Preferences, Adherence, and Satisfaction: Three Years of Treatment Experiences of People with Multiple Sclerosis.

Background: To reduce the risk of long-term disability in people with Multiple Sclerosis (pwMS), an increasing number of disease-modifying immune therapies (DMT) are available, involving diverse mechanisms of action, levels of efficacy, treatment risks, and tolerability aspects. Including patient preferences and expectations in shared decision-making may improve treatment satisfaction, adherence, and persistence. Purpose: To investigate long-term alignment of individual preferences and expectations of pwMS with their actual DMT and its effect on treatment satisfaction, health-related quality of life (HRQoL), adherence, and treatment discontinuation. Methods: A total of 401 pwMS beginning a new DMT were enrolled from 2015 to 2018 in a non-interventional study at three German MS centres. Patient preferences regarding DMT, TSQM-9, SF36, and self-reported adherence as well as relapses and EDSS were recorded at baseline and every 3 to 6 months for up to 3 years. Results: Efficacy and tolerability were the highest-ranking preferences at baseline. Actual selection of DMT corresponded more closely to safety than efficacy, tolerability, or convenience preferences. Participants reported excellent adherence throughout the study. DMT persistence was 69.0%, with earlier discontinuation for injectable vs oral or infusion therapies. Breakthrough disease, rather than patient-reported outcomes, was the main driver of DMT discontinuation. For all routes of administration, global treatment satisfaction increased over time despite lower satisfaction with convenience. Several patterns of changing preferences were observed. Conclusion: This study provides insight into the interaction of DMT preferences of pwMS with their actual treatment experience. Treatment decisions should be aligned with long-term expectations of pwMS to promote continuous adherence.

On the Reliability of Examining Dual-Tasking Abilities Using a Novel E-Health Device-A Proof of Concept Study in Multiple Sclerosis.

The assessment of neuropsychological functions and especially dual-tasking abilities is considered to be increasingly relevant in the assessment of neurological disease, and Multiple Sclerosis (MS) in particular. However, the assessment of dual-tasking abilities is hindered by specific software requirements and extensive testing times. We designed a novel e-health (progressive web application-based) device for the assessment of dual-tasking abilities usable in "bedside" and outpatient clinic settings and examined its reliability in a sample of N = 184 MS patients in an outpatient setting. Moreover, we examined the relevance of dual-tasking assessment using this device with respect to clinically relevant parameters in MS. We show that a meaningful assessment of dual-tasking is possible within 6 min and that the behavioral readouts overall show good reliability depending on dual-tasking difficulty. We show that dual-tasking readouts were correlated with clinically relevant parameters (e.g., EDSS, disease duration, processing speed) and were not affected by fatigue levels. We consider the tested dual-tasking assessment device suitable for routine clinical neuropsychological assessments of dual-tasking abilities. Future studies may further evaluate this test regarding its suitability in the long-term follow up assessments and to assess dual-tasking abilities in other neurological and psychiatric disorders.

Data Collection in Multiple Sclerosis: The MSDS Approach.

Multiple sclerosis (MS) is a frequent chronic inflammatory disease of the central nervous system that affects patients over decades. As the monitoring and treatment of MS become more personalized and complex, the individual assessment and collection of different parameters ranging from clinical assessments via laboratory and imaging data to patient-reported data become increasingly important for innovative patient management in MS. These aspects predestine electronic data processing for use in MS documentation. Such technologies enable the rapid exchange of health information between patients, practitioners, and caregivers, regardless of time and location. In this perspective paper, we present our digital strategy from Dresden, where we are developing the Multiple Sclerosis Documentation System (MSDS) into an eHealth platform that can be used for multiple purposes. Various use cases are presented that implement this software platform and offer an important perspective for the innovative digital patient management in the future. A holistic patient management of the MS, electronically supported by clinical pathways, will have an important impact on other areas of patient care, such as neurorehabilitation.

A Digital Patient Portal for Patients With Multiple Sclerosis.

