How effective is FITNET-NHS for children and young adults with CFS/ME

University of Bristol (UOB) Bristol Medical School (BMS) require data from NHS Digital for a research project, the FITNET NHS (Fatigue In Teenagers on the interNET in the NHS) trial.

The FITNET-NHS Trial is a large randomised controlled trial which will investigate the clinical and cost-effectiveness of the FITNET-NHS intervention compared with Activity Management [a], among children/young people (aged 11-17 years) with Chronic Fatigue Syndrome or Myalgic Encephalomyelitis (CFS/ME) who do not have a local NHS specialist CFS/ME service. The FITNET-NHS intervention delivers specialist cognitive behavioural therapy for CFS/ME via the internet. Participants and their parents/carers work through 21 modules and have e-consultations with therapists. Activity Management is used as the comparator in this study as recommended by the National Institute of Health and Clinical Excellence (NICE guidance CG53 published August 2007) and is currently the best alternative for children/young people in regions without a local specialist CFS/ME service.

[a] Activity Management is an individualised approach that aims to establish a baseline (the same every day) level of cognitive (schoolwork, social activities and hobbies) and physical activity (walking, any exercise) using diaries. This usually requires an initial reduction in activity on some days and an increase on other days but overall, activity levels are unchanged. Both physical activity and cognitive activity are then gradually increased in a flexible approach (when participants feel able to do so). If participants’ symptoms increase, they are advised to either plateau (keep activity the same) or reduce activity depending on the severity and cause of the symptoms. Activity management is delivered by specialist therapists (e.g. occupational therapists, physiotherapists) via video calls with patients.

Many adolescents have severe fatigue but the prevalence of CFS is less common. The prevalence of CFS in children and adolescents is between 0.11% and 4%. CFS/ME can have a devastating impact on children in terms of quality of life, school, social life, and family function at the crucial time of development. It also has an impact on health service provision. Children with CFS/ME have an increase in medical consultations, tests, and prescriptions, up to five years before receiving a diagnosis. Most children/young people attending a specialist service attended 40% of school or less. About one-third of them suffer from comorbid anxiety and/or depression.

The National Institute for Health and Clinical Excellence (NICE) recommended Cognitive Behavioural Therapy (CBT) as a treatment option for paediatric CFS/ME because there is good evidence that it is effective (NICE Guidance CG53 published August 2007). Despite this, most children/young people in the UK are unable to access local specialist CBT for CFS/ME. A randomised controlled trial (RCT) showed FITNET was effective in the Netherlands but it is not known if it is effective in the National Health Service (NHS) or if it is cost-effective.

This trial will investigate whether FITNET-NHS is clinically effective and cost-effective in the NHS. The findings from this study be used to inform decision-making within the NHS. More specifically, the results will aim to provide evidence on whether FITNET-NHS, when compared to Activity Management, is better value for money for: (a) children/young people suffering from CFS/ME; and (b) children/young people suffering from CFS/ME with mild/ moderate comorbid mood disorders. If FITNET-NHS is effective and cost-effective, it could be made available to all children/young people and adolescents with CFS/ME in the UK. Its provision by the NHS has the potential to deliver substantial health gains for the large number of children/young people suffering from CFS/ME but unable to access treatment because there is no local specialist service.

The original recruitment target of the trial was 734 individuals. The trial revised its recruitment target due to under-recruitment, and the NIHR HTA agreed to fund a 6-months extension to the overall project timeframe. The new and current revised recruitment target was adjusted to 314. The trial recruitment start date was 1/11/2016. The trial successfully achieved the recruitment target of 314 on 11/11/2020 and is now in its follow-up phase. The end of the follow-up period is 11/11/2021 (the absolute follow-up end date is 11/02/2022) with the overall project end date being 30/04/2022.

FITNET was developed in consultation with adolescents. The study team have discussed this project with a UK Young People’s Advisory Group and employed a research nurse to provide trial information and discuss reservations or misunderstandings during recruitment.

The University of Bristol is both the Data Controller who will also process the data. The study is funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA). The NIHR HTA Programme funds research about clinical and cost-effectiveness and broader impact of healthcare treatments and tests for those who plan, provide or receive care from NHS and social care services. The NIHR HTA do not make any decisions determining the purposes and means of the processing of data or the study purpose and methodology, and are therefore not considered a Data Controller.

