Objective: To assess the comparative efficacy and safety of cladribine tablets versus alternative disease modifying treatments (DMTs) in patients with active relapsing-remitting multiple sclerosis ...(RRMS), and in a subgroup with high disease activity (HRA + DAT), using systematic literature review (SLR) and network meta-analysis (NMA).
Methods: MEDLINE, Embase, MEDLINE In-Process and CENTRAL databases were systematically searched to identify English-language publications of relevant studies of approved DMTs for RRMS. Searches were conducted from database inception to January 2017. Conference websites and trial registries were also searched. NMA considered the effects of DMTs on annualized relapse rate (ARR), confirmed disease progression (CDP), no evidence of disease activity (NEDA) and safety.
Results: Of 10,825 articles retrieved and screened, 44 studies assessing 12 DMTs contributed to the NMA. In patients with active RRMS, cladribine tablets were associated with a significant 58% reduction in ARR versus placebo (p < .05); cladribine tablets were similar or significantly better than other DMT regimens and ranked fourth among DMTs, behind alemtuzumab, natalizumab and ocrelizumab. For CDP for 6 months and NEDA, improvements with cladribine tablets were significantly greater than those of placebo (p < .05), with no comparator DMT demonstrating significantly better results. Similar findings were reported in the HRA + DAT population. Overall adverse event risk for cladribine tablets did not differ significantly from that of placebo and most alternative DMTs.
Conclusion: In this first NMA to consider cladribine tablets, ocrelizumab and daclizumab for treatment of RRMS, cladribine tablets are a comparatively effective and safe alternative to other DMTs in both active RRMS and HRA + DAT populations.
Objectives: To estimate the comparative efficacy of cladribine tablets versus alternative disease modifying therapies (DMTs) - fingolimod, natalizumab, alemtuzumab and ocrelizumab - in adults with ...active relapsing-remitting multiple sclerosis (RRMS), using meta-regression to provide subpopulation-specific estimates of drug effect. Additionally, to determine the feasibility of conducting a matching-adjusted indirect comparison (MAIC) to validate the meta-regression results.
Methods: A published systematic literature review (SLR) identified studies evaluating the efficacy of cladribine tablets and alternative DMTs in the management of active RRMS. A series of meta-regression models were run with adjustment for baseline risk, fitted to data from the intention-to-treat cohorts of trials identified in the SLR. A non-parametric MAIC analysis adjusted for differences between studies by reweighting patient-level data from the index trial to match the mean baseline characteristics reported for trials with only aggregate data.
Results: The meta-regression analysis showed significant overlap in credible intervals for the hazard ratios of 6 month confirmed disability progression (CDP-6M) and annualized relapse rate (ARR), with no therapy statistically dominating in terms of efficacy and all therapies estimated to reduce the ARR compared to placebo in all subpopulations. In the MAIC analysis, cladribine tablets showed a reduction in CDP-6M and ARR comparable to alemtuzumab before and after matching.
Conclusion: This analysis has demonstrated that cladribine tablets have comparable relative efficacy to other highly efficacious DMTs in active RRMS across all subpopulations, thus validating the comparative effectiveness results from previous network meta-analysis. The MAIC analysis showed that cladribine tablets are comparable in efficacy to alemtuzumab in the treatment of patients with RRMS.
Aims: Cladribine tablets were the first oral short-course treatment approved for highly active relapsing multiple sclerosis (MS). The Association of British Neurologists guidelines currently ...recommend two infusion therapies, alemtuzumab and natalizumab, to treat high disease activity relapsing remitting MS (HDA-RRMS). This analysis assessed the cost-effectiveness of cladribine tablets in HDA-RRMS compared with alemtuzumab and natalizumab, from the perspective of the National Health Service (NHS) in England.
Materials and methods: A cohort-based Markov model with 11 health states (10 Expanded Disability Status Scale EDSS plus death) was developed. Transition matrices from the British Columbia registry were used to model the natural history of EDSS. The treatment effect on EDSS was modelled using hazard ratios for 6-month confirmed disability progression from an indirect treatment comparison (ITC). Relapses and drug-related adverse events were modeled via annualized relapse rates and event probabilities, with associated costs and quality-adjusted life year (QALY) losses. Utilities were derived from trials and the literature, and costs from NHS and literature sources. Uncertainty was assessed via probabilistic and deterministic sensitivity analyses.