Background: Multiple Sclerosis is a chronic inflammatory disease of the central nervous system that requires a complex, differential, and lifelong treatment strategy, which involves high monitoring efforts and the accumulation of numerous medical data. A fast and broad availability of care, as well as patient-relevant data and a stronger integration of patients and participating care providers into the complex treatment process is desirable. The aim of the ERDF-funded project "Integrated Care Portal Multiple Sclerosis" (IBMS) was to develop a pathway-based care model and a corresponding patient portal for MS patients and health care professionals (HCPs) as a digital tool to deliver the care model. Methods: The patient portal was created according to a patient-centered design approach which involves both the patients' and the professionals' view. Buurmann's five iterative phases were integrated into a design science research process. A problem analysis focusing on functions and user interfaces was conducted through surveys and workshops with MS patients and HCPs. Based on this, the patient portal was refined and a prototype of the portal was implemented using an agile software development strategy. Results: HCPs and patients already use digital hardware and are open to new technologies. Nevertheless, they desire improved (digital) communication and coordination between care providers. Both groups require a number of functions for the patient portal, which were implemented in the prototype. Usability tests with patients and HCPs are planned to consider whether the portal is deemed as usable, acceptable as well as functional to prepare for any needed ameliorations. Discussion: After testing the patient portal for usability, acceptability, and functionality, it will most likely be a useful and high-quality electronic health (eHealth) tool for patient management from day care to telerehabilitation. It implements clinical pathways in a manner which is comprehensible for patients. Future developments of the patient portal modules could include additional diseases, the integration of quality management and privacy management tools, and the use of artificial intelligence to personalize treatment strategies.

The Multiple Sclerosis Health Resource Utilization Survey (MS-HRS): Development and Validation Study.

BACKGROUND: Survey-based studies are frequently used to describe the economic impact of multiple sclerosis (MS). However, there is no validated health resource survey available, preventing comparison of study results and meaningful conclusions regarding the efficiency of long-term treatments. OBJECTIVE: The aim of this study was to develop and validate a tablet- and paper-based MS health resource utilization survey. METHODS: We developed and validated the Multiple Sclerosis Health Resource Utilization Survey (MS-HRS), consisting of 24 cost items for paper and tablet users. Data for validation came from two large German observational studies. Survey practicability was assessed according to the response rate. Reliability was described using test-retest reliability as well as Guttman lambda. Construct validity was assessed as convergent and discriminant validity via correlations with associated patient-reported outcomes and known-group analyses. RESULTS: In total, 2207 out of 2388 (response rate: 92.4%) patients completed the survey and were included to determine psychometric properties. The test-retest reliability had an intraclass correlation coefficient of 0.828 over a course of 3 months. Convergent validity analyses showed that total costs correlated positively with increased disability (r=0.411, P<.001). For discriminant validity, correlations of total costs with the Treatment Satisfaction Questionnaire for Medication ranged from -0.006 (convenience) to -0.216 (effectiveness). The mean annual cost was €28,203 (SD €14,808) (US $39,203; SD US $20,583) with disease-modifying therapies. CONCLUSIONS: The MS-HRS is a multilingual, reliable, valid, electronically available, and easy-to-administer questionnaire providing a holistic cross-sectional and longitudinal assessment of resource utilization in patients with MS.

Nonwalking response to fampridine in patients with multiple sclerosis in a real-world setting.

OBJECTIVES: Mobility impairments constitute a long-term burden in patients with multiple sclerosis (MS). Currently there is evidence that the drug fampridine may improve nonwalking symptoms in MS patients. The main objective of this study is to analyze whether participants showing a beneficial walking response to fampridine, also show a positive response in nonwalking assessments in a real-world clinical setting. METHODS: Subjects enrolled were part of a study analyzing gait parameters, for which response to treatment with fampridine was monitored after a period of 2 weeks. Neurologists then decided whether patients were responders to fampridine (RF) according to their global impression of patients' gait improvement. As nonwalking outcomes, we included the nine-hole peg test (9-HPT), the EuroQoL five dimensions questionnaire (EQ-5D) for quality of life, The Würzburger Fatigue Inventory for MS (WEIMuS), the Center for Epidemiologic Studies depression scale (CES-D), and the Paced Auditory Serial Addition Test (PASAT). Minimal clinically important difference (MCID) was evaluated for each test. RESULTS: A total of 189 participants were included: 122 were women (64.55%), with a mean age of 53.55 (±10.83). RFs showed significant improvement in all of the nonwalking outcomes (p < 0.05), except for a nonsignificant improvement in nondominant upper limb function and PASAT; the largest score improvement was seen in the physical and cognitive sections of the WEIMuS (25.69% and 29.81%, respectively, p < 0.001). CONCLUSION: We provide evidence that physician's global judgement of walking improvement is a reliable measure for determining response to fampridine in nonwalking parameters, with fatigue showing the greatest score improvement after 2 weeks.

