Investigating the effectiveness and cost-effectiveness of FITNET-NHS (Fatigue In Teenagers on the interNET in the NHS) compared to Activity Management to treat paediatric chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME): protocol for a randomised controlled trial

This is an RCT comparing FITNET-NHS with Activity Management for paediatric CFS/ME. An internal pilot study will be conducted with continuation of the trial based on achieving defined criteria. Integrated qualitative methods will be used to optimise recruitment and retention. Pilot data will be used in the effectiveness analyses unless changes to the interventions or trial design are significant.

Young people will be assessed by their general practitioner (GP), referred for local paediatric assessment and investigated using NICE guidance [4]. If a diagnosis of CFS/ME is made and there is no local specialist paediatric CFS/ME service, GPs will be able to refer patients diagnosed with CFS/ME to the Bath specialist paediatric CFS/ME service. This is the standard referral pathway for out-of-area patients.

Young people will be eligible if they are: (1) aged 11–17 years, (2) diagnosed with CFS/ME (using NICE guidance [4]) and (3) do not have access to a local specialist paediatric CFS/ME service. Young people will be excluded if any of the following apply: (1) they are not disabled by fatigue (defined in eligibility screening), (2) their fatigue is due to another cause, (3) they are unable to complete video calls or FITNET-NHS online chapters or (4) they report pregnancy at assessment.

The clinical team at the Bath specialist paediatric CFS/ME service will identify potentially eligible young people referred to the service and telephone them and their parents/carers to discuss treatment options, including the option to take part in the trial. Young people and parents/carers who are interested will be emailed an information pack including: an age-appropriate Patient Information Leaflet (PIL), and links to an online ‘consent to contact’ form and Revised Children’s Anxiety and Depression Scale (RCADS) questionnaire [20, 21]. The ‘consent to contact’ form and RCADS questionnaire will be completed using a secure electronic system used for data capture called Research Electronic Data Capture http://​project-redcap.​org (REDCap). After ‘consent to contact’ is completed an eligibility assessment will be carried out with both the young people and their parents/carers. Following this, the recruitment consultation is performed. The eligibility assessment and recruitment discussions usually take place during one telephone/video call; however, they can also take place over separate telephone/video calls if preferred. These discussions will be audio-recorded with consent/assent. The trial design and interventions will be explained; young people and their parents will be given the opportunity to read the age-appropriate PIL, ask questions and can have as long as required to make an informed decision. The researcher will seek age-appropriate consent/assent from the young person and parents/carers via the online REDCap system. Those who decide not to take part will be invited to talk to a qualitative researcher about their decision and verbal agreement will be recorded during the recruitment consultation. They will be offered a face-to-face assessment and treatment by the Bath specialist paediatric CFS/ME service and continue to receive standard medical care. Further consent for an interview will be obtained at the time of the interview.

Participants will be randomised in a 1:1 ratio, by the research team, to receive either FITNET-NHS or Activity Management using an automated web randomisation service. Allocation will use minimisation to facilitate balance by age and gender, and preserve allocation concealment. Because of the nature of the intervention, it is not practical to blind either the participant, family or the clinical service to treatment allocation. GPs will be informed of the allocation.

The Bath specialist paediatric CFS/ME service will provide both treatment arms. Both interventions will be delivered so that participants receive treatment at home, online. The Activity Management arm is akin to usual care for out-of-area referrals, who would normally have an assessment (face-to-face) with follow-ups via video call. The difference with Activity Management delivered within the FITNET-NHS Trial is that participants do not need to travel for the initial assessment as this too is delivered via video call. See Fig. 1 for the standard referral and treatment pathway for out-of-area patients, compared with the trial processes.

The following data will be collected from participants at the clinical assessment: age, sex, post code, ethnicity, symptoms (Centers for Disease Control and Prevention (CDC) and NICE criteria), months of illness, and diagnoses of co-morbid illnesses. At baseline participants will complete the following questionnaires: SF-36 physical function subscale (SF-36-PFS) [22], fatigue (using the Chalder Fatigue Scale and the Checklist Individual Strength (CIS) [23] fatigue severity subscale), school attendance, RCADS [21, 24], pain Visual Analogue Scale [25], EQ-5D-Y (EuroQoL health-related quality of life questionnaire, Youth version) [26] and the Clinical Global Impression Scale questionnaire [27], the Cognitive Behavioural Responses to Symptoms Questionnaire (CBRSQ) [28, 29] and the Children’s Negative Cognitive Error Questionnaire Revised (CNCEQ-R) [30]. Parents will complete the following questionnaires at baseline: an adapted existing Healthcare Resource Use questionnaire to measure health service use and the adapted six-item Work Productivity and Activity Impairment Questionnaire General Health V2.0 (WPAI:GH) [31].

The primary outcome is disability measured using the SF-36-PFS 6 months after randomisation.

Secondary outcomes will be measured at 3-, 6- and 12-month follow-ups unless otherwise stated: SF-36-PFS measured at 3 and 12 months after randomisation; fatigue (Chalder Fatigue Scale and CIS); school attendance; RCADS); pain Visual Analogue Scale; Clinical Global Impression Scale; EQ-5D-Y; parental completed: Healthcare Resource Use questionnaire; WPAI:GH. All these measures are important and relevant domains [32] that are used in UK services, Child and Adolescent Mental Health Services (CAMHS) and/or tested in previous trials [16, 33, 34].

