Testing the efficacy of web-based cognitive behavioural therapy for adult patients with chronic fatigue syndrome (CBIT): study protocol for a randomized controlled trial

In total 240 patients will participate in the study. All patients are referred to the Expert Centre for Chronic Fatigue (ECCF), a tertiary treatment centre for chronic fatigue of the Radboud university medical center in the Netherlands. All patients will meet CDC consensus criteria for CFS [1, 2]. They will all be severely fatigued with a score 35 or higher on the subscale fatigue of the Checklist Individual Strength (CIS). According to the consensus criteria the fatigue must be associated with significant disabilities. The latter is operationalized as scoring 700 or higher on the Sickness Impact Profile 8 (SIP8 total score). The other inclusion criteria are described in Table 1. Patients will be (temporarily) excluded when engaged in a legal procedure concerning disability-related financial benefits or when participating in other research [17]. We will assess the presence of psychiatric disorders using the MINI and clinical assessment and exclude patients who do not meet the inclusion criteria of the CDC with respect to current psychiatric disorders and/or having a medical history with psychiatric disorders.

This study will be carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments that involve humans. This study has been reviewed and approved by the Medical Ethical Committee of the Radboud university medical center (reference NL42543.091.12) and has been registered in the Dutch Trial Register (trial number: NTR4013). Patients will receive verbal and written information about the study and will be asked to sign a written informed consent form before randomization and were requested not to follow other treatments for fatigue during participation in the study. Patients will receive written information about the study results when the paper reporting on the study has been published.

Patients will be randomly allocated to one of the three conditions. This web-based randomization was computer-generated by creating blocks of 12 patients. Patients are contacted one week later to ask them if they want to participate in the study. An administrative assistant will call the patient and will perform randomization during this phone call. If patients do not need time to think about their decision and decide to participate, randomization will take place immediately at the second intake session. This will be performed by an administrative assistant in the presence of the therapist and patient. After randomization, therapists and patients will be able to read the randomization result on the screen i.e. ‘1) Internet therapy’ or ‘2) Internet therapy’ or ‘wait list’. Patients will not be informed that there are two web-based CBT treatment conditions. Knowledge of the two different treatment arms could affect the behaviour of the patient while following the web-based CBT. During the second intake session the therapist will explain that the therapist will be available to support them during the web-based CBT without specifying the frequency of support. In an instruction on the first page of the web-based application, only available after randomization, participants can read how to contact their therapist and when their therapist will contact them. The cognitive behavioural therapist who performs the intake will also deliver the web-based CBT. Test assistants will do all assessments. Therapists and test assistants are not blinded with respect to condition. This will most probably not introduce a bias as there is no contact between test assistants and patients following randomization. The test assistant sends a link via email to the patient, patients will fill in the questionnaires at home.

With data from the actometer, two activity patterns can be discerned: a low activity pattern and a relatively active pattern. The individuals' activity patterns will be based on the 12 daily physical activity scores (van der Werf, Prins, Vercoulen, van der Meer, & Bleijenberg, 2000). Two physical activity patterns can be discerned. The average daily physical activity scores of low active patients stay below the general mean physical activity of CFS patients in at least 11 of 12 days. Relative active patients score at least 2 of 12 days above the mean physical activity score of CFS patients. Relative active patients have fluctuating activity levels with bursts of activity followed by (prolonged) periods of rest [18]. In case of missing actometer data at baseline, therapists will determine the activity pattern by using a structured interview [21].

In accordance with the CBT protocol for face-to-face therapy, we developed a low active and a relatively active variant of the two web-based CBT formats. Low active patients will start with a graded activity program early in therapy. Relatively active patients will first learn to spread their activities more evenly before starting the graded activity program. Following Stulemeijer [22] we do not expect different treatment outcomes for low or relatively active patients.

The therapists delivering the web-based CBT are psychologists and cognitive behavioural therapists who are trained and experienced in delivering CBT for CFS. They will receive weekly group supervision regarding the web-based CBT. All therapists received training to improve their online communication skills with patients. The therapist will aim to write the emails in such a way that it motivates patients to follow the instructions of the intervention.

All outcome measures are listed in Table 3. See Fig. 2 for a schedule of enrolment, interventions and assessments.

Fatigue severity will be assessed with the subscale fatigue severity of Checklist Individual Strength [23]. This subscale consists of eight items assessing fatigue severity over the past two weeks. Scores range between eight (no fatigue) and 56 (severe fatigue). The cut-off score for severe fatigue is 35. This is two standard deviations above the mean of healthy controls [24]. The CIS is a reliable and valid instrument for the assessment of fatigue in CFS patients [23‐25]. The Cronbach's alpha reliability coefficient for the subscale fatigue severity is .88 [23]. This outcome measure and cut-off point was also used in previous trials assessing the efficacy of a minimal intervention for CFS [26].

Level of disability will be measured with the total score of the Sickness Impact Profile (SIP8) [25]. The SIP8 assesses functional disability on the following eight domains: ambulation, home management, mobility, alertness behaviour, sleep and rest, work, social interactions, and recreation and pastimes. A weighted total score is computed from the scores on the eight subscales [12, 27]. This widely used measure has good reliability [27] and validity [5, 11].

Physical functioning will be assessed with the Medical Outcomes Survey Short Form-36 (SF-36) [28]. The subscale ‘physical functioning’ will be used. Scores on both scales range from 0 (maximum limitations) to 100 (no limitations). The SF-36 is a reliable and valid instrument to assess self-reported health status in CFS patients [28, 29].

Psychological distress will be assessed with the total score of the Symptom Checklist 90 (SCL-90) [30]. In total 90 items are answered on a five-point Likert scale. Total scores range from 90 to 450, with higher scores being indicative of more psychological distress. This widely used measure has good reliability and discriminating validity [31].

Clinical significant improvement in fatigue is defined as a reliable change index > 1.96 [32] and a score of < 35 on the CIS ‘fatigue severity’ subscale at second assessment.

Based on the CBT for CFS model several fatigue related behaviours and cognitions will be assessed [33, 34]. The therapist will register invested therapist time for each patient. Actigraphy will be used to assess the level of physical activity. The actometer has been shown to be a reliable and valid instrument for the assessment of physical activity in CFS [18].

The presence of psychiatric disorders will be assessed using a structured diagnostic interview, the Mini International Neuropsychiatric Interview (MINI) screen test [19].

Adverse events will be assessed six months post randomization. Patients will be asked if they experienced new symptoms or an increase of existing symptoms during therapy or wait period. Patients who have received treatment will be asked if therapy in their opinion had negative side effects. Previous treatment studies have shown that regular face-to-face CBT and guided self-instructions for CFS are safe [35, 36].