Study objectives
The primary study objectives are to assess in patients with MS the long-term changes in 1) disabilities, 2) disabilities perception and 3) HRQoL. The secondary objectives are to assess the interrelations between 1) changes in disabilities and changes in disabilities perceptions, 2) changes in disabilities and changes in HRQoL, 3) relapses and changes in disabilities, 4) (adherence to) DMD treatment and changes in disabilities, and 5) (adherence to) DMD treatment and change in fatigue.
Study design
The Dutch Multiple Sclerosis Study is a prospective, web-based, patient-centred, longitudinal, observational study in The Netherlands, with patient-driven inclusion. Given the innovative character of the study concept initially a follow-up of 2 years was planned to assess the feasibility of the project. Since then the study has been extended annually and is now expected to have a follow-up of 15 years.
Study population
The population under study are the MS and CIS patients in The Netherlands. Accordingly, the eligibility criteria for patients to participate were not restrictive: 1) diagnosis of MS or CIS, 2) willing and able to comply with the study protocol, 3) having access to the internet, and 4) having given informed consent.
Patient recruitment
Patients were informed on the possibility to participate via the websites of the patient organisations National MS Foundation The Netherlands (NMSF) (www.nmsf.nl) and Multiple Sclerose Vereniging Nederland (MSVN) (www.msweb.nl), the website of the MS4 Research Institute (www.ms4ri.nl), the study website www.msstudie.nl. By regular mail neurologists and MS-nurses in The Netherlands were sent an informative letter with patient brochures, which they were asked to hand out to their patients. The brochure was also sent to the patrons of the NMSF as an attachment to the foundations’ quarterly journal and related mailings. In the journal, study information was presented by the principal investigator (PJJ). Twice information about the study was published in health specials of large national and regional Dutch newspapers.
The informed consent text was available on www.msstudie.nl en www.ms4ri.nl. For further information the principal investigator (PJJ) could be contacted via www.ms4ri.nl. Patients who were willing to participate confirmed that they had read the information and gave their informed consent online by clicking on a specific page of the study website. The electronic consent also pertained the storage of personal data and the responses in the database. Once informed consent was obtained, a patient could start the baseline assessment.
Ethical aspects
The protocol was submitted to the ethics committee Medisch Ethische Toetsing Onderzoek Patiënten en Proefpersonen in Tilburg, The Netherlands (nr M379). The committee concluded that a review was not indicated, as the study did not qualify for being tested according to the Dutch Medical Research Involving Human Subjects Act of 1999 (http://wetten.overheid.nl/BWBR0009408) [25]. The study is being performed in agreement with the Declaration of Helsinki (Ethical Principles for Medical Research Involving Human Subjects version 2013; 64th World Medical Association General Assembly, Fortaleza, Brazil, October 2013) (www.wma.net) and the Wet medisch-wetenschappelijk onderzoek met mensen (www.wetten.overheid.nl/BWBR0009408). The data analyses plan will be checked by an independent supervisory board (Stichting Infometer). Patients were informed that they have the right to discontinue their participation or withdraw their consent at any time and are not obliged to state their reasons. The completion of the questionnaires takes about 30–45 min every six months; the optional completion of the monthly questionnaires takes about 15 min every month; every three years the assessment of the EDSS by phone takes about 10 to 20 min (see below).
Data acquisition
After having given their consent, patients received a personal code and logged on to the website of the study www.msstudie.nl, to choose a username and password. Online they go through various web pages containing the electronic case record forms (e-CRFs) with questions and questionnaires. Patients are informed by e-mail that an assessment is due and that the corresponding e-CRFs have been made available for completion. E-CRFs are to be completed within one week. Within this time frame e-CRFs may be filled in at moments that are suitable to the patient. Completion may take as many sessions as needed, as answers are saved automatically. The items of the questionnaire are fixed and the responses are automatically captured. Automated completeness checks are done before questionnaires can be submitted. The respondents see an overview of all questions and answers before submission and they can change the answers before submitting. After confirmation the e-CRF is automatically sent to the study centre. After submission changes are no longer possible. In case a e-CRF has not been completed within one week the help desk sends a reminder by e-mail.
Technical aspects
The study is a modular application on the Curavista e-Health Platform, built on an Oracle database with JAVA-scripting, XML-applets and AJAX protocols. Data processing is 256-bits encrypted with VPN-tunnelling. The databases are physically and software secured in a dedicated data centre in The Netherlands. The database of the study is compliant with EU-regulations on data storage and activation for medical purposes. There are four separated databases: one with personal identifiers (name, address, identification number), one with medical records (answers to the questions, identification number), one with the social security number, and one with the key. Only after login the data are presented as a whole on the screen (encrypted key).
Outcome measures
Disabilities and disabilities perception
The EDSS is a widely used disability measure in MS. The EDSS quantifies disability in eight functional systems and allows neurologists to assign a functional system score in each of these [26]. The functional systems are: pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, cerebral and other. EDSS steps 1.0 to 4.5 refer to patients with MS who are fully ambulatory, and EDSS steps 5.0 to 9.5 are defined by the impairment to ambulation. A version of the EDSS that can be used by phone is available and will be used in this study [27].
