NAPS-MS: Natalizumab Effects on Parameters of Sleep in Patients with Multiple Sclerosis.

BACKGROUND: Patients with multiple sclerosis (MS) have higher rates of fatigue, mood disturbance, and cognitive impairments than healthy populations. Disease-modifying agents may affect sleep. Although patients taking natalizumab often show improvement in fatigue during the first year of therapy, the mechanism behind this effect is unknown. The aim of the NAPS-MS study was to investigate whether natalizumab affected objective measures of sleep as determined by polysomnography (PSG) and multiple sleep latency testing (MSLT) in patients with MS with fatigue or sleepiness initiating therapy. Additional goals were to evaluate changes in measures of fatigue, mood, and cognition and to correlate these measures with objective sleep measures. METHODS: Patients underwent PSG and MSLT before their first natalizumab infusion and after their seventh. Patients completed the Modified Fatigue Impact Scale, Fatigue Severity Scale (FSS), Epworth Sleepiness Scale (ESS), and visual analogue scale for fatigue (VAS-F) at their first, fourth, and seventh natalizumab infusions. NeuroTrax cognitive tests and the Hospital Anxiety and Depression Scale (HADS) were performed at the first and seventh natalizumab infusions. RESULTS: Changes in sleep efficiency, wakefulness after sleep onset, and multiple sleep latency from baseline to 6 months of therapy did not reach significance. The FSS, VAS-F, ESS, and HADS scores were significantly improved after 6 months of therapy; cognitive scores were not significantly improved. CONCLUSIONS: Although treatment with natalizumab was associated with improvements in fatigue, sleepiness, and mood, changes in objective measures of sleep were not significant.

Treatment selection and experience in multiple sclerosis: survey of neurologists.

BACKGROUND: Multiple sclerosis (MS) is a complex disease with many therapeutic options. Little is known about how neurologists select particular disease-modifying therapies (DMTs) for their patients. OBJECTIVE: To understand how neurologists make decisions regarding the prescription of DMTs for patients with MS, and to explore neurologists' experiences with individual DMTs. METHODS: From December 2012 to January 2013, members of a nationwide physician market research panel were sent an online study invitation with a link to a survey website. Eligible neurologists were included if they currently practice medicine in the United States, and if they treat ≥20 patients with MS. RESULTS: A total of 102 neurologists (n=63 general neurologists; n=39 MS specialists; 81.4% male) completed the survey. The mean (standard deviation) number of years in practice since completing medical training was 16.4 (8.6) years. Overall, the most commonly prescribed DMTs were subcutaneous interferon (IFN) ß-1a and glatiramer acetate; approximately 5.5% of patients were untreated. The most important attributes of DMT medication selection were (in order of importance) efficacy, safety, tolerability, patient preference, and convenience. The DMT with the highest neurologist-reported percentage of patients who were "Very/Extremely Satisfied" with their therapy was fingolimod (31.0%), followed by glatiramer acetate (13.9%; P=0.017). Compared with fingolimod (94.0%), significantly fewer (P<0.05) neurologists reported that "All/Most" of their patients were adherent to treatment with glatiramer acetate (78.0%), subcutaneous IFN ß-1a (84.0%), and IFN ß-1b (75.0%); no significant differences were observed with intramuscular IFN ß-1a (92.9%; P=0.75). Patients' calls to neurologists' offices were most commonly related to side effects for all self-injectable DMTs, whereas calls about fingolimod primarily involved insurance coverage issues. CONCLUSION: Our survey results showed that very few patients with MS did not received any DMT. Among the DMTs available at the time of the survey, neurologists reported that patients were most satisfied with, and adherent to, fingolimod, but these patients also faced more problems with insurance coverage when compared with those taking self-injectable DMTs.

Compliance to fingolimod and other disease modifying treatments in multiple sclerosis patients, a retrospective cohort study.

