to care (Badawy 2017). Given the high frequency of SCD inpatient admissions at the University of Chicago Medical Center (UCMC) and thus the limited opportunity for outpatient care where disease modifying therapies can be initiated, we proposed a quality improvement project to monitor HU education and usage during inpatient encounters. Methods Our project was reviewed by the UCMC Institutional Review Board and approved to meet quality improvement (QI) determination. To address the question of HU initiation in SCD during inpatient encounters, we surveyed key stakeholders including patients with SCD and providers. We identified consecutive patients with SCD who were either established with primary care or hematology at UCMC (n=197) and distributed our deidentified survey through a REDCap secure link to patients with active email accounts (n=135). We designed a provider survey eliciting knowledge, beliefs, and perspectives on HU use in SCD and distributed this through REDCap to 182 frontline providers. We analyzed the data qualitatively, identifying patterns and common themes from aggregate responses and free text answers. Results The patient survey response rate was 31% (n=42/135). Forty-five percent (n=18) of patients agreed that they missed follow up appointments due to admissions. Approximately half of patient respondents indicated they were not taking HU (n=19). Additionally, of those patients, 72% (n=14) indicated they would be willing to deal with the side effects of HU if it improved their SCD symptoms and 32% (n=6) said they would consider initiation of HU during an inpatient encounter. Patient respondents cited the benefits of HU, including improving quality of life (33%; n=13), preventing pain episodes (43%; n=17), improving mortality (18%; n=7), and helping prevent hospitalizations (36%; n=14). In terms of further education, 35% (n=14) of patient respondents indicated they would like to learn more about HU. 88% (n=35) indicated they would like to learn more about other disease modifying therapies. The provider survey response rate was 73% (n=132/182), of whom, 40% (n=52) were IM or Med/Peds residents, 28% (n=37) were medicine attendings, and 11% (n=15) were Hematology/Oncology faculty or fellows. 98% (n=129) of respondents overall agreed that HU initiation should be offered to patients with SCD during inpatient encounters and that the benefits of HU in SCD outweighed the potential harms. Providers requested tools to facilitate prescribing HU during inpatient encounters, including bundled orders ("orderset") within the EMR (55%; n=73), an option for inpatient SCD consult services (28%; n=37), education sessions and materials (45%; n=59), and a linked outpatient hematology referral system (58%; n=77). Conclusion: Results from our patient survey demonstrate an unmet need for expanding access to HU into inpatient encounters and providing access to other disease modifying therapies and potential cures. Providers would be comfortable with initiation and monitoring of HU during inpatient SCD encounters. To facilitate this, providers request additional education and process resources. Results from both surveys inform a plan to address disparities in HU utilization rates among patients with SCD at UCMC, in addition to providing opportunities to enhance SCD care overall. The path forward will include building curricula for providers, educational handouts on disease modifying therapies for patients, generating a HU prescribing orderset embedded in the EMR, and innovating a SCD inpatient consult service at UCMC.

Oral disease modifying therapies – A game changer for treatment decision in untreated patients with RRMS and CIS? – A swiss single center cross-sectional study

IntroductionSeveral disease-modifying therapies (DMTs) show efficacy in relapsing-remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS). However, there is still a relevant proportion of patients who remain untreated. We provide real-world data on untreated and treated patients and we report whether and how the introduction of oral DMTs changed the treatment decision. Furthermore, we discuss possible reasons for not receiving DMTs. MethodsWe conducted a retrospective cross-sectional study and analysed demographic and clinical data of patients with RRMS and CIS at our MS center. Comparison was made between untreated and treated patients in 2010 (before the introduction of oral DMTs) and in 2014 (after the introduction of oral DMTs). Furthermore, we analysed reasons for the decision against DMTs in patients who never received DMTs and patients who discontinued DMTs. ResultsWe analysed datasets of 344 MS patients in 2010 and 253 in 2014. There were more untreated patients in CIS than in RRMS. In RRMS, the proportion of untreated patients decreased significantly between 2010 and 2014 from 23.6% to 11.1%, while the use of oral medications increased significantly from <1% to more than 50% in 2014. In CIS, there was no significant change in untreated patients between 2010 and 2014 (61.1% in 2010 to 52.6% in 2014). Untreated patients with RRMS were significantly older and had lower ARR than treated patients. Patients who never received DMT had lower EDSS compared to patients that had been treated before. The main reasons for the decision against DMT were "belief in a benign course" and "fear of adverse effects". Treatment discontinuation was caused mainly by the adverse effects. DiscussionIn our data a relevant proportion of patients with RRMS and CIS did not receive any DMT. We hypothesize that in patients with RRMS the introduction of oral DMTs translated to a higher rate of treatment, whereas in CIS there no change was observed. This could be due to limited therapeutic options in CIS. There is more information needed regarding the treatment recommendation for older patients and patients with mild course of the disease.

