Study protocol: to investigate effects of highly specialized rehabilitation for patients with multiple sclerosis. A randomized controlled trial of a personalized, multidisciplinary intervention

A recently updated version (April 2011) of a Cochrane review [6] identified ten studies of varying quality and concluded that although MS rehabilitation may have limited effect on body functions, short-term improvement in activity and participation could be observed. Another Cochrane review suggested that exercise therapy might be beneficial for muscle power function, exercise tolerance, mobility-related activities and mood in patients with MS, although no clear effects could be identified in relation to fatigue or perception of handicap [7].

The efficacy and cost-effectiveness of the Sclerosis Hospitals rehabilitation program for MS patients were investigated in a longitudinal study [8], in which participants completed a single outcome instrument (FAMS questionnaire) to measure quality of life at referral, admission, discharge and up to five months after discharge. The study showed an increase in the FAMS score from referral and admission to discharge and thereby identified a statistically significant improvement in quality of life. Although the FAMS scores had decreased five months after discharge, there was still a statistically significant improvement compared with the score at referral. The study had a number of design issues that complicated assessment of the rehabilitation effort. As the study had no control group, part of the observed effect may have been due to factors other than the rehabilitation program. The considerable variation in participants' personal and disease-related factors could also have influenced the observed effects.

The aim of the planned study is to document the effects of a highly personalized rehabilitation program for MS patients as provided by the Sclerosis hospitals using a randomized controlled study design and standard generic and disease-specific outcome measures. The objective is to assess the program’s effect on patients in terms of changes in disease-specific quality of life and to answer the following questions:

Study participants will be recruited among all patients referred to the four-week individual rehabilitation program during March 2012 to June 2013. Patients referred for shorter rehabilitation programs or theme courses will not be eligible for the study.

Participants must meet the following inclusion criteria: aged between 18 and 65 years; diagnosis of MS (relapsing remitting, primary or secondary progressive MS); Expanded Disability Status Scale (EDSS) score ≤ 7.5 [11]; can use a personal computer or has a support person/relative who can; ability to read and understand sufficient Danish to understand instructions both orally and in writing; completion of written informed consent.

The following exclusion criteria will apply: less than six months between diagnosis of MS and referral to the program; disease relapse within three months of the neurological appraisal; recipient of sclerosis-specific hospital-based rehabilitation within the last six months; cognition score (KFS) > 2 or cognitive limitations which hinder completion of self-reported questionnaires and/or informed consent; severe depression; severe heart or lung disease; drug or alcohol abuse; any other illness that can impede participation in the study. If participants develop a disease that might impair their participation in the study they will be excluded from the study at that time.

The final decision on participant inclusion or exclusion will be based on the physician/neurologist assessment.

The purpose of the rehabilitation program is to provide a personalized approach that allows the patient to develop knowledge and understanding of the disease and to maintain or develop the necessary resources and abilities to manage their life situation.

The stages of the study intervention are described below and include: initial screening; clinical examination prior to inclusion; randomization; a preparation day; four-week hospitalization; six and twelve months follow-up.

Patients referred to the hospitals are routinely sent a brief health screening questionnaire that upon return is assessed by the admission nurse to exclude patients who have a dependency level requiring intensive care and thus lack the rehabilitation potential defined by the inclusion criteria (equivalent to a EDSS score >7.5). The screening includes two basic models: factor evaluation and prototype evaluation, and includes assessment of physical and cognitive function/limitations (modified Barthel-100 index) [12‐14]. The screening can be conducted as a home visit if necessary. Proposals for patient exclusion from the study will be discussed with a neurologist. The initial screening does not exclude wheelchair users or patients who need help from others to complete the questionnaire.

Patients who fulfill the initial screening criteria will receive by ordinary mail a study information pack including detailed information about the study and patients’ rights in a health science research project. Patients willing to participate in the study should respond within 10 days by phone or mail.