Improving multiple sclerosis management and collecting safety information in the real world: the MSDS3D software approach.

INTRODUCTION: For safety evaluation, randomized controlled trials (RCTs) are not fully able to identify rare adverse events. The richest source of safety data lies in the post-marketing phase. Real-world evidence (RWE) and observational studies are becoming increasingly popular because they reflect usefulness of drugs in real life and have the ability to discover uncommon or rare adverse drug reactions. AREAS COVERED: Adding the documentation of psychological symptoms and other medical disciplines, the necessity for a complex documentation becomes apparent. The collection of high-quality data sets in clinical practice requires the use of special documentation software as the quality of data in RWE studies can be an issue in contrast to the data obtained from RCTs. The MSDS3D software combines documentation of patient data with patient management of patients with multiple sclerosis. Following a continuous development over several treatment-specific modules, we improved and expanded the realization of safety management in MSDS3D with regard to the characteristics of different treatments and populations. EXPERT OPINION: eHealth-enhanced post-authorisation safety study may complete the fundamental quest of RWE for individually improved treatment decisions and balanced therapeutic risk assessment. MSDS3D is carefully designed to contribute to every single objective in this process.

Fampridine response in MS patients with gait impairment in a real-world setting: Need for new response criteria?

OBJECTIVE: The primary objective of this real-world study was to describe the response to fampridine and changes of gait parameters in multiple sclerosis (MS) patients' walking disability (Expanded Disability Status Scale (EDSS): 4-7) after treatment with fampridine for 2 weeks as recommended by the European Medicines Agency (EMA) and compare it with the overall physician's judgement. METHODS: A total of 211 adult MS patients were analyzed using a multimodal gait assessment including the timed 25-foot walk test (T25FW), 2-minute walking test (2-MWT), 12-item Multiple Sclerosis Walking Scale (MSWS-12), the GAITRite electronic walkway system, and the patients' clinical global impression (CGI). Multimodal gait assessment was compared with the clinician's impression of overall improvement after 2 weeks. RESULTS: In total, 189 subjects were included, of which 133 (70.37%) were responders to fampridine (RF), according to physician's judgement. Looking at independent multimodal gait assessment, RFs showed improvement of 12.60% in the T25FW, 19.25% in the 2-MWT, 21.12% in the MSWS-12, and 6.54% in their Functional Ambulation Profile (FAP) score. The combination of the T25FW and the MSWS-12 would offer the best sensitivity and specificity for determining response to fampridine according to both neurologists' and patients' classification. CONCLUSION: This study provides new information on the use of fampridine in a real-world setting with a large patient sample on the potential benefit of using more definitive responder criteria to fampridine for the clinical setting.

[Implementation of the National Guidelines for the treatment of Diabetes mellitus type 2 in secondary diabetes centers]. / Umsetzung der Nationalen VersorgungsLeitlinie (NVL) zur Therapie des Diabetes mellitus Typ 2 in diabetologischen Schwerpunktpraxen.