Evaluation of Simvastatin as a Disease-Modifying Treatment for Patients With Parkinson Disease

Current treatments manage symptoms of Parkinson disease (PD), but no known treatment slows disease progression. Preclinical and epidemiological studies support the potential use of statins as disease-modifying therapy. To determine whether simvastatin has potential as a disease-modifying treatment for patients with moderate PD. This randomized clinical trial, a double-blind, parallel-group, placebo-controlled futility trial, was conducted between March 2016 and May 2020 within 23 National Health Service Trusts in England. Participants aged 40 to 90 years with a diagnosis of idiopathic PD, with a modified Hoehn and Yahr stage of 3.0 or less while taking medication, and taking dopaminergic medication with wearing-off phenomenon were included. Data were analyzed from May 2020 to September 2020, with additional analysis in February 2021. Participants were allocated 1:1 to simvastatin or matched placebo via a computer-generated random sequence, stratified by site and Hoehn and Yahr stage. In the simvastatin arm, participants entered a 1-month phase of simvastatin, 40 mg daily, followed by 23 months of simvastatin, 80 mg daily, before a 2-month washout period. The prespecified primary outcome was 24-month change in Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) part III score measured while not taking medication (high scores indicate worse outcome). The primary futility analysis included participants who commenced the 80-mg phase and had valid primary outcome data. The safety analysis included all participants who commenced trial treatment and is reported by dose at time of event. Of 332 patients assessed for eligibility, 32 declined and 65 were ineligible. Of 235 recruited participants, 97 (41%) were female, 233 (99%) were White, and the mean (SD) age was 65.4 (9.4) years. A total of 216 patients progressed to the 80-mg dose. Primary outcome analysis (n = 178) indicated the simvastatin group had an additional deterioration in MDS-UPDRS III score while not taking medication at 24 months compared with the placebo group (1.52 points; 2-sided 80% CI, -0.77 to 3.80; 1-sided futility test P = .006). A total of 37 serious adverse events (AEs), including 3 deaths, and 171 AEs were reported for participants receiving 0-mg simvastatin; 37 serious AEs and 150 AEs were reported for participants taking 40 mg or 80 mg of simvastatin. Four participants withdrew from the trial because of an AE. In this randomized clinical trial, simvastatin was futile as a disease-modifying therapy in patients with PD of moderate severity, providing no evidence to support proceeding to a phase 3 trial. ISRCTN Identifier: 16108482.

P.105 Safety and effectiveness of onasemnogene abeparvovec (OA) alone or with other disease-modifying therapies (DMTs): Findings from RESTORE