Potential participants will be invited to an ambulatory consultation with a neurologist. The consultation will include standard neurological examination, screening for severe depression [15] and a walking test. The neurologist completes a screening form covering information about the patient's previous and current medical treatment and information relevant to the in- and exclusion criteria. Patients will receive additional oral information about the study and a final decision about participation is taken. Patients who are not included in the study will continue in the usual rehabilitation program. Information on fulfillment of the in- and exclusion criteria, and stated reasons for non-participation will be recorded. Patients who need time to make a final decision whether to participate in the study or not, should return a completed consent form within two days of the clinical examination.

Randomization will be performed by staff at the admitting hospital using specialized computer software. To ensure balance between different patient groups, the randomization will be stratified according to gender, age (four groups), MS type (three groups), duration of diagnosis (five groups), EDSS score (three groups), and whether or not the patient is admitted to the hospital for the first time (two groups).

The preparation day will take place seven days prior to the scheduled hospitalization. The overall purpose of the rehabilitation program will be explained and the individual areas for rehabilitation efforts will be defined in a collaboration between the patient and an appointed supervisor who serves as both the patient’s coach and as an 'orchestra conductor' for the rehabilitation team during the entire hospitalization. Prior to this preparation day, the patient will complete a FAMS form [16], a questionnaire on diet, smoking, alcohol and exercise, and indicate which of five focus areas is most important for him/her:

The patient will also complete Form one in MYCaW [17, 18]. The conversation follows clinical guidelines for target setting content and includes COPM [19‐22] as identification and qualification of the decision basis for the objective. The conversation leads to identification of the primary goal within the five main areas (see above) and specific subsidiary goals and described cf. International Classification of Functioning, Disability and Health (ICF) classification of activity or participation level, supplemented by specific milestones [23].

A hospitalization period of 20 days is organized as four weeks of continuous hospitalization. A team of relevant professionals is composed based on the assessment of the patient's needs and may include neuropsychologist, clinical psychologist, occupational therapist, physiotherapist, nutritional therapist or dietitian, nurse, healthcare assistant, nursing assistant, social worker. The neurologist will carry out the primary standard neurological examination and serve as consultant for the patient and supervisor for the team. Symptomatic drug therapy is organized or administered after the usual guidelines and the neurologist’s judgment.

The patient’s supervisor is responsible for the content of the patient's program and should oversee that it contributes to the work of the team and patient, works towards the agreed objectives and milestones and that the necessary adjustments are made during hospitalization. The supervisor and the patient continuously evaluate the program, for example by weekly conversations, and at discharge. According to patients’ wish, relatives and other team members may participate in one or more of the conversations.

During the rehabilitation period process data are collected on selected specific rehabilitation interventions, their nature, number, duration and medication.

Patient outcome will be measured by a variety of standardized quality of life (QoL), mastery and individual goal-related endpoints. A combination providing the basis for analyzing the complexity of MS and outcomes of a personalized rehabilitation.

After randomization, each participant will attend a preparation day, when individual goals and endpoints for the rehabilitation program will be determined according to the following areas:

These questionnaires and physical tests are selected to capture changes in individual goals.

The Mastery (heiQ) and QoL (FAMS) are the only tests to be performed also one month after discharge in order to assess any changes in mastery and QoL shortly after returning home.

The individually chosen tests will be supplemented by Assessment of Motor and Process Skills (AMPS) [62, 63] that include measurements of efficiency, safety, autonomy and effort in motor and process skills. This is relevant for measurements of changes in all five focus areas.

Physical tests will be performed at the clinical examination prior to inclusion, at the preparation day, at discharge and at 6 and 12 months follow-up. If the patient has received an aid during the rehabilitation program, the discharge tests will be performed both with and without aids. For practical reasons and to avoid patient burden, it is probably not possible to conduct all the physical tests for a participant during one morning session. Some tests may thus be delayed (after a rest or the following day). Such an approach is not expected to influence the validity of the test results [64]. However as patients are typically tested in the afternoon at inclusion, they will also be retested in the afternoon at discharge to avoid any effects of time differences.