Results: Cladribine tablets were dominant (i.e., less costly and more effective) vs alemtuzumab and natalizumab in pairwise comparisons, and the dominant strategy in fully incremental analyses. Incremental cost was driven largely by drug acquisition and administration costs, and incremental QALY gain largely by differences in delayed EDSS progression. Cladribine tablets had a 93% probability of being cost-effective at a threshold of GBP 30,000 per QALY gained, and remained dominant across the scenario analyses tested. The greatest influence on results was the treatment effect on disability progression derived from the ITC.
Limitations: Uncertainty over the efficacy of DMT beyond trial durations. In line with other comparative effectiveness analyses, the network meta-analysis informing this cost-effectiveness analysis was associated with a degree of uncertainty. No treatment switching analyses were undertaken.
Conclusions: Cladribine tablets are a cost-effective alternative to alemtuzumab and natalizumab in the treatment of HDA-RRMS from the perspective of the NHS in England.
Relapsing-remitting multiple sclerosis (RRMS) patients with high disease activity (HDA) experience more severe disease than those without HDA. This analysis describes the efficacy of cladribine ...tablets 3.5 mg/kg in HDA patient subgroups that were either treated with disease-modifying drugs (DMDs) prior to study entry or were treatment naïve.
Post hoc analysis of the 96 week Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) study compared cladribine tablets 3.5 mg/kg to placebo in subgroups of patients meeting the high relapse activity plus disease activity on treatment definition of HDA. Patients were categorized into either prior DMD treatment or DMD treatment-naïve subgroups. Endpoints included annualized relapse rate (ARR), time to first relapse, time to disability progression and magnetic resonance imaging (MRI) outcomes. No inferential statistical analyses were conducted between subgroups.
The DMD-naïve cohort (n = 187) was larger than the prior-DMD cohort (n = 102). In both the DMD-naïve and prior-DMD cohorts, cladribine tablets were associated with a reduction in ARR (rate ratio RR: 0.26; 95% confidence interval CI: 0.16-0.42; p < .0001 and RR: 0.55; 95% CI: 0.32-0.95; p = .0324, respectively). In both subgroups, cladribine tablets increased the time to relapse versus placebo (hazard ratio HR: 0.36; 95% CI: 0.21-0.62; p = .0002 for DMD-naïve cohort and HR: 0.50; 95% CI: 0.24-1.02; p = .0557 for prior-DMD cohort). Significant differences were observed for all assessed disability and MRI outcomes independently of previous treatment.
Post hoc evidence suggests consistent treatment benefits of cladribine tablets 3.5 mg/kg during the 96 week CLARITY study among HDA-RRMS patients who were either previously treated with DMDs or were treatment naïve.
•Real-world treatment patterns and effectiveness of cladribine tablets were investigated among 539 US patients with relapsing forms of multiple sclerosis using a large claims database.•The majority ...of patients (93 %) did not switch treatment during the follow-up period.•Additionally, 83 % of patients were relapse-free during the 2-year follow-up period.•Overall, patients showed improved clinical outcomes and reduced corticosteroid use.
Real-world evidence on the use of cladribine tablets (CladT) for relapsing forms of multiple sclerosis (RMS) in the United States is emerging. The objective of this study was to assess the real-world treatment patterns and effectiveness of CladT in RMS.
Adults with RMS initiating CladT were selected from the Symphony Integrated Dataverse. Baseline and follow-up periods were the 12 months before and 24 months after CladT initiation (index date). Switching to another disease-modifying therapy (DMT) and number of CladT courses were described during follow-up. Annualized relapse rate (ARR), MS disease severity, Expanded Disability Status Scale-Derived Disability Indicators (EDSS-DDI), corticosteroid use, and healthcare resource utilization (HRU) were described during Years 1 and 2 of follow-up and compared with baseline.
A total of 539 CladT-treated patients were included (mean age: 49.9 years; 77.6 % female). Over the 2-year follow-up, 91 % and 59 % of patients had one and two CladT courses, respectively, and 7 % of patients had evidence of switching to another DMT. ARR, MS disease severity score, and corticosteroid use decreased significantly during follow-up compared with baseline, while EDSS-DDI remained stable. All-cause and MS-related HRU decreased during follow-up.