BACKGROUND: Adherence to disease-modifying therapies (DMTs) results in the reduction of the number and severity of relapses and delays the progression of multiple sclerosis (MS). Patients with lower adherence rates experience more inpatient visits and higher MS-related medical costs. Fingolimod, the first oral DMT approved by the US Food and Drug Administration, may improve the access and compliance to MS treatment when compared to injectable DMTs. METHODS: This retrospective cohort study used pharmacy claims from Medco Health Solutions, Inc., of patients who initiated DMTs between October 2010 and February 2011. Initiation was defined as no prescription fills for the same DMT in the prior 12 months. Patients without a DMT prescription fill 12 months before the index date were considered naïve users. Compliance was measured via proportion of days covered (PDC) and medication possession ratio (MPR) for 12 months post-index. Discontinuation was defined as a ≥60-day gap of index DMT supply. Cox proportional hazard models compared time to discontinuation between cohorts. RESULTS: Of 1,891 MS patients (mean age: 45.7; female: 76.4%), 13.1% initiated fingolimod, 10.7% interferon beta-1b, 20.0% intramuscular interferon beta-1a, 18.8% subcutaneous interferon beta-1a, and 37.4% glatiramer acetate. Patients initiating fingolimod had highest average PDC and MPR in both experienced (fingolimod: mean PDC=0.83, 73.7% with PDC≥0.8; mean MPR=0.92, 90.5% with MPR≥0.8) and naïve DMT users (fingolimod: mean PDC=0.80, 66.7% with PDC≥0.8; mean MPR=0.90, 87.4% with MPR≥0.8). The proportion of patients discontinuing index DMT within 12 months was significantly lower for the fingolimod cohort (naïve: 31.3%; experienced: 25.7%). Adjusted results found that patients receiving self-injected DMTs discontinued significantly sooner than fingolimod users. This association was generally stronger in experienced DMT users. CONCLUSIONS: Fingolimod initiators were more compliant, less likely to discontinue treatment, and discontinued later than patients who initiated self-injected DMT.

A cross-sectional survey of patient satisfaction and subjective experiences of treatment with fingolimod.

BACKGROUND: Fingolimod is the first oral disease-modifying therapy indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS) to reduce the frequency of clinical relapses and delay the progression of physical disability caused by MS. OBJECTIVE: To obtain data from MS patients who have taken fingolimod regarding their treatment choice, first-dose observation (FDO) experience, and treatment satisfaction. METHODS: Patients ≥ 18 years old with physician-diagnosed MS in the United States who had taken at least one dose of fingolimod for the treatment of MS were invited to complete a web-based survey, which captured information on the reasons for starting fingolimod, FDO experience, and treatment satisfaction as measured by the Treatment Satisfaction Questionnaire for Medication (TSQM). A high TSQM scale score denotes high satisfaction. RESULTS: Survey respondents (n = 380; 55% female) had a mean (standard deviation) age of 39.8 (12.6) years, and a mean (standard deviation) duration of MS of 9.8 (10.3) years. Overall, more than 80% of patients reported the first dose was moderately/very/extremely manageable, convenient, and easy to take. Although 80% of patients reported experiencing a side effect with the first dose, most were highly tolerable and only eleven patients (2.9%) reported they were "Not at all" satisfied with the FDO experience. TSQM scale scores were highest for the side effect (79.4), followed by convenience (71.7), effectiveness (70.1), and global satisfaction (68.9) domains; relatively higher scores were observed among treatment-experienced patients. Both treatment-naïve and treatment-experienced patients indicated physician recommendation as the primary reason for starting fingolimod. Among treatment-experienced respondents (n = 273), 58% reported that their first choice for MS treatment would be fingolimod if selecting today. CONCLUSION: Most fingolimod patients were satisfied with their FDO experience. Satisfaction with fingolimod was high and observed higher among treatment-experienced compared to treatment-naïve patients. Additional research is needed to understand key clinical and medication attributes underlying treatment satisfaction with fingolimod and other disease-modifying therapies.

Implications of real-world adherence on cost-effectiveness analysis in multiple sclerosis.