The data collection is planned as outlined in Table 1. Measurement times for the early admission group include baseline (Time A1), preparation day (Time A2), day of discharge (Time A3), one-month follow-up after discharge (Time A4), six-month follow-up after baseline (Time A5) and twelve-month follow-up after baseline (Time A6).

Similarly, the six measurement times for the usual admission group are baseline (Time B1), six-month follow-up after baseline (Time B2 - acts as the control measurement – no intervention), the preparation day (Time B3), day of discharge (Time B4), one-month follow-up after discharge (Time B5) and twelve-month follow-up after baseline (Time B6).

Collection of patient-reported outcomes will mainly be based on online versions of the questionnaires, but questionnaires administered at the preparation day and at discharge will be in paper versions (Table 2). Patients who have completed the consent form will be assigned a unique study identification number and a login code to the web-based data collection system SurveyXact (http://​www.​surveyXact.​dk). This password provides access to the questionnaire to be answered in accordance with the measurement time.

In November 2011 a pilot study was conducted to test and adjust the screening and randomization processes, and to test the online survey facility. Data were collected for 8 patients in accordance with the protocol for the two groups. This pilot study identified a number of practical challenges that were addressed in the final study protocol. The target group was expanded from only patients who were referred for the first time to also include patients who had previously been admitted to the hospitals. The inclusion criteria were tightened to require that participants should be able to respond to the computerized questionnaires. A maximum age of 65 years and an additional exclusion criterion regarding other illnesses that could impede participation in the study were introduced. In addition, the screening for depression was changed to be part of the clinical assessment rather than being based on self-assessment.

In addition to data from questionnaires, data from routine administrative health registries will be obtained from the Sclerosis Hospitals, the national patient registry and the primary care registry (through the National Board of Health’s research service) and the registry of primary care prescription medicine. Data available in these registries include records of actual resource consumption (number of hospitalizations, outpatient visits and consultations) and costs in terms of service fees, fees paid to health care providers and pharmacy retail prices (AUP). Data on vital status will be obtained from the national mortality registry. These data will be obtained for the years 2010–14, i.e. for the two years prior to baseline and up to the 12 months of follow-up.

Analysis will be both descriptive and comparative.

Differences in personal and disease characteristics will be compared between participants completing the study, those who fulfill the inclusion criteria but decline participation (primary drop-out), and those who participate in parts of the study but for various reasons end participation (secondary drop-out). We will investigate for specific characteristics that distinguish drop-out individuals from those who complete the study.

The included study population will be described and the intervention and control groups will be compared for eventual significant differences in personal and disease characteristics. 'Intention to treat' analysis will be used for comparing the efficacy of the two groups and longitudinal random effects regression models (panel analysis) will be applied.

The following comparative analysis will be conducted:

Subgroup analyses will be performed on the individual focus areas, based on data from participants who have completed the goal-related questionnaires.

Patient recruitment will be ongoing and is expected to be completed by mid-2013. Data collection is expected to last a further twelve months until mid-2014. This period will be followed by a one-year period of data analysis and manuscript preparation.

It is not possible to blind participants in relation to which group they are randomized to. Similarly, it is not possible to blind the staff at the two hospitals regarding participation in the study and randomization group. Study participants will be admitted to the rehabilitation program concurrently with non-participants. This means that the intervention group and control group will be treated alongside patients outside the study.

Participation in the study will have no influence on the offer of rehabilitation or its content. Patients who do not wish to participate in the study will be treated as usual. All study participants will regardless of the randomization be offered rehabilitation.

The study is organized to meet the standards of the Declaration of Helsinki and the study protocol has been approved by the Research Ethics Committee of the Zealand Region (ref.no. 1-01-83-0002-07). The Danish Data Authority has granted permission to collect and store the required project information (ref. no. 2011-41-6751). The study is registered in the clinical trials database: http://​www.​controlled-trials.​com/​ISRCTN05245917/​

The study has obtained permissions to use the standardized outcome instruments.