The MSIP is a measure of MS-related disabilities and perception of disabilities with established psychometric properties [28, 29]. The MSIP is based on the International Classification of Functioning, Disability and Health and reflects an objectified view of the prevalence and severity of the impact of MS. The MSIP comprises 36 questions assessing disability (Q1a-Q36a) and disability perception (Q1b-Q36b) in the domains Muscle and Movement Functions (MMF), Excretion and Reproductive Functions (ERF), Basic Movement Activities (BMA), Activities of Daily Living (ADL), Participation in Life Situations (PLS), Environmental Factors (EF), Mental Functions (MF), and the symptoms fatigue, pain, speech and vision. The MSIP yields validated domain scores, ranging from 0 to 12 (ERF, MF), 0 to 15 (BMA), 0 to 16 (MMF), 0 to 20 (EF), 0 to 24 (ADL), and 0 to 26 (PLS), and symptom scores, ranging from 0 to 4. Higher scores indicate a worse condition.
HRQoL
HRQoL is assessed with the MSQoL-54 and the LMSQoL questionnaires. The MSQoL-54 is a psychometrically validated MS-specific multi-dimensional inventory of patient-centered health status [13]. It consists of the 36-item Short Form health survey as a generic core measure to enable comparisons to other patient populations and to the general population, supplemented with 18 additional questions exploring items relevant to patients with MS in the areas of health distress (four items), sexual function (four items), satisfaction with sexual function (one item), overall quality of life (two items), cognitive function (four items), energy (one item), pain (one item) and social function (one item) [30]. The MSQoL-54 contains 52 items distributed into 12 scales, and two single items. A physical and a mental dimension underlie the MSQoL-54: the physical and mental domains. Scores for each domain range from 0 to 100, where higher values indicate better HRQoL.
The Leeds Multiple Sclerosis Quality of Life (LMSQoL) questionnaire is a psychometrically validated scale that consists of eight questions, examining MS-related aspects of QoL over the past month [31]. Answers are rated on a 5-point scale from 0 to 4. The resulting score ranges from 8 to 32, with higher scores reflecting higher levels of well being. In a study of MS patients with acute relapses, it was found to be responsive to change with higher effect sizes than the sub-scales of the MSQoL-54, and it also showed a correlation with a detailed impact diary [32].
Relapses
Patients report the occurrence of relapses, the relapse intensity and eventual steroid treatment over the past six months.
Medication and adherence to DMD
The Medication and Adherence Inventory gives a patient-reported update of medications that are taken, the number of missed doses DMD in the past month (if applicable), and the date and reason of DMD discontinuation (if applicable).
Fatigue
Fatigue is measured by the Multiple Sclerosis Fatigue Impact Scale 5-item version (MFIS-5), a validated, short questionnaire examining a patient’s perceived impact of fatigue on a variety of daily activities over the past month [33]. Answers to each question are rated on a 5-point scale from 0 to 4. The MFIS-5 total score consists of the sum of the raw scores on these 5 items and ranges from 0 to 20, where higher scores indicate more experienced fatigue.
Assessment schedule
At baseline the MSIP, MSQoL-54, Relapse Report, Medication and Adherence Inventory and MFIS-5 were completed, and the EDSS score was assessed by phone (MH). At follow-up the MSIP, MSQoL-54, Relapse Report, Medication and Adherence Inventory and MFIS-5 are completed every 6 months, and the EDSS score is assessed every 3 years. The monthly completion of MFIS-5, LMSQoL and Medication and Adherence Inventory is optional.
Statistical analyses
The statistical analyses will be performed at the Department for Health Evidence, University Medical Centre Radboud Nijmegen, The Netherlands. Results will be described using means and standard deviations for continuous variables, and frequencies for categorical variables. Relations between time points, variables, patient and treatment characteristics will be evaluated in random effects repeated measures models. Multi-variate analyses will be performed to examine the interrelations described under the section Ojectives.
Study status
A total of 391 patients have been included, the first patient in May 2011 and the last patient in September 2012.
Organisation and funding
The study is an initiative of MS4 Research Institute (PJJ), and carried out by the institute in collaboration with Curavista bv. The study’s Advisory Committee includes Prof. Raymond Hupperts, neurologist, Academic MS Centre Limburg, Sittard, The Netherlands, Dr. Freek Verheul, neurologist, Groene Hart Hospital Gouda, Gouda, The Netherlands, Dr. Thea Heersema, University Medical Centre Groningen, Groningen, The Netherlands, and Dr. Ruud van der Kruijk, neurologist, Slingeland Hospital Doetinchem, Doetinchem, The Netherlands.
The study is funded by the National MS Foundation The Netherlands, Curavista bv and MS4 Research Institute.