All data will be collected on REDCap and anonymised at source. Table-based authentication will be used which utilises the storage of username/password pairs in a database table. Participants will be sent a web link to REDCap which will only allow access to their data. All data will either be stored on secure University of Bristol servers and or in secure locked cabinets. They will create a password which they will use each time they log in. The schedule of data collection is shown in Fig. 2, the SPIRIT Figure [35]. An email will be sent to participants with a link to complete questionnaires online. If these are not completed, two automated reminders will be sent and then we will telephone participants where possible. If this is not successful, an email with a link to a reduced set of questionnaires will be sent out (SF-36-PFS, Chalder Fatigue Scale, school attendance, EQ-5D-Y and Clinical Global Impression Scale).

Full trial: we plan to randomise 734 young people in the full trial. The study will proceed to full trial assuming the stop criteria (see below) are not met. Assuming 10% attrition (withdrawal or non-provision of primary outcome data) [16, 33], data on 660 young people will be available for the primary analysis. This gives 97% power at 1% significance to detect a 0.35-SD difference in treatment effect on the SF-36-PFS. The analysis of effectiveness in 198 young people with co-morbid mood disorders of anxiety and depression (30% of those recruited and with data available for analysis (after 10% attrition)) will have 80% power to detect a 0.4-SD difference at 5% significance. A difference of 10 points on the SF-36-PFS is considered to be the Minimal Clinically Important Difference (MCID) [36, 37]. The mean SF-36-PFS is 49.8 with SD 24.8 in young people with CFS/ME at assessment by the Bath specialist paediatric CFS/ME service (n = 1075). A 0.4-SD is 9.92 and, therefore, our trial is powered to detect the MCID of 10 in young people with co-morbid mood disorders of anxiety and depression.

We will perform sensitivity analyses on young people who fulfil the CDC diagnostic criteria. We estimate this will be 80% of those randomised (529 after 10% attrition) which will give us 98% power to detect a difference in treatment effect of 0.35 SD at 5% significance, which is at least the MCID.

The internal pilot study will run for 12 months using integrated qualitative methods to determine feasibility of trial processes and acceptability of interventions. Defined criteria (see below) will be used to determine whether the study should proceed to full trial, in which case data from the internal pilot phase will be included in full trial analysis.

We will prospectively collect data on serious and non-serious adverse events reported to the clinician or research team during the intervention and follow-up period. These will be reported according to the sponsor’s guidelines. We will investigate whether young people randomised to one arm are at higher risk of having a serious deterioration in health compared to another arm. We will define a serious deterioration in health as: (1) clinician-reported serious deterioration in health, (2) a decrease of ≥ 20 in SF-36-PFS between baseline and 3, 6 or 12 months or scores of ‘much’ or ‘very much’ worse on the Clinical Global Impression Scale or (3) withdrawal from treatment because of feeling worse.

Safety outcomes will be analysed by the Data and Safety Monitoring Committee (DSMC) at 11 months after the start of recruitment, before the trial progresses from internal pilot to full trial and when approximately 50% of participants have been recruited (estimated 23 months after the start of recruitment).

Following the baseline mood assessment (using RCADS), the research team will not routinely monitor depression or anxiety. Participants will be made aware of this and if they are worried about anxiety or depression, or disclose information about this during the course of the trial, they will be advised to discuss this with their routine care providers (e.g. GP, paediatrician), and clinicians will inform them about relevant services if appropriate. Participants will be made aware that if they report any serious problem outside of business hours, it may not be followed-up until business hours resume and they should contact their GP, paediatrician or emergency service.

This will be the largest RCT conducted in paediatric CFS/ME. It is designed to investigate the effectiveness and cost-effectiveness of using FITNET-NHS, delivering online CBT, compared to Activity Management delivered via video calls, to treat paediatric CFS/ME in the UK. If effectiveness and cost-effectiveness are demonstrated for either arm, the NHS has the potential to deliver substantial health gains for the large number of young people suffering from CFS/ME but unable to access treatment because there is no local specialist service. If it is feasible this method could be used for other long-term conditions where young people do not have local specialist services. Results from the qualitative methods will tell us about patient experiences of the intervention content and mode of delivery, how to improve these types of interventions and how to deliver treatment from a single centre in the UK. Results will be disseminated as widely as possible including: open-access journals, conferences and public events. This is likely to benefit young people from other conditions, their families, clinicians and the NHS.

There is currently limited evidence of treatment effect in children with co-morbid mood disorders [45]. Most, but not all [46], studies in adults suggest that CBT is less effective in patients with co-morbid depression [47‐49]. Anxiety and depression is common for young people with CFS/ME [8, 50, 51]. FITNET-NHS is designed to treat young people with co-morbid mood disorders as well as CFS/ME and this trial is powered to test whether the effects of FITNET-NHS differ in this subgroup of young people.

Our trial design includes usual care delivered by a specialist service. This is because it was felt to be unethical to offer no treatment to children in the control arm, though for many children in the UK ‘usual care’ is no treatment.

As Activity Management and CBT are behavioural interventions it is not feasible to blind participants or clinicians to allocation. However, the research team have worked to ensure the information sheets present the two treatments in a balanced way, and recruiters have had training to try and encourage participant equipoise. The analyses will be conducted by a researcher blinded to treatment allocation. As we are investigating CFS/ME, the outcomes are patient-reported outcomes. These outcomes are consistent with illness domains that are the most important to patients. The outcomes at follow-up are not reported to clinicians to reduce performance bias.

There is potential for contamination between interventions because of contact between therapists of two treatment arms (working in the same treatment centre); however, both treatment arms are protocolised and adherence will be checked.

If differences in effectiveness are found between the treatments, further research will be required to explore mechanisms of effectiveness.

Opened to recruitment November 2016. Recruitment is ongoing into 2020. For details see: www.​bristol.​ac.​uk/​fitnet-nhs/​.