Development and Evaluation of a Web-based Programme on Relapse Management for People With Multiple Sclerosis
Condition: Multiple Sclerosis, Relapsing-Remitting
MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis; Recurrence
Study type: Interventional

Summary: 
      This randomized controlled trial will evaluate a web-based relapse management programme,
      which is easily accessible for people with multiple sclerosis. The trial is accompanied by a
      mixed-methods process evaluation and a health economic evaluation.

      It is expected that the programme will positively change patients' relapse management and
      strengthen their autonomy and participation.
    

Detailed description: 
      Multiple sclerosis (MS) is a chronic inflammatory, degenerative disease of the central
      nervous system manifesting at first with relapses in about 85% of the cases. In Germany,
      intravenous mostly inpatient therapy with high-dose corticosteroids is the treatment standard
      of acute relapses. The treatment leads to short-term faster reduction of symptoms in about 25
      of 100 treated patients (absolute risk reduction), but has no long-term benefits over placebo
      treatment. Also intravenous treatment is not superior to oral treatment. Therefore, informed
      decisions on relapse management are required. An earlier randomized controlled trial (RCT)
      showed that evidence-based patient information (EBPI) and education on relapse management
      leads to significantly more informed decisions and more relapses not treated or treated with
      oral steroids. POWER@MS2 builds on that evidence by transferring the content to a
      web-platform and making the intervention easily accessible and implementable.

      The intervention will be evaluated in a pragmatic double-blind (PwMS and outcome assessors)
      RCT. Participants will be randomized to an interactive web-based programme (intervention
      group) or a web-based programme with standard information on relapse management based on the
      contents of the German Multiple Sclerosis Society (DMSG).

      POWER@MS2 aims to demonstrate fewer glucocorticoid relapse therapies, and, in case of treated
      relapses, less intravenous and more orally administered therapies (primary endpoint:
      proportion of relapses not treated or treated with oral steroids). PwMS will be recruited via
      all participating centres (private neurology practices and MS outpatient departments
      (academic and community hospitals)) in Germany. In the federal state of Schleswig-Holstein
      all neurologists will be contacted. Interested and eligible PwMS will be provided with a
      study information sheet by the participating MS centres. Informed consent will be obtained by
      a physician in the MS centre. After giving their informed consent, contact data (address,
      email, telephone) will be forwarded to the study centre (UKE) via a secure communication
      platform or phone. After this, baseline data will be collected and group assignment will be
      performed by a block randomization procedure within the database secuTrial®. After successful
      randomization, PwMS will receive access (login) details to the intervention or control
      platform within 4-6 weeks.

      Participants will be monitored for at least 12 up to 36 months (on average 24 months). Every
      three months, measures are recorded by a standardized phone interview executed by the
      coordinating study centre. Recruitment will be completed after approximately nine months. The
      trial will end as soon as the last participant has reached 12 months of follow-up. All
      participants, who have not reached 36 month of follow-up, will be called for a final phone
      interview.

      We consider the specific risks for participating PwMS to be very low. No negative effects on
      the quality of life of PwMS as well as disability or other undesired events due to omitted or
      oral steroid administration are to be expected as previous studies showed. It is more likely
      that there will be positive effects for trained PwMS in terms of more autonomous
      decision-making and differentiated use of steroids. Participants will be educated on
      potentially dangerous side effects of steroid therapies and their early detection by an
      information sheet. To assist the physician in assessing whether oral medication is
      acceptable, participants will be issued a certificate with documented decision-making
      knowledge. As part of this study, all study participants will be contacted by phone every
      three months. This will also allow individual risk identification and the initiation of
      appropriate measures if required.

      Nonetheless, it could be possible that some participants feel harassed or pressured by the
      intervention or the permanent contact attempts. In order to detect possible adverse events,
      PwMS and physicians will be asked by questionnaires throughout the study as part of the
      process evaluation. As relevant adverse events are unlikely, no stopping rules will be
      applied. Nevertheless, safety measures are applied to control for anxiety, depression and
      disease specific quality of life. Furthermore, standard disease monitoring parameters will be
      collected (e.g. relapse rate, disability status) and discussed by the steering committee.
      Adverse effects will be documented in the secuTrial® system. Since the programme is accessed
      from home, there is little organisational and time expenditure. Study participants may leave
      the study at any time and may withdraw consent to study participation without negative
      consequences. Reasons will be asked for and, if provided, recorded.

      The unit of analysis for the primary endpoint is the occurrence of relapses. Eighty one
      relapses per group yield a power of 85% at a two-tailed significance level of 5% given
      proportions of 78% and 56% of orally treated or non-treated relapses in the intervention
      group and the control group, respectively, as observed in a previous study. It is expected
      that these relapse rate can be observed in a total of 170 patients with 1 to 2 years
      follow-up, corresponding to an annual relapse rate of 0.64. The dropout rate is expected be
      about 10%, as in the previous study. Therefore, 188 participants will be randomized.