OBJECTIVES: Adherence to medication is essential for optimal outcomes, especially for chronic diseases such as multiple sclerosis (MS). Studies in MS indicate that lower adherence is associated with an increased risk of relapse, hospitalization or emergency room (ER) visits, and higher medical costs. A previous investigation assessed the cost per relapse avoided for patients with MS receiving first-line disease modifying therapies (DMTs); however, the model assumed 100% adherence. METHODS: Because real-world utilization patterns influence the actual effectiveness of medications, this analysis assessed the impact of real-world adherence from a US commercial payer perspective, using updated costs. RESULTS: As was seen in the original study, in this revised model, fingolimod was associated with the lowest cost per relapse avoided ($90,566), followed by SC IFN ß-1b (Extavia: $127,024), SC IFN ß-1b (Betaseron: $137,492), SC IFN ß-1a ($144,016), glatiramer acetate ($160,314), and IM IFN ß-1a ($312,629). The model inputs that had the greatest impact on the results were adherence-adjusted relative relapse rate reduction (RRR) of fingolimod, the wholesale acquisition costs of fingolimod, and the average number of relapses in untreated patients with MS. LIMITATIONS: The estimates of DMT adherence are from a single claims database study of a large national pharmacy benefit manager that only measured adherence, not actual relapses, and the model does not incorporate manufacturer discounts and rebates, which are not publicly available. CONCLUSION: These results suggest that economic analyses of MS therapies should incorporate real-world adherence rates where available, rather than relying exclusively on trial-based efficacy estimates when considering the economic value of treatment alternatives, and that highly efficacious therapies with low adherence may yield real-world efficacy that is substantially lower than that observed in closely monitored clinical trials.

Quantifying the role of natalizumab in health and economic outcomes in multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system defined by inflammation, demyelination, and axonal degeneration. MS progresses slowly and usually strikes at a fairly young age, causing both the direct and indirect costs of treating the disease to be very high. The direct costs to treat MS can average up to $30,000 per year; including indirect costs raises this to as high as $47,000. Natalizumab has proven to be able to reduce the signs of MS and has been associated with improvements in health-related quality-of-life measures; these effects have the potential to also reduce some of the economic burden of this debilitating disease. The significant clinical burden of MS can be quantified by cost and societal impact, important information to both payers and employers.

The role of glatiramer acetate in the early treatment of multiple sclerosis.

The treatment of the underlying disease process causing multiple sclerosis has continued to evolve since the initial approval of interferon-beta-1b in 1993. Current emphasis is on early treatment, including treatment after a single clinical attack (clinically isolated syndrome). The assessment of which disease modifying medication to use as initial therapy has continued to remain a combination of science and the art of medicine. Equally important are the assessment of treatment failure and the subsequent choice of medication change. This article will present scientific information, as well as information about clinical decision making, about these choices, with emphasis on the changing role of glatiramer acetate in this process.

Redefining functionality and treatment efficacy in multiple sclerosis.

Although our understanding of multiple sclerosis (MS) has grown exponentially in the past century and a half, there is still some divergence between physicians' perceptions of effects of MS on patients and those of the patients themselves. This article examines current practices in MS assessment and clinical trial design, highlighting certain deficiencies associated with commonly used measurement techniques (e.g., the Expanded Disability Status Scale and MRI) that are reflective of these discrepancies. In particular, the authors note that there is only minimal clinical awareness of the effects of MS on patient quality of life (QoL). We posit that QoL elements including impaired cognition, fatigue, pain, a variety of visual disturbances, depression, and degrading social function may have at least as much impact on people with MS as ambulatory issues. And because QoL measures often do not correlate with Expanded Disability Status Scale or MRI findings, we recommend that QoL be assessed independently. Various validated measures do exist to assess QoL elements, which are outlined here, along with thoughts on how to incorporate these into regular patient management visits. Ultimately, we believe that expanding on the traditionally accepted definitions of "functionality" and "efficacy" will allow for the adoption of a more holistic picture of MS and its impact.

A review of disease-modifying therapies for MS: maximizing adherence and minimizing adverse events.

BACKGROUND: In a chronic disabling disorder such as multiple sclerosis (MS), adherence to treatment is of critical importance in maximizing benefits of therapy over the long term. Adverse events (AEs) are often cited by patients who discontinue therapy. METHODS: Databases including Medline, CINAHL, and International Pharmaceutical Abstracts were searched for literature pertaining to adherence and AEs in MS published between January 1970 and August 2008. Clinical studies and case reports of AEs were included, as were papers that outlined factors that influence adherence. An advisory board with extensive experience in managing patients with MS developed guidelines to assist healthcare providers in maximizing adherence to disease-modifying therapy. DISCUSSION: Internally based factors such as self-image, and externally based factors such as AEs, may influence patients' willingness and ability to adhere to therapy. Management of AEs associated with disease-modifying therapies and other therapies is reviewed, including intramuscular and subcutaneous interferon beta (IFNbeta)-1a, IFNbeta-1b, glatiramer acetate, natalizumab, methylprednisolone, mitoxantrone, cyclophosphamide, methotrexate, azathioprine, and intravenous immunoglobulin. CONCLUSIONS: Effective management of MS is an ongoing, dynamic process that can enhance patients' adherence to therapy. Healthcare practitioners may address factors influencing adherence among patients with MS by managing treatment expectations, maintaining good communication with the patient, and managing AEs of treatment. Although the guidelines proposed herein originate from a single advisory board, it seems clear that by addressing patient concerns, healthcare practitioners can work with patients to enhance their ability to continue to adhere to their therapies and thereby gain the benefits of their treatment over the long term.