We aimed to describe real-world safety and effectiveness of OA alone or in combination with other DMTs for patients with SMA. RESTORE is an ongoing, prospective, multicenter, multinational, observational SMA patient registry. We evaluated patients with 2 or 3 SMN2 gene copies receiving OA alone or with any other DMTs. As of Nov. 23, 2021, data were available for 247 patients who received OA: 121 (49.0%) received OA alone (group 1); 48 (19.4%) received OA before (group 2); and 78 (31.6%) received OA after (group 3) another DMT. All patients in group 3 received nusinersen, and none received risdiplam. Of patients with ≥2 milestone assessments (≥1 post-OA administration; n=112), 71 (63.4%) achieved new milestones: 35 (49.3%) in group 1, 15 (21.1%) in group 2, and 21 (29.6%) in group 3. There was no significant difference in time to first milestone achievement after OA administration among groups (p=0.2). Median changes in CHOP INTEND scores for Groups 1, 2, and 3 were 11 (n=43; 38 [88.4%] achieved increase of ≥4 points), 11 (n=19; 16 [84.2%] achieved increase of ≥4 points), and 4 (n=33; 20 [60.6%] achieved increase of ≥4 points), respectively. Median changes in HFMSE scores for groups 1, 2, and 3 were 13.5 (n=12; 10 [83.3%] achieved increase of ≥3 points), 5 (n=9; 6 [66.7%] achieved increase of ≥3 points), and 4 (n=10; 7 [70%] achieved increase of ≥3 points), respectively. Median changes in HINE scores for groups 1, 2, and 3 were 6.5 (n=14), 6.5 (n=6), and 3.5 (n=8), respectively. Any-grade treatment-emergent AEs were recorded in groups 1, 2, and 3 for 51 (42.2%; 23 [19.0%] with grade ≥3), 28 (58.3%; 15 [31.3%] with grade ≥3), and 49 (62.8%; 26 [33.3%] with grade ≥3) patients, respectively. No new safety signals were identified. Real-world effectiveness was observed for patients receiving OA monotherapy and in patients who switched from nusinersen or who received subsequent DMTs. Patients who received nusinersen experienced more frequent and severe AEs.

Disease activity after discontinuation of disease-modifying therapies in patients with multiple sclerosis in Argentina: data from the nationwide registry RelevarEM

ABSTRACT Introduction The discontinuation of disease-modifying therapies (DMTs) in multiple sclerosis (MS) is commonly seen in real-world settings due to several factors. Area cover The aim of this study is to describe the frequency of disease activity after discontinuation of DMTs in MS patients included in the Argentinean MS and NMOSD registry. Discusion Patients with relapsing remitting MS (RRMS) and active secondary progressive MS (SPMS) were included based on the following criteria: they discontinued treatment for more than 6 months, they had been treated with a DMT for ≥2 years, and they had at least 6 months of follow-up in the registry after discontinuation. Demographic and clinical data were collected. Disease activity during follow-up was defined as the presence of a clinical relapse or a new magnetic resonance (MRI) lesion (either new lesions on T2-weighted sequence and/or contrast enhancement). Bivariate analysis was applied to identify clinical and demographic factors related to disease activity. Conclusion We included 377 patients (75.5% RRMS, 22.5% SPMS) who had discontinued DMTs. The mean (SD) follow-up after discontinuation was 15.7 (7.9) months. After discontinuation, the presence of relapse was detected in 18.8% and 3.5% in RRMS and SPMS, respectively; and new MRI activity in 22% and 3.5%, respectively. We found that higher risk of relapse and MRI activity was associated with younger age (p < 0.001), shorter disease duration (p < 0.001), and RRMS phenotype (p = 0.006). Males showed higher MRI activity (p 0.011). This study provides real-world data that can guide physicians when considering discontinuation of DMTs.

Influence of diabetes on sacubitril/valsartan titration and clinical outcomes in patients hospitalized for heart failure.