CladT-treated patients with RMS had low switch rates, reduced ARR, disease severity, corticosteroid use, and HRU.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective: To estimate real-world treatment patterns, safety, and relapse outcomes of subcutaneous (sc) interferon (IFN) β-1a (Rebif) vs dimethyl fumarate (DMF; Tecfidera), to treat ...relapsing-remitting multiple sclerosis (RRMS).
Methods: A US retrospective chart review of 450 randomly selected adults newly diagnosed with RRMS who received sc IFN β-1a (n = 143) or DMF (n = 307) was conducted. Patients were either (a) treatment-naïve, initiating first-line treatment with sc IFN β-1a or DMF, or (b) previously treated, switching to sc IFN β-1a or DMF. Two years' follow-up data were captured. Patient characteristics, persistence, and adverse events between treatment groups were compared using t-tests or Chi-square tests. Kaplan-Meier curves with log-rank tests and Cox proportional hazards models were used to compare time to, and risk of non-persistence. Annualized Relapse Rates (ARR) were calculated using a robust variance Poisson model adjusting for covariates. Propensity scores were used to address possible selection bias.
Results: One hundred and twelve patients became non-persistent, most commonly due to an adverse event (n = 37). No difference was observed in time to overall non-persistence between sc IFN β-1a and DMF patients. Among treatment-naïve patients, those receiving DMF had 2.4-times the risk (HR = 2.439, 95% CI = 1.007-5.917, p = .0483) of experiencing a discontinuation than patients receiving sc IFN β-1a. Non-persistent patients receiving DMF had 2.3-times the risk (HR = 2.311, 95% CI = 1.350-3.958, p = .0023) of experiencing an adverse event at a given time point than patients prescribed sc IFN β-1a. No differences in relapse risk or ARR between sc IFN β-1a- and DMF-treated patients were observed.
Conclusions: sc IFN β-1a-treated patients had comparable persistence and relapse outcomes, and better safety outcomes vs DMF-treated patients across 2 years.
Objective: Rituximab is used as an off-label treatment for relapsing-remitting multiple sclerosis (RRMS); however, the comparative efficacy and safety of rituximab versus currently licensed ...disease-modifying drugs (DMDs) for RRMS is unknown. A systematic literature review was conducted to evaluate the available data pertaining to efficacy and safety of rituximab in adult patients with RRMS and highly active relapsing multiple sclerosis (HA-RMS); data quality was critically assessed via risk of bias (RoB) assessment.
Methods: Biomedical literature databases were searched until mid-2018 and key proceedings were searched from 2016 to 2018. Critical appraisal of non-randomized studies was conducted using the Cochrane RoB assessment tool; randomized controlled trials (RCTs) were appraised using comprehensive assessment criteria based on the NICE guidelines.
Results: Thirty-eight unique studies based on 49 publications were identified: 25 RRMS studies (one RCT) and 13 HA-RMS studies (no RCTs). The evidence among patients with RRMS generally favored rituximab in comparison to placebo (relapse rate) and interferons/glatiramer acetate (relapse rate and disability progression), although much of the non-randomized data were descriptive and/or not statistically significant. In comparison to placebo, rituximab was associated with a greater risk of adverse events. Two-thirds of the non-randomized RRMS studies were associated with critical/serious RoB; the single RCT was associated with low RoB. Furthermore, all of the non-randomized HA-RMS studies were associated with critical/serious RoB.
Conclusions: Available evidence of off-label rituximab use for the treatment of patients with RRMS suggests generally favorable efficacy versus placebo and interferons/glatiramer acetate; however, the poor quality of the included studies limits any robust conclusions.
This study aims to compare the disease progression and disease-modifying treatment–switching patterns between patients with high-disease-activity (HDA) relapsing-remitting multiple sclerosis (RRMS) ...and patients with low-disease-activity (LDA) RRMS in real-world clinical practice.
The confirmed disease progression and time to switch of 6647 patients from the Swedish multiple sclerosis registry were analyzed using a marginal structural model that compared patients with relapsing HDA (HDA-R) and lesion HDA (HDA-L) following definitions in European labels of disease-modifying therapies with patients with LDA. Time to milestone and stratified drug cohort analyses were used for internal validation.