The co-applicants listed on the protocol are members of the trial management and oversight committee and are involved in supporting and advising the trial team on various aspects of the study. They support the study in an advisory capacity and do not make any decisions determining the study purposes, determine the manner in which the data will be processed, nor have any access to record-level pseudonymised data. These co-applicants are not considered by the FITNET-NHS study team as Data Processors or Data Controllers.

University of Bristol obtained consent to use routinely collected Hospital Episode Statistics (HES) data and Mental Health Services Data Set (MHSDS) (previously called Mental Health and Learning Disabilities Data Set (MHLDDS)) from NHS Digital. Data from the HES Admitted Patient Care (APC), Outpatients (OP), Accident and Emergency (A&E) and Emergency Care Dataset (ECDS)datasets, and the MHSDS will allow measurement of the use of Child and Adolescent Mental Health Services (CAMHS) among trial participants in both treatment arms (i.e. Activity management and FITNET-NHS) in the year after they enrol in the trial. Health care use will be costed using National Unit Costs where available (e.g., NHS Reference Costs, Annual Survey Of Health and Earnings) to estimate whether FITNET-NHS reduces the use and cost of healthcare needs among children with CFS/ME.

The main objectives of the trial for the processing the requested data is to:

1. Estimate the cost-effectiveness of FITNET-NHS compared to Activity Management:

- Primary analysis: The study's primary economic evaluation to assess the cost-effectiveness of FITNET-NHS compared to Activity Management will compare incremental NHS costs and health gains, measured in Quality Adjusted Life Years (QALYs). Data will be collected directly from participants on primary care use and link to administrative data (HES and MHSDS) for secondary care and longer-term outcomes. Further details are provided in the published protocols here:

A) https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-018-2500-3)

B) https://doi.org/10.1186/s13063-019-3895-1

2. Estimate the cost-effectiveness of FITNET-NHS compared to Activity Management for those with mild/moderate comorbid mood disorders (anxiety/depression).

- Appropriate statistical analysis will be used to explore the interaction between pre-morbid mood disorders and the cost-effectiveness of FITNET-NHS.

GDPR Legal basis for processing:

On the advice received from the Research Data Governance Office at the University of Bristol, to access patient data, for this research project can rely on the following GDPR Articles for the processing of health data to be received from NHS Digital:

1) Article 6(1)(e) of the GDPR, i.e. processing is necessary for the performance of a task carried out in the public interest. Research is a task that University of Bristol performs in the public interest, as part of their core function as a university.

2) Article 9(2)(j) of the GDPR, i.e. processing is necessary for research purposes or statistical purposes. The work is in the public interest because it helps the NHS to maximise public health from the limited resources available to it. The study's work aims to improve public health by providing evidence to help NHS decision-makers identify effective and cost-effective healthcare for children with CFS/ME.

Patient and Public Involvement is dealt with in Section 5(c) Expected Output.

Data held for analysis will not be transferred outside of the University of Bristol to any third countries or organisations. Outputs will be aggregated with small number suppression applied as per the HES analysis guide.

Only data/items relating to the purpose of the study are requested. University of Bristol have not requested identifying data fields. Details of the proposed data linkage were provided to trial participants in the study Patient Information Leaflet (PIL) and data is only requested for those participants who have provided their consent. Study participants who have consented are also able to withdraw their consent at any time during the study and only data between the date of consent and date of withdrawal will be requested.

University of Bristol cannot filter on diagnosis codes to minimise the data requested because:

i) Chronic fatigue is often underdiagnosed and healthcare contacts which are related to chronic fatigue may well be coded using a diverse range of diagnosis codes.

ii) Diagnosis codes in HES OP and ECDS in particular, are not recorded in a way suitable for the applicant to process in accordance with their purposes.

Each child/young person recruited to the trial is assigned a unique study identifier (Pseudo-ID) to maintain pseudonymisation. Towards the end of the trial follow up (October 2021), University of Bristol will provide NHS Digital with a file containing this study identifier and other patient identifiers (NHS number, date of birth and postcode) for all trial participants recruited in England who have consented to linkage to routinely collected data. University of Bristol will also provide the participant 'Date of Recruitment' as the study only requires HES records from the date of recruitment until the end of the follow-up period. The file will be securely transferred to NHS Digital via Secure Electronic file Transfer (SEFT) system.