Diabetes mellitus is associated with worse outcomes and lower attainment of disease-modifying therapies in patients with heart failure with reduced ejection fraction (HFrEF). This post hoc analysis of TRANSITION compared the patterns of tolerability and uptitration of sacubitril/valsartan in patients with HFrEF stabilized after hospital admission due to acute decompensated HF depending on the presence or absence of diabetes as a co-morbidity. TRANSITION, a randomized, open-label study compared sacubitril/valsartan initiation pre-discharge vs. post-discharge (up to14days) in 991 patients hospitalized for acutely decompensated HFrEF. The impact of diabetes status on tolerability and safety was studied at 10-week and 26-week post-randomization. Among the 991 patients analysed at baseline, 460 (46.4%) had diabetes and exhibited a higher risk profile. At 10weeks, sacubitril/valsartan target dose (97/103mg bid) was achieved in a similar proportion of patients in each subgroup, when initiated pre-discharge or post-discharge respectively [diabetes subgroup: 47% (n=105/226) vs. 50% (n=115/228); relative risk ratio (RRR), 0.923; P=0.412; non-diabetes subgroup: 45% (n=119/267) vs. 51% (n=133/261); RRR, 0.878; P=0.155]. The proportions of patients achieving and maintaining either 49/51mg or 97/103mg bid [diabetes subgroup: 61.1% (n=138/226) vs. 67.5% (n=154/228); RRR, 0.909; P=0.175; non-diabetes subgroup: 62.9% [n=168/267] vs 69.3% [n=181/261]; RRR, 0.906; P=0.118] or any dose for ≥2weeks leading to Week 10 [diabetes subgroup: 85% (n=192/226) vs. 88.2% (n=201/228); RRR, 0.966; P=0.356; non-diabetes subgroup: 86.9% (n=232/267) vs. 90.8% (n=237/261); RRR, 0.963; P=0.215] were also similar in each subgroup, when initiated pre-discharge or post-discharge, respectively. At 10weeks, hypotension and renal dysfunction rates were similar, although hyperkalaemia was higher among patients with diabetes (15.9% vs. 9.5%). The rate of permanent discontinuation due to adverse events was similar in the diabetes and non-diabetes subgroups at 10weeks, respectively: pre-discharge (7.5% vs. 7.1%) or post-discharge (5.7% vs. 4.2%). Similar patterns of uptitration and tolerability were observed at 26weeks. Cardiac biomarkers including NT-proBNP (P<0.005) and hs-TnT (P<0.005) reduced significantly from baseline levels in both subgroups at Weeks 4 and 10; however, the response was greater among patients without diabetes. Mortality (diabetes vs. non-diabetes subgroups: 3.3% vs 4.0%; P=0.438) and HF rehospitalization (diabetes vs. non-diabetes subgroups: 36.3% vs. 33.0%; P=0.295) did not differ between the groups at 26weeks. Despite a higher risk profile among patients with diabetes, sacubitril/valsartan initiation either before or shortly after discharge in hospitalized patients with HFrEF resulted in comparable rates of dose up-titration and tolerability as in those without diabetes.

The Association Between Persistence and Adherence to Disease-Modifying Therapies and Healthcare Resource Utilization and Costs in Patients With Multiple Sclerosis.

Background: Persistence and adherence to disease-modifying therapies (DMTs) affects treatment efficacy and economic outcomes, both of which contribute to overall patient disease burden. Current literature suggests that patients with multiple sclerosis (MS) who adhere to DMT for 12 months have fewer relapses and reduced MS-related healthcare resource utilization (HCRU) and medical costs than nonadherent patients.Objective: To expand on previous research by estimating the association of persistence and adherence with all-cause and MS-related HCRU and non-DMT costs of patients with MS across 12 and 24 months of therapy use.Methods: This study was a retrospective analysis of adult patients with MS in the IBM MarketScan Commercial and Medicare Supplemental databases using claims data between April 2016 and December 2019. The index date was defined as the initiation of the DMT. Patients were required to have ≥12 months’ continuous enrollment pre-index and ≥12 or ≥24 months’ continuous enrollment post-index. Persistence was defined as no gap in DMT supply for ≥60 days within the post-index period or switch to another DMT. Adherence was calculated using the proportion of days covered (for this study, number of days covered by the DMT was 365 or 730 days), with ≥80% proportion of days covered considered adherent. Multivariable analyses were conducted to estimate total and individual components of non-DMT costs by persistence and adherence while controlling for baseline differences.Results: Patients who were persistent with medication for 12 months showed a reduction in mean total non-DMT medical costs of $10 022 compared with nonpersistent patients; these savings nearly doubled ($19 230) after 24 months of persistence. A similar pattern was observed for adherent vs nonadherent patients (reduction in costs at 12 months, $8543; at 24 months, $16 091). The largest reduction in all-cause HCRU costs was observed in the inpatient setting, while the largest reduction in MS-related costs was observed in the outpatient setting.Discussion: Patients with MS who were persistent and adherent to medication had substantially lower all-cause and MS-related non-DMT medical costs compared with those who were nonpersistent or nonadherent.Conclusions: These findings further support the importance of persistence and adherence to DMTs in patients with MS.