A total of 262 patients with LDA, 985 patients with HDA-R, and 683 patients with HDA-L were included in the primary analysis. The HDA-R subgroup had statistically significant greater risk of disease progression (hazard ratio = 1.23; 95% CI, 1.03–1.46) and no difference in time to switch compared with the LDA subgroup. The HDA-L subgroup had statistically significant shorter time to switch (hazard ratio = 1.47; 95% CI, 1.31–1.66) and no difference in disease progression compared with the LDA subgroup.
Compared with past research on HDA RRMS grounded mainly in randomized controlled trials of individual disease-modifying therapies, the main contribution of this study is that HDA, as identified by relapses, in real-world clinical settings has a clearer association with disease progression than HDA identified by new magnetic resonance imaging lesions. Taking into account that the HDA-L subgroup had a shorter time to switch, there is evidence of an unmet need for effective treatments in clinical practice for both the HDA-R and HDA-L subgroups.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Introduction
To develop a simulation model assessing the efficiency of using cladribine tablets versus infusion-based disease-modifying drugs (DMDs) for the treatment of relapsing-remitting multiple ...sclerosis (RRMS) from a facility perspective in the UK
.
Methods
A scheduling algorithm was developed to simulate day-case admissions and calculate the mean changes to resource use and time burden for patients in a facility that transitions from infusion-based treatments to cladribine tablets over 1 year. Model inputs and assumptions were based on previous research and expert opinion. Model validation and quality checks were performed and additional scenario analyses were also conducted
.
Results
The model successfully scheduled all infusion treatments in the base case and no patients were left off the schedule as a result of lack of capacity. Modeled base-case outcomes increased in future scenarios owing to a 35% increase in demand. The introduction of cladribine tablets reduced these impacts. Specifically, the difference in mean daily utilization was reduced in the future scenario from 13% to 3% as 8% of patients moved to cladribine tablets; annual administration costs decreased by 96% and annual time burden decreased by 90%. Results from additional scenarios showed the largest benefits from switching current infusion patients to cladribine tablets were realized in facilities having moderate to high resource utilization.
Conclusions
This model provides facility decision-makers the ability to assess the efficiency of using cladribine tablets rather than an infusion-based DMD. The simulation quantified the benefits gained from reducing the burden on facility resources by switching some patients with RRMS from infusion-based DMDs to cladribine tablets. Overall, modeled outcomes increased in future scenarios owing to an increase in demand, although the introduction of cladribine tablets reduced this impact.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Liver resection is a key therapeutic strategy to improve survival in patients with colorectal cancer liver metastases. Underutilization may negatively affect outcomes. Using a Web-based ...survey and standardized imaging scenarios, this study assessed medical oncologists’ (MOs) perceptions of resectability, preferences for chemotherapy sequencing, and referral for surgical consultation in a static patient profile of good performance status and no extrahepatic spread but varying bulk and distribution of disease.
Methods
A total of 190 US-based MOs were surveyed. A single patient profile was created and combined with 10 different sets of liver computed tomographic images displaying a broad spectrum of metastases. Assessments of resectability and ranking were compared with the results obtained from an expert panel of 3 hepatic surgeons.
Results
The expert hepatic surgeons designated 8 scans resectable, 1 borderline resectable/convertible, and 1 unresectable. In the 8 resectable cases, 34.4 % of MOS perceived the case to be initially resectable, 41.7 % potentially resectable after chemotherapy response, and 23.9 % unresectable. Increasing number of lesions, larger tumor diameter, and bilateral disease were associated with lower resectability perception (
P
< 0.01). Among those cases considered resectable by MOs, they preferred initial resection (54.2 %) over neoadjuvant chemotherapy (38.4 %). Initial referral for surgical consultation was generally favored only for cases considered initially resectable by MOs.
Conclusions
This study confirms both potential discrepancies between MOs’ and hepatic surgeons’ perception of resectability and underutilization of early surgical consultation for patients with potentially resectable colorectal cancer liver metastases and underscores the importance of an evaluation that includes an experienced hepatic surgeon.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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