      Data will be obtained at different time points using paper-based (primary choice) and (if
      requested) web-based questionnaires. First of all, informed consent and patient-related
      contact data will be obtained from interested PwMS in the MS centres and a copy will be send
      to the study centre (UKE) by regular mail. Baseline data will be obtained by participating MS
      centres before randomisation. From this point in time, the study centre (UKE), will take over
      the handling of the participants. To secure follow-up data, study participants will be
      contacted by the study centre via phone within the first two weeks to secure communication
      lines and to perform the phone interview. Student assistants will be trained on this
      interaction. Trial data will be collected throughout the course of the study as well as in
      the last follow-up in order to examine the intervention effect on the study outcomes.
      However, beyond 3-monthly phone interviews, major assessments will be only at baseline and
      after 12 months. All study relevant data will be entered in secuTrial® and provided online.
      PwMS and medical staff of centres as well as the central study team (defined health
      researchers and study assistants) can enter data.

      The preparation of the declaration of consent (including voluntariness) and the handling of
      all data collected within the scope of the study will be carried out in accordance with the
      recommendations of the Ethics Committee of the University of Lübeck and the EU General Data
      Protection Regulation (Datenschutz-Grundverordnung, DSGVO). Data protection concerns with
      regard to the intervention platform will be met by securing a protected web platform. The
      intervention programme as well as the control programme will be provided via a secure online
      platform that meets all legal requirements (SSL Encryption).

      All study data will be used and evaluated pseudonymously by the members of the coordinating
      centre and consortium partners involved. The publication of the study results and the
      provision of the data in an online resource will only take place in an anonymised form. Study
      participants will be informed about the results of the survey through a publication of the
      results on the DMSG website after completion of the study.

      The primary endpoint is evaluated using a generalized linear model with mixed effects and
      logit link function. Subject specific effects are modelled as random, whereas intervention
      group (IG vs. CG) and study centre are included as fixed effects in the model. The
      intervention effect is reported as odds ratio (OR) with 95% confidence interval (CI) and
      p-value testing the null hypothesis of no intervention effect (i.e. OR=1). Longitudinal
      assessments of quality of life and impairment are analysed by means of Gaussian linear models
      for repeated measures (so-called mixed model for repeated measurements (MMRM)) with
      intervention group (IG vs. CG), time, intervention-by-time interaction, and study centre as
      factors and baseline score as covariate. The error terms are assumed to follow a multivariate
      normal distribution with unstructured covariance. Least squares mean changes from baseline
      will be reported for both groups with 95% CI as well as the difference between the least
      squares intervention group means (IG vs. CG) with 95% CI and p-value testing the null
      hypothesis of no treatment effect. In subgroup and regression analyses, effects of age,
      gender, level of education, centre and impairment will be explored.

      Reasons for study withdrawal will be reported. All PwMS will be analysed in the group they
      were randomized to following the intention-to-treat principle. Early study discontinuations
      will be treated as independent right censoring in the primary analysis. In case of
      substantial or differential study discontinuations the validity of the independent censoring
      assumption will be explored in shared random effects models of the primary endpoint and time
      to study discontinuation. To handle missing data in baseline variables or follow-up
      assessments, multiple imputation models will be applied. All details of the statistical
      analyses including definitions of analysis populations will be prespecified in the
      statistical analysis plan.
    

Intervention name(s): web-based intervention programme; web-based information material offered via the same platform (broca®) in addition to usual care
Intervention type(s): Behavioral; Behavioral
Intervention description(s): The intervention will be designed as an individualized, dialogue-based system that will provide PwMS coordinated, individually tailored information based on the software platform broca®. The intervention programme will consist of three sections:
EBPI/decision aid (five modules plus decision aid in case of an acute relapse) provided by the broca® programme. The key element of the EBPI/decision aid is the information on glucocorticosteroids for the treatment of acute relapses.
A webinar led via WebEx by a trained MS nurse with questioning/chat session (approx. 60-75min).
A supervised chat room provided via the DMSG (https://www.dmsg.de/ms-connect). In addition, email reminders will be used to enhance involvement of participants.; Participants in the control group will have access to web-based information material offered via the same platform (broca®) in addition to usual care. The control group intervention will be based on material of the German Multiple Sclerosis Society (DMSG) on relapse management. The programme will accompany the participants over a period of 4 weeks and a reminder system with neutral e-mail reminders will be used to promote the use of the programme.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Supportive Care
Keywords: Multiple Sclerosis; Relapsing Remitting; Relapse Management; Steroids; Autonomy