2. NHS Digital will use the patient identifiers to achieve linkage to the datasets requested for the years encompassing trial recruitment and follow up (projected to be 2016/17 to end 2021 inclusive). NHS Digital will prepare data files containing the required HES/ECDS/MHSDS data fields. NHS Digital will remove the direct patient identifiers (e.g. NHS Number, Date of Birth and Postcode) but retain the Study Pseudo-ID. The pseudonymised files will be securely transferred to the FITNET-NHS study team at the University of Bristol via Secure Electronic file Transfer (SEFT) system.

3. The FITNET-NHS Trial team will store the data in the University of Bristol encapsulated Virtual Machine (eVM) which will be set-up by University of Bristol’s IT specialists prior to receiving the data. The ‘encapsulated virtual machine’ (eVM) is a purpose-built secure research server. It provides a secure way for approved University of Bristol substantive employees who are part of the FITNET-NHS research team to access the data from approved University of Bristol computers. The University of Bristol eVM is compliant with the existing University of Bristol organisational Data Security and Protection Toolkit (DSPT). The record-level pseudonymised data that NHS Digital supplies will be linked via the study identifier (Study ID) to the pseudonymised patient data collected as part of the trial. For example, this will allow University of Bristol to compare whether healthcare use differs according to the severity of CFS/ME at the time of trial enrolment and before the start of treatment. The cohort identifiers will be kept separate from the pseudonymised study data on the eVM.

4. All data analysis will be performed by substantive employees of the University of Bristol who are members of the FITNET-NHS study team. The team will aggregate the HES and MHSDS data (e.g. to calculate the total number and cost of hospital admissions for each patient). The primary analysis will be a comparison of healthcare use between patients randomised to receive activity management or FITNET-NHS.

At no point will University of Bristol link the NHS Digital data back to direct patient identifiers (e.g. NHS number) in an attempt to re-identify individuals, or attempt to link to any other datasets collected outside of the auspices of the trial.

The FITNET-NHS study team will only be able to access the data from designated encrypted university owned computers with an assigned Internet Protocol (IP) address on site at University of Bristol. Remote access is not permitted. All analysis will take place on designated encrypted computers working within the eVM. Download of NHS Digital data to device hard-drives is not permitted.

University of Bristol believe that using routine data, with consent, to measure healthcare use across England represents the least intrusive way of collecting this data. The NIHR final report is scheduled for 30/04/2022. University of Bristol anticipate that the research outputs will be submitted and peer-reviewed within 12 months of the NIHR final report (i.e. approximately 30/04/23). At the end of the archiving period of 15 years, University of Bristol will securely destroy the data received from NHS Digital and provide a certificate of Data Destruction as evidence.

University of Bristol have taken the following steps/actions to meet their Data Sharing and Protection Toolkit:

1. Detailed information of the researchers (including name, department, building and computer IT system number) accessing, processing and handling data have been provided to the Information Governance Team at the University of Bristol and has met the eligibility criteria for the DSPT.

2. Named Researchers accessing, processing and handling data have completed the "GDPR Information Security Training" and "Medical Research Council Research, GDPR and Confidentiality Training" scoring 80% or higher.

3. Once the data is obtained and stored in the respective eVM, the University of Bristol Information Governance Team would carry out a Data Quality Audit.

Virtus and AQL Leeds provide secure buildings within which University of Bristol equipment is hosted and maintained. Virtus and AQL Leeds do not access data held under this agreement as they only supply the building and are therefore not listed as a Data Processor. Therefore, any access to the data held under this agreement would be considered a breach of the agreement. This includes granting of access to the database containing the data.

MHSDS, HES and ECDS DISCLOSURE CONTROL / SMALL NUMBER SUPPRESSION

In order to protect patient confidentiality, when presenting results calculated from HES record level data, outputs will contain only aggregate level data with small numbers suppressed in line with HES Analysis Guide. When publishing HES data, you must make sure that:

· National-level figures only may be presented unrounded, without small number suppression

· cell values from 1 to 7 (inclusive) are suppressed at a local level to prevent possible identification of individuals from small counts within the table.

· Zeros (0) do not need to be suppressed.

· All other counts will be rounded to the nearest 5.

Data will not be made available to any third parties other than those specified except in the form of aggregated outputs with small numbers suppressed in line with the HES Analysis Guide.

