Prevalence and burden of multiple sclerosis-related fatigue: a systematic literature review.

BACKGROUND: Multiple sclerosis (MS) is a chronic, demyelinating disease of the central nervous system that results in progressive and irreversible disability. Fatigue is one of the most common MS-related symptoms and is characterized by a persistent lack of energy that impairs daily functioning. The burden of MS-related fatigue is complex and multidimensional, and to our knowledge, no systematic literature review has been conducted on this subject. The purpose of this study was to conduct a systematic literature review on the epidemiology and burden of fatigue in people with multiple sclerosis (pwMS). METHODS: Systematic searches were conducted in MEDLINE, Embase, and Evidence-Based Medicine Reviews to identify relevant studies of fatigue in pwMS. English-language records published from 2010 to January 2020 that met predefined eligibility criteria were included. We initially selected studies that reported quality of life (QoL) and economic outcomes according to categories of fatigue (e.g., fatigued vs non-fatigued). Studies assessing associations between economic outcomes and fatigue as a continuous measure were later included to supplement the available data. RESULTS: The search identified 8147 unique records, 54 of which met the inclusion criteria. Of these, 39 reported epidemiological outcomes, 11 reported QoL, and 9 reported economic outcomes. The supplementary screen for economic studies with fatigue as a continuous measure included an additional 20 records. Fatigue prevalence in pwMS ranged from 36.5 to 78.0%. MS-related fatigue was consistently associated with significantly lower QoL. Results on the economic impact of fatigue were heterogeneous, but most studies reported a significant association between presence or severity of fatigue and employment status, capacity to work, and sick leave. There was a gap in evidence regarding the direct costs of MS-related fatigue and the burden experienced by caregivers of pwMS. CONCLUSION: Fatigue is a prevalent symptom in pwMS and is associated with considerable QoL and economic burden. There are gaps in the evidence related to the direct costs of MS-related fatigue and the burden of fatigue on caregivers. Addressing fatigue over the clinical course of the disease may improve health and economic outcomes for patients with MS.

The impact of race on survival in metastatic prostate cancer: a systematic literature review.

BACKGROUND: Prostate cancer (PC) is the second most diagnosed cancer in men worldwide. While racial and ethnic differences exist in incidence and mortality, increasing data suggest outcomes by race among men with newly diagnosed PC are similar. However, outcomes among races beyond Black/White have been poorly studied. Moreover, whether outcomes differ by race among men who all have metastatic PC (mPC) is unclear. This systematic literature review (SLR) provides a comprehensive synthesis of current evidence relating race to survival in mPC. METHODS: An SLR was conducted and reported in accordance with PRISMA guidelines. MEDLINE®, Embase, and Cochrane Library using the Ovid® interface were searched for real-world studies published from January 2012 to July 2022 investigating the impact of race on overall survival (OS) and prostate cancer-specific mortality (PCSM) in patients with mPC. A supplemental search of key congresses was also conducted. Studies were appraised for risk of bias. RESULTS: Of 3228 unique records identified, 62 records (47 full-text and 15 conference abstracts), corresponding to 54 unique studies (51 United States and 3 ex-United States) reporting on race and survival were included. While most studies showed no difference between Black vs White patients for OS (n = 21/27) or PCSM (n = 8/9), most showed that Black patients demonstrated improved OS on certain mPC treatments (n = 7/10). Most studies found no survival difference between White patients and Hispanic (OS: n = 6/8; PCSM: n = 5/6) or American Indian/Alaskan Native (AI/AN) (OS: n = 2/3; PCSM: n = 5/5). Most studies found Asian patients had improved OS (n = 3/4) and PCSM (n = 6/6) vs White patients. CONCLUSIONS: Most studies found Black, Hispanic, and AI/AN patients with mPC had similar survival as White patients, while Black patients on certain therapies and Asian patients showed improved survival. Future studies are needed to understand what aspects of race including social determinants of health are driving these findings.

Indirect treatment comparison of anifrolumab efficacy versus belimumab in adults with systemic lupus erythematosus.

Aim: Assess the comparative efficacy of anifrolumab 300 mg versus belimumab 10 mg/kg in adults with moderate-to-severe systemic lupus erythematosus (SLE) receiving standard therapy. Patients and methods: Population-adjusted simulated treatment comparisons (primary analyses) and matching-adjusted indirect comparisons (supporting analyses) were conducted using individual patient data from TULIP-1/TULIP-2 and summary-level data from BLISS-52/BLISS-76. Results: Compared with belimumab-treated patients, anifrolumab-treated patients were more than twice as likely to achieve a reduction of four or more points in SLE Disease Activity Index 2000 score (simulated treatment comparison odds ratio: 2.47; 95% CI: 1.16-5.25) and SLE Responder Index-4 response (odds ratio: 2.61; 95% CI: 1.22-5.58) at 52 weeks. Conclusion: Patients with moderate-to-severe SLE are more likely to achieve an improvement in disease activity with anifrolumab than with belimumab.