Background The German National Disease Management Guideline (NVL) on treatment of Type 2 Diabetes recommends lowering of blood glucose in four therapy steps. There is little evidence, how NVL is implemented for the individual patients. Methods 810 patients in secondary diabetes centers were examined within the DiabCheckOCTplus trial. Data about the patient's health status (electronic medical record) were classified according to the NVL treatment steps. The degree of implementation was assessed for every person with diabetes type 2 (NCT02 311 504). Results Related to the levels of treatment, 81 % of patients received metformin in level 2, 48 % the dual combination of metformin with DPP4-Inhibitors (level 3) and 41 % an intensified insulin therapy in combination with metformin (level 4). The overall percentage for metformin was 67 %, for DPP4-Inhibitors 20 % and 10 % for sulfonylureas.The duration of diabetes significantly increased with higher NVL level. After 3 years of diabetes 55 % received more than one antihyperglycemic drug. Half of the patients were treated with complex insulin strategies after 9 years, however almost all after 25 years. Conclusion The therapy in secondary care centers met national guidelines to a large extent. Similar proof of implementation would be important for primary care by general practitioners. As the factual information of the therapy level strongly correlated with the duration of disease, it might be used for structured communication (risk profile).

Patients' preferences for involvement in the decision-making process for treating diabetic retinopathy.

BACKGROUND: To assess factors associated with the preferred role of the attending ophthalmologist in the decision-making processes before treating diabetic retinopathy (DR). METHODS: Cross-sectional study of 810 adults attending secondary diabetes care centers (NCT02311504). Diabetes patients were classified using a validated questionnaire in an ophthalmologist-dominant decision-making (ODM), shared decision-making (SDM) and patient-dominant decision-making (PDM) style. Multivariate logistic regression was performed to determine factors associated with the decision-making process. RESULTS: A majority of 74.3% patients preferred SDM between ophthalmologist and patient, 17.4% patients wanted ODM, delegating the decision-making process to the ophthalmologist, 8.3% preferred the autonomous style of PDM. Patients wanting ODM were older (OR = 1.2 per decade, p = 0.013), had a lower level of education (OR = 1.4, p = 0.001) and had a higher frequency of consultations per year (OR = 1.3, p = 0.022). Patients with better basic knowledge in DR and memorizing their HbA1c level showed a higher propensity for SDM (OR = 1.1, p = 0.037). Patients wanting PDM had a significantly higher education (OR = 1.3, p = 0.036) and a greater desire for receiving information from self-help groups (OR = 1.3, p = 0.015). CONCLUSIONS: The first evaluation of the general patient wishes for the treatment of DR confirmed the concept of SDM, which was favored by three quarters. In particular, older patients with low educational attainment wanted to delegate the decision-making process to the ophthalmologist. Amelioration of ophthalmologic education in diabetic programs might take up patients' propensity for SDM. Regardless of the decision-making group, nearly all patients wanted the medical and scientific information to be transferred by and shared with the ophthalmologist. TRIAL REGISTRATION: The study was registered on www.clinicaltrials.gov (identifier: NCT02311504) on December 4th 2014.

Limited Time from the Diabetes Patients' Perspective: Need for Conversation with the Eye Specialist.

PURPOSE: Facing the lack of time, busy retina consultants should be aware of how the patients would prefer that time is spent and whether they wish the specialist to talk more at the expense of other medical activities. METHODS: 810 persons with diabetes were asked to divide the time of 10 min between examination, consultation and treatment when envisioning a real-life scenario of diabetic retinopathy (NCT02311504). RESULTS: With the increasing duration of diabetes, patients wanted significantly more time for diagnostics (p = 0.028), while age was found to be associated with less time for treatment (p = 0.009). Female subjects tended to prefer only little more time for talking (p = 0.051) in comparison with males, who slightly favored therapy (p = 0.025). CONCLUSIONS: The large majority recognized the need for diagnostics in their allocation of time. If individual patients are confronted with the health care perspective of time constraints, this might improve the understanding of prioritization.

Multiple sclerosis: clinical profiling and data collection as prerequisite for personalized medicine approach.

Multiple sclerosis (MS) is a highly heterogeneous disease as it can present inter-individually as well as intra-individually, with different disease phenotypes emerging during different stages in the long-term disease course. In addition to advanced immunological, genetic and magnetic resonance imaging (MRI) profiling of the patient, the clinical profiling of MS patients needs to be widely implemented in clinical practice and improved by including a greater range of relevant parameters as patient-reported outcomes. It is crucial to implement a high standard of clinical characterization of individual patients as this is key to effective long-term observation and evaluation.To generate reliable real-world data, individual clinical data should be collected in specific MS registries and/or using intelligent software instruments as the Multiple Sclerosis Documentation System 3D. Computational analysis of biological processes will play a key role in the transition to personalized MS treatment. Major breakthroughs in the areas of bioinformatics and computational systems biology will be required to process this complex information to enable improved personalization of treatment for MS patients.