A comprehensive report of the trial findings will be submitted in approximately May 2022 for publication in the NIHR journals library. To increase dissemination, University of Bristol also intend to publish research outputs in a small number of high impact peer-reviewed scientific journals (e.g. British Medical Journal) during 2022/2023. University of Bristol also plan to disseminate the findings through conference presentations – for example, Paediatric Conference in the United States of America, The Royal College of Paediatrics and Child Health (RCPCH UK) and Academic GP Conference. University of Bristol will also work with the University of Bristol press office and the Science Media Centre to disseminate plain English summaries of results to the public. In line with NIHR policy, papers will be open access and made publicly available for free on University of Bristol’s website.

University of Bristol intend to keep the participants informed by sending them annual study newsletters (the first batch of newsletters were sent in February 2020) and by updating study websites. University of Bristol also organised a Research Festival in September 2020 where all participants and their families recruited on FITNET-NHS Trial were invited to attend. The event was attended by research and clinical teams based at the University of Bristol and The Bath Royal United Hospital. Members of the Patient Advisory Group (PAG) were also invited. The purpose was to update the families and patients of any changes made to the trial – how University of Bristol are using and will use their data; hold workshops and questions and answer sessions to address trial related queries.

All outputs will include only aggregate data with small numbers suppressed in line with the HES Analysis Guide. No record level data will be shared with any third party not named in this agreement.

Previous research from the study trail was cited by NICE in their most recent evidence review and guidance (NICE Guidance NG206 published October 2021) – for example, see references below. The study team expect that evidence from the FITNET trial will inform the next iteration of NICE guidance.

Beasant L, Mills N, Crawley E. Adolescents and mothers value referral to a specialist service for chronic fatigue syndrome or myalgic encephalopathy (CFS/ME). Primary Health Care Research & Development. 2014; 15(2):134-142

Crawley E, Mills N, Beasant L, Johnson D, Collin SM, Deans Z et al. The feasibility and acceptability of conducting a trial of specialist medical care and the Lightning Process in children with chronic fatigue syndrome: feasibility randomized controlled trial (SMILE study). Trials. 2013; 14:415

Crawley EM, Gaunt DM, Garfield K, Hollingworth W, Sterne JAC, Beasant L et al. Clinical and cost-effectiveness of the Lightning Process in addition to specialist medical care for paediatric chronic fatigue syndrome: Randomised controlled trial. Archives of Disease in Childhood. 2018; 103(2):155-164

The study team hope to send the findings of the study in the form of journal articles and lay summary reports to the NICE Committee that develops clinical guidelines for management of chronic fatigue syndrome, in order that the findings from this study be used to inform decision-making within the NHS. It is hoped that the results and findings of the FITNET study can be incorporated into future NICE clinical guidelines.

More specifically, the results aim to provide evidence on whether FITNET-NHS, when compared to Activity Management, is better value for money for: (a) children suffering from CFS/ME; and (b) children suffering from CFS/ME with mild/ moderate comorbid mood disorders. If FITNET-NHS is effective and cost-effective, it could be made available to all children and adolescents with CFS/ME in the UK. Its provision by the NHS has the potential to deliver substantial health gains for the large number of children suffering from CFS/ME but unable to access treatment because there is no local specialist service.

Potential benefits to participants:

Most children in the UK are unable to access treatment for CFS/ME because there is no local specialist service. Children who take part in this study will be offered treatment delivered by specialist CFS/ME therapists in both treatment arms (Activity Management or specialist CBT for CFS/ME delivered online).

Potential benefits to society:

Health economic benefits: Children with CFS/ME use significant health care resources. Most mothers of children with CFS/ME reduce or stop work. Effective treatment has the potential to reduce NHS and wider societal costs and improve school attendance and quality of life. The trial is needed now because ~90% of children with CFS/ME do not have access to treatment shown to be effective.

Attitudes and awareness:

Approximately 90% of GPs and paediatricians in England do not have effective treatments for children with CFS/ME. The dissemination programme will increase awareness among the public, GPs and paediatricians. If FITNET-NHS is effective, it could change attitudes about paediatric CFS/ME being ͞untreatable͟ to being ͞treatable͘͟. This trial aims to provide useful information on the treatment of co-morbid mood disorders and what factors are important mediators in paediatric CFS/ME. This may change the treatment offered by specialist CFS/ME services and will generate hypotheses for researchers. This trial aims to provide an intervention in the homes of children throughout England. If it is feasible this method could be used for other long term conditions where children do not have local specialist services. Results from the qualitative methods could inform about how to improve these type of interventions. It is hoped this is likely to benefit children from other conditions, their families, clinicians and the NHS.

Yielded Benefits is not a requirement for new applications.