Simulated treatment comparison of efficacy outcomes for ofatumumab in ASCLEPIOS I/II versus ocrelizumab in OPERA I/II for the treatment of patients with relapsing multiple sclerosis.

BACKGROUND: Ofatumumab is a subcutaneously administered anti-CD20 monoclonal antibody (MoAb) therapy that has been evaluated in two identically designed randomized controlled trials (RCTs), ASCLEPIOS I (NCT02792218) and ASCLEPIOS II (NCT02792231), in patients with relapsing multiple sclerosis (RMS). Ocrelizumab is another anti-CD20 MoAb therapy, administered intravenously, that has been evaluated in two identically designed RCTs, OPERA I (NCT01247324) and OPERA II (NCT01412333) in RMS. Given the absence of published RCTs with head-to-head comparisons between these MoAbs, this study assessed the indirect comparative efficacy of ofatumumab and ocrelizumab. METHODS: Given the availability of individual patient data for ASCLEPIOS I/II and summary-level data for OPERA I/II, simulated treatment comparisons were used to assess the comparative efficacy of ofatumumab versus ocrelizumab while adjusting for differences in baseline characteristics between trials. Comparative efficacy was estimated for the proportion of patients with 3- and 6-month confirmed disability progression (CDP) and for annualized relapse rate (ARR). Exploratory analyses were conducted for the outcome of no evidence of disease activity based on three parameters (NEDA-3) and magnetic resonance imaging (MRI) outcomes (proportion of patients with gadolinium-enhancing T1 lesions and brain volume change). RESULTS: Although comparative results were not significant for 3-month CDP (hazard ratio [HR]: 0.90 [95% confidence interval [CI]: 0.57-1.42]) or 6-month CDP (HR: 0.84 [95% CI: 0.47-1.49]), ofatumumab showed a significant improvement in ARR (rate ratio: 0.60 [95% CI: 0.43-0.84]) compared with ocrelizumab. Significantly favorable results were also associated with ofatumumab for NEDA-3 and MRI outcomes. CONCLUSION: Ofatumumab was associated with more favorable efficacy results compared with ocrelizumab for clinical, NEDA-3, and MRI outcomes.

Indirect comparisons of siponimod with fingolimod and ofatumumab in multiple sclerosis: assessing the feasibility of propensity score matching analyses.

OBJECTIVE: Head-to-head trials comparing siponimod with fingolimod or ofatumumab in patients with multiple sclerosis (MS) are lacking. Instead, the comparative efficacy of siponimod can be derived from indirect treatment comparisons (ITCs). We assessed the suitability of ITCs leveraging individual patient data from relevant phase III trials across different MS phenotypes. METHODS: One siponimod trial in patients with secondary progressive MS (SPMS), four fingolimod trials (three in relapsing-remitting MS [RRMS], and one in primary progressive MS [PPMS]), and two ofatumumab trials in relapsing MS (RMS) were considered. The suitability of ITCs was evaluated based on trial design, patient eligibility criteria, baseline patient characteristics, placebo response, and outcome definitions for each trial. Analyses deemed feasible were conducted using one-to-one propensity score matching (PSM). RESULTS: An ITC between siponimod in SPMS and either fingolimod in RRMS or ofatumumab in RMS was not feasible because of insufficient overlap in key patient characteristics (e.g. disability level and relapse history) and differences in placebo response. However, a comparison between siponimod in SPMS and fingolimod in PPMS was feasible because of sufficient overlap in eligibility criteria and baseline characteristics. One-to-one PSM demonstrated siponimod was favored relative to fingolimod for time to 6- and 3-month confirmed disability progression though not significantly different (hazard ratio 0.76 [95% confidence interval 0.48-1.20; p-value = .240] and hazard ratio 0.80 [95% confidence interval 0.52-1.22; p-value = .300], respectively). CONCLUSIONS: For trials in MS, clinical phenotype is an important determinant of ITC feasibility. An ITC between siponimod in SPMS and either fingolimod in RRMS or ofatumumab in RMS was not feasible. The only feasible comparison was between siponimod in SPMS and fingolimod in PPMS.

Efficacy classification of modern therapies in multiple sclerosis.