Managing adverse effects of disease-modifying agents used for treatment of multiple sclerosis.

BACKGROUND: First-line agents approved in the United States for treatment of relapsing multiple sclerosis (MS) include intramuscular interferon beta (IFNbeta)-1a, subcutaneous (SC) IFNbeta-1a, SC IFNbeta-1b, and SC glatiramer acetate. Intravenous mitoxantrone is the only agent approved for secondary progressive MS, progressive relapsing MS, and worsening relapsing MS. Intravenous natalizumab is approved for relapsing forms of MS generally in patients who have an inadequate response to, or are unable to tolerate, first-line therapies. Corticosteroids are commonly used to treat relapses. This paper reviews the incidence and management of common adverse events (AEs) associated with these treatments. METHODS: MEDLINE and EMBASE were searched for clinical trials and other publications between 1985 and 2007 reporting AEs associated with MS therapies, using these search terms: multiple sclerosis, interferon, Avonex, Betaseron, Rebif, glatiramer, copolymer 1, Copaxone, mitoxantrone, natalizumab, adverse events. RESULTS: A class-specific flu-like syndrome associated with IFNbeta can be managed through initial dose escalation and administration of analgesics and antipyretics, prophylactically or symptomatically. Injection-site reactions can occur in patients receiving injectable therapies, particularly SC IFNbeta or glatiramer acetate. The greatest risk to patients receiving mitoxantrone is cardiotoxicity; thus, the cumulative dose is limited. Allergic reactions occur rarely with natalizumab, and there is a potential risk of progressive multifocal leukoencephalopathy. AEs associated with short-term pulse corticosteroid therapy are usually transient and largely resolve after treatment is completed. CONCLUSIONS: To improve adherence to therapy, it is important to educate patients regarding AEs and to manage AEs proactively.

Alleviating flu-like symptoms with dose titration and analgesics in MS patients on intramuscular interferon beta-1a therapy: a pilot study.

OBJECTIVE: To determine the effectiveness of dose titration and choice of analgesic in reducing flu-like side effects of intramuscular interferon beta-1a (i.m. IFNbeta-1a). METHODS: Patients were randomly assigned to receive weekly i.m. IFNbeta-1a, with or without dose titration, plus acetaminophen or ibuprofen. After 27 patients had been randomized, the original formulation of i.m. IFNbeta-1a became unavailable and the remaining patients used a pre-packaged liquid formulation, necessitating a change in protocol from initially quarter-dose to half-dose titration. Patients scored presence and intensity of muscle aches, chills, and weakness, and measured body temperature; information was recorded in diaries. RESULTS: Forty-seven patients were enrolled; 36 completed the study. Fifteen patients received full-dose therapy plus acetaminophen, eight patients received quarter-dose titration and acetaminophen, 10 patients received quarter-dose titration and ibuprofen, eight patients received half-dose titration and acetaminophen, and six patients received half-dose titration and ibuprofen. The mean number of acetaminophen doses taken was not statistically different from the mean number of ibuprofen doses taken per patient per week in any dose-titration group over measured time intervals (p > 0.05). Symptom scores from acetaminophen and ibuprofen dose-titration groups were combined and compared with the no-titration group. The proportion of patients with a mean increase of > or = 2 from baseline in flu-like symptom score trended lower in the titrated group compared with the no-titration group at 4 hours and 12-15 hours post-injection; these differences reached statistical significance only during the first 2 weeks of treatment (p = 0.015, quarter-dose vs. no titration). CONCLUSION: This study supports the findings of previous studies demonstrating no difference in the effectiveness of acetaminophen and ibuprofen in controlling flu-like symptoms associated with IFNbeta treatment in patients with relapsing-remitting MS. Trends in this small pilot study suggest that the combination of initial dose titration and analgesic administration is useful for the reduction of flu-like symptoms with IFNbeta-1a therapy.