Study design of PANGAEA 2.0, a non-interventional study on RRMS patients to be switched to fingolimod.

BACKGROUND: The therapeutic options for patients with Multiple Sclerosis (MS) have steadily increased due to the approval of new substances that now supplement traditional first-line agents, demanding a paradigm shift in the assessment of disease activity and treatment response in clinical routine. Here, we report the study design of PANGAEA 2.0 (Post-Authorization Non-interventional GermAn treatment benefit study of GilEnyA in MS patients), a non-interventional study in patients with relapsing-remitting MS (RRMS) identify patients with disease activity and monitor their disease course after treatment switch to fingolimod (Gilenya®), an oral medication approved for patients with highly active RRMS. METHOD/DESIGN: In the first phase of the PANGAEA 2.0 study the disease activity status of patients receiving a disease-modifying therapy (DMT) is evaluated in order to identify patients at risk of disease progression. This evaluation is based on outcome parameters for both clinical disease activity and magnetic resonance imaging (MRI), and subclinical measures, describing disease activity from the physician's and the patient's perspective. In the second phase of the study, 1500 RRMS patients identified as being non-responders and switched to fingolimod (oral, 0.5 mg/daily) are followed-up for 3 years. Data on relapse activity, disability progression, MRI lesions, and brain volume loss will be assessed in accordance to 'no evidence of disease activity-4' (NEDA-4). The modified Rio score, currently validated for the evaluation of treatment response to interferons, will be used to evaluate the treatment response to fingolimod. The MS management software MSDS3D will guide physicians through the complex processes of diagnosis and treatment. A sub-study further analyzes the benefits of a standardized quantitative evaluation of routine MRI scans by a central reading facility. PANGAEA 2.0 is being conducted between June 2015 and December 2019 in 350 neurological practices and centers in Germany, including 100 centers participating in the sub-study. DISCUSSION: PANGAEA 2.0 will not only evaluate the long-term benefit of a treatment change to fingolimod but also the applicability of new concepts of data acquisition, assessment of MS disease activity and evaluation of treatment response for the in clinical routine. TRIAL REGISTRATION: BfArM6532; Trial Registration Date: 20/05/2015.

Rationale, design, and methods of a non-interventional study to establish safety, effectiveness, quality of life, cognition, health-related and work capacity data on Alemtuzumab in multiple sclerosis patients in Germany (TREAT-MS).

BACKGROUND: Alemtuzumab, a humanized monoclonal antibody directed against the cell surface glycoprotein CD52, is licensed in Europe since October 2013 as treatment for adult patients with active relapsing-remitting multiple sclerosis (RRMS). In three randomized, rater-blinded active comparator clinical trials studies, alemtuzumab administered in two annual courses, had superior efficacy as compared to subcutaneous interferon beta-1a, and durable efficacy over 5 years in an extension study with a manageable safety profile in RRMS patients. Data on the utilization and the outcomes of alemtuzumab under clinical practice conditions are limited. METHODS: Here we describe the rationale, design and methods of the TREAT-MS study (non-interventional long-Term study foR obsErvAtion of Treatment with alemtuzumab in active relapsing-remitting MS). DISCUSSION: TREAT-MS is a prospective, multicenter, non-interventional, long-term study to collect data on safety, effectiveness, quality of life, cognition and other aspects from 3200 RRMS patients treated with alemtuzumab under the conditions of real-world clinical practice in Germany. TRIAL REGISTRATION: As non-interventional trial in Germany.

Designing an Electronic Patient Management System for Multiple Sclerosis: Building a Next Generation Multiple Sclerosis Documentation System.