Background: The Association of British Neurologists (ABN) 2015 guidelines suggested classifying multiple sclerosis therapies according to their average relapse reduction. We sought to classify newer therapies (cladribine, ocrelizumab, ofatumumab, ozanimod) based on these guidelines. Materials & methods: Therapies were classified by using direct comparative trial results as per ABN guidelines and generating classification probabilities for each therapy based on comparisons versus placebo in a network meta-analysis for annualized relapse rate. Results: For both approaches, cladribine and ofatumumab were classified as high efficacy. Ocrelizumab and ozanimod (1.0 mg) were classified as moderate or high efficacy depending on the approach used. Conclusion: Cladribine and ofatumumab have an efficacy comparable with therapies classified in the ABN guidelines as high efficacy.

Comparison of ofatumumab and other disease-modifying therapies for relapsing multiple sclerosis: a network meta-analysis.

Aim: To compare the efficacy of ofatumumab to other disease-modifying therapies (DMTs) for relapsing multiple sclerosis (RMS). Materials & methods: A network meta-analysis was conducted to determine the relative effect of ofatumumab on annualized relapse rate and confirmed disability progression at 3 months and 6 months. Results: For each outcome, ofatumumab was as effective as other highly efficacious monoclonal antibody DMTs (i.e., alemtuzumab, natalizumab and ocrelizumab). Conclusion: Ofatumumab offers beneficial outcomes for RMS by reducing relapse and disability progression risk.

The importance of considering differences in study and patient characteristics before undertaking indirect treatment comparisons: a case study of siponimod for secondary progressive multiple sclerosis.

Background: Indirect treatment comparisons (ITCs) provide valuable evidence on comparative efficacy where head-to-head clinical trials do not exist; however, differences in patient populations may introduce bias. Therefore, it is essential to assess between-trial heterogeneity to determine the suitability of synthesizing ITC results. We provide an illustrative case study in multiple sclerosis (MS) where we assess the feasibility of conducting ITCs between siponimod and interferon beta-1b (IFN ß-1b) and between siponimod and ocrelizumab.Methods: We assessed the feasibility of conducting ITCs using standard unadjusted methods (e.g. Bucher or network meta-analysis [NMA]) as well as matching-adjusted indirect comparisons (MAICs) using individual patient data (IPD) from the siponimod (EXPAND) trial, based on guidance from NICE. Time to confirmed disability progression (CDP) at 3 or 6 months was assessed.Results: Bucher ITCs and NMAs, which rely on summary-level data, were not able to account for important cross-trial differences. Comparisons between siponimod and IFN ß-1b were feasible using MAIC; the HRs (95% CI) for CDP-6 and CDP-3 were 0.55 (0.33-0.91) and 0.82 (0.42-1.63), respectively. ITCs were not feasible between siponimod and ocrelizumab because study designs and patient populations were too dissimilar to conduct a reliable ITC.Conclusions: This study highlights the importance of conducting a detailed feasibility assessment before undertaking ITCs to illuminate when excessive between-trial heterogeneity would cause biased results. MAIC was performed for siponimod and IFN ß-1b in the absence of a head-to-head trial and was considered a more valid approach than a traditional ITC to examine comparative effectiveness.

Matching-adjusted indirect treatment comparison of siponimod and other disease modifying treatments in secondary progressive multiple sclerosis.

Background: Siponimod, interferon beta-1a (IFNß-1a), IFNß-1b and natalizumab have been evaluated as treatments for secondary progressive multiple sclerosis (SPMS) in separate randomized controlled trials (RCTs), but not head-to-head. These trials included heterogeneous patient populations, which limits the use of standard network meta-analysis (NMA) for indirect treatment comparison (ITC) of relative efficacy. Matching-adjusted indirect comparison (MAIC) aims to correct these cross-trial differences. We compared siponimod to other disease modifying treatments (DMTs) in SPMS using MAIC.Methods: Individual patient data (IPD) were available for siponimod (EXPAND), while only published summary data were available for IFNß-1a (Nordic Study, SPECTRIMS, IMPACT), IFNß-1b (North American Study, European Study) and natalizumab (ASCEND). MAICs were conducted between siponimod and the other DMTs by re-weighting patients in EXPAND based on logistic regression.Results: Siponimod was determined to be statistically significantly more effective for the outcome of time to 6 month confirmed disability progression (CDP) compared with 22 µg IFNß-1a and 250 µg IFNß-1b, and for the outcome of time to CDP-3 compared with 60 µg IFNß-1a. Siponimod was numerically but not statistically superior for CDP in all other comparisons. For annualized relapse rate (ARR), with the exception of natalizumab, siponimod was numerically but not statistically superior to all comparators.Conclusions: EXPAND provides evidence of the efficacy of siponimod compared with placebo, and these MAICs complement this by demonstrating improved efficacy of siponimod relative to DMTs. Siponimod offers a significant therapeutic advance that may slow disease progression compared to other DMTs in an EXPAND-like population with secondary progressive disease.