Evolution of Disease Modifying Therapy Benefits and Risks: An Argument for De-escalation as a Treatment Paradigm for Patients With Multiple Sclerosis

BackgroundStrategies for sequencing disease modifying therapies (DMTs) in multiple sclerosis (MS) patients include escalation, high efficacy early, induction, and de-escalation.ObjectiveTo provide a perspective on de-escalation, which aims to match the ratio of DMT benefit/risk in aging patients.MethodsWe reanalyzed data from a retrospective, real-world cohort of MS patients to model disease activity for oral (dimethyl fumarate and fingolimod) and higher efficacy infusible (natalizumab and rituximab) DMTs by age. For patients with relapsing MS, we conducted a controlled, stratified analysis examining odds of disease activity for oral vs. infusible DMTs in patients <45 or ≥45 years. We reviewed the literature to identify DMT risks and predictors of safe discontinuation.ResultsYounger patients had lower probability of disease activity on infusible vs. oral DMTs. There was no statistical difference after age 54.2 years. When dichotomized, patients <45 years on oral DMTs had greater odds of disease activity compared to patients on infusible DMTs, while among those ≥45 years, there was no difference. Literature review noted that adverse events increase with aging, notably infections in patients with higher disability and longer DMT duration. Additionally, we identified factors predictive of disease reactivation including age, clinical stability, and MRI activity.ConclusionIn a real-world cohort of relapsing MS patients, high efficacy DMTs had less benefit with aging but were associated with increased risks. This cohort helps overcome some limitations of trials where older patients were excluded. To better balance benefits/risks, we propose a DMT de-escalation approach for aging MS patients.

Reasons for switching immunomodulatory therapy in patients with relapsing-remitting multiple sclerosis

Aim: The aim of the study was to assess switching disease-modifying therapy in patients with relapsing-remitting multiple sclerosis. Materials and methods: This observational single-centre study involved a retrospective evaluation of data of patients with relapsing-remitting multiple sclerosis receiving disease-modifying therapy under drug programmes reimbursed by the National Health Fund. Demographic data, the level of disability, disease activity and treatment methods were analysed with a particular emphasis on the reasons for switching the therapy. Results: Data were collected from patients with a mean age of 39.6 years, with women accounting for 68%. Therapy was switched in 32% (n = 118) of patients. In this group, 72% (n = 85) of patients modified their first-line treatment, and 28% (n = 33) required switching to a second-line drug. Treatment failure (52.5%, n = 62), followed by treatment intolerance (47.5%, n = 56) were the main reasons for switching. Patients on first line-treatment mostly required switching from interferon beta-1a, which was usually replaced with dimethyl fumarate and glatiramer acetate. The most common adverse events included skin reactions and needle fatigue, which were the most common reasons for switching treatment due to intolerance. Conclusions: The currently used immunomodulatory treatment is relatively well tolerated, and its failure is a more frequent reason for therapy switching. This indicates the need for diseasemodifying treatments that are highly effective, safe and well tolerated.

Application of definitions for conversion to secondary progressive MS in a Danish nationwide population

BackgroundThe number of patients with relapsing remitting multiple sclerosis (RRMS) who convert to secondary progressive (SP) MS is uncertain, and with emerging treatment options for SPMS, it is important to identify RRMS patients in transition to the SP phase. The objective of the present study was to characterize clinical parameters and use of disease modifying therapies in patients diagnosed with SPMS and RRMS patients already entered the SP phase by use of the Danish Multiple Sclerosis Registry (DMSR). MethodsWe used a cross-sectional design, including all living patients with MS as of June 30, 2020 from DMSR. First, we applied the MSBase definition of SPMS on all RRMS patients. Second, we applied the slightly modified inclusion criteria from the EXPAND clinical trial on patients with clinically confirmed SPMS and patients with RRMS fulfilling the MSBase definition of SPMS to identify SPMS patients recently progressed who may benefit from treatment with disease modifying therapy. We compared clinical characteristics and disease-modifying therapy use in the different patient groups. ResultsAmong patients with clinically confirmed SPMS, application of a slightly modified EXPAND trial inclusion criteria for SPMS (m-EXPAND) captured patients who had converted to SPMS more recently and who had relapsed and initiated high-efficacy treatment more frequently. Moreover, our RRMS patients fulfilling the “SPMS”-criteria according to MSBase and recently progression according to m-EXPAND had similar characteristics and remarkably resembled the SPMS population in the EXPAND trial. ConclusionOur results indicate that data-driven diagnostic definitions might help identify RRMS patients at risk for SPMS and we highlight the challenges and reluctance in diagnosing SPMS in clinical practice.