BACKGROUND: Technologies like electronic health records or telemedicine devices support the rapid mediation of health information and clinical data independent of time and location between patients and their physicians as well as among health care professionals. Today, every part of the treatment process from diagnosis, treatment selection, and application to patient education and long-term care may be enhanced by a quality-assured implementation of health information technology (HIT) that also takes data security standards and concerns into account. In order to increase the level of effectively realized benefits of eHealth services, a user-driven needs assessment should ensure the inclusion of health care professional perspectives into the process of technology development as we did in the development process of the Multiple Sclerosis Documentation System 3D. After analyzing the use of information technology by patients suffering from multiple sclerosis, we focused on the needs of neurological health care professionals and their handling of health information technology. OBJECTIVE: Therefore, we researched the status quo of eHealth adoption in neurological practices and clinics as well as health care professional opinions about potential benefits and requirements of eHealth services in the field of multiple sclerosis. METHODS: We conducted a paper-and-pencil-based mail survey in 2013 by sending our questionnaire to 600 randomly chosen neurological practices in Germany. The questionnaire consisted of 24 items covering characteristics of participating neurological practices (4 items), the current use of network technology and the Internet in such neurological practices (5 items), physicians' attitudes toward the general and MS-related usefulness of eHealth systems (8 items) and toward the clinical documentation via electronic health records (4 items), and physicians' knowledge about the Multiple Sclerosis Documentation System (3 items). RESULTS: From 600 mailed surveys, 74 completed surveys were returned. As much as 9 of the 10 practices were already connected to the Internet (67/74), but only 49% preferred a permanent access. The most common type of HIT infrastructure was a complete practice network with several access points. Considering data sharing with research registers, 43% opted for an online interface, whereas 58% decided on an offline method of data transmission. eHealth services were perceived as generally useful for physicians and nurses in neurological practices with highest capabilities for improvements in clinical documentation, data acquisition, diagnosis of specific MS symptoms, physician-patient communication, and patient education. Practices specialized in MS in comparison with other neurological practices presented an increased interest in online documentation. Among the participating centers, 91% welcomed the opportunity of a specific clinical documentation for MS and 87% showed great interest in an extended and more interconnected electronic documentation of MS patients. Clinical parameters (59/74) were most important in documentation, followed by symptomatic parameters like measures of fatigue or depression (53/74) and quality of life (47/74). CONCLUSIONS: Physicians and nurses may significantly benefit from an electronically assisted documentation and patient management. Many aspects of patient documentation and education will be enhanced by eHealth services if the most informative measures are integrated in an easy-to-use and easily connectable approach. MS-specific eHealth services were highly appreciated, but the current level of adoption is still behind the level of interest in an extended and more interconnected electronic documentation of MS patients.

The PANGAEA study design - a prospective, multicenter, non-interventional, long-term study on fingolimod for the treatment of multiple sclerosis in daily practice.

BACKGROUND: Fingolimod (Gilenya) is an oral medication for patients with highly active relapsing-remitting Multiple Sclerosis (RRMS). Clinical trials and post-marketing experience on more than 114,000 patients have established a detailed safety profile. Total patient exposure now exceeds 195,000 patient-years as stated in the last financial report (Dec 2014) of the Novartis Pharma AG, Basel, Switzerland. However, less is known about the safety of long-term fingolimod use in daily practice. Here, we describe the study design of PANGAEA (Post-Authorization Non-interventional German sAfety of GilEnyA in RRMS patients), a prospective, multicenter, non-interventional, long-term study to collect safety, efficacy, and pharmacoeconomic data on RRMS patients treated with fingolimod (0.5 mg/daily) under real-world conditions in Germany. METHODS: PANGAEA is striving to assess a real-world safety and efficacy profile of fingolimod, based on data from 4,000 RRMS patients, obtained during a 60-month observational phase. A pharmacoeconomic sub-study of 800 RRMS patients further collects patient-reported outcome measures of disability, quality of life, compliance, treatment satisfaction, and usage of resources during a 24-month observational phase. Descriptive statistical analyses of the safety set as well as of stratified subgroups such as patients with concomitant diabetes mellitus and pretreated patients (e.g., natalizumab) will be conducted. DISCUSSION: PANGAEA seeks to confirm the current safety profile of fingolimod obtained in phase I-III clinical trials. The study design presented here will additionally provide guidance on the therapeutic use of fingolimod in clinical practice and possibly assists physicians in making evidence-based decisions.