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): amendment to the published protocol

Abstract The FITNET-NHS Trial is a UK, national, trial investigating whether an online cognitive behavioural therapy program (FITNET-NHS) for treating chronic fatigue syndrome/ME in adolescents is clinically effective and cost-effective in the NHS. At the time of writing (September 2019), the trial was recruiting participants. This article presents an update to the planned sample size and data collection duration previously published within the trial protocol. Trial registration ISRCTN, ID: 18020851. Registered 8 April 2016.


Background
The FITNET-NHS Trial is a United Kingdom (UK), national ,randomised controlled trial testing the acceptability, effectiveness and cost-effectiveness of an online cognitive behavioural therapy (CBT) programme, FITNET-NHS (Fatigue In Teenagers on the interNET in the National Health Service), designed to treat adolescents with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) [1]. In the UK, most young people with CFS/ME do not have access to local NHS specialist medical care for the condition, as there are limited paediatric CFS/ME specialist centres in the UK. The FITNET-NHS trial was set up to test the online delivery of specialist care from one specialist paediatric CFS/ME site in the south west of England as a means of addressing this problem. Recruitment projections were estimated in advance and were based on reaching national paediatric CFS/ME populations at high volumesmade possible due to our innovative methodology using entirely remote processes for recruitment and treatment delivery. The original sample size target if achieved would have given us sufficient statistical power to detect a true effect of FITNET-NHS within the subgroup of participants with co-morbid mood disorder.
The current article is an amendment to our previously published protocol for the FITNET-NHS Trial: Baos et al. (2018) [1].

Amendment
Recruitment into the FITNET-NHS Trial began on 1 November 2016. In mid-2018, it became apparent that the recruitment rate would not allow us to achieve our original sample size target (n = 734) without a substantial extension to the recruitment period. The original sample size was selected to provide 80% power to detect a 0.4standard deviation (SD) difference at 5% significance with 10% attrition on the primary outcome in a subgroup of participants (estimated to be 30% or n = 220) with comorbid mood disorders of anxiety and depression. For all participants (with or without co-morbid mood disorders), the original sample size provided 97% power at 1% significance to detect a 0.35-SD difference on the primary outcome (Short Form Health Survey; Physical function Subscale (SF-36-PFS) score) at 6 months.
We reviewed the trial with the funders -National Institute for Health Research, Health Technology Assessment (NIHR HTA, on 10 July 2018) and consulted with the Trial Management Group (TMG, on 12 September 2018 and 18 October 2018), the Data Safety Monitoring Committee (DSMC, on 10 October 2018 and by email report on 11 March 2019) and the Trial Steering Committee (TSC, on 28 November 2018).
In September 2018, we calculated the required sample size for the primary outcome in all participants (with or without co-morbid mood disorders): Data on 266 children will give us 90% power at 5% significance to detect a 0.4-SD difference on the SF-36-PFS. With attrition currently at approximately 15%, we will need to recruit 314 children. This is achievable (based on recruitment rates to date) by the end of October 2020.
This gave us a new recruitment target of 314 children in total, 157 in each treatment group We considered the issue of co-morbid disorders. On 2 October 2018, we investigated the rate of co-morbid mood disorders in FITNET-NHS participants at baseline. This was higher than our original estimates as the rate of co-morbid mood disorders was 40% (compared to 30% in our original estimates). With the revised sample size target of 314 there will be approximately 106 participants with co-morbid mood disorders (53 in each treatment group). This will give 53% power at 5% significance to detect a 0.4-SD difference on the SF-36-PFS between treatment groups within this co-morbid subgroup.
From consultation with the NIHR HTA, TSC, DSMC and TMG, the decision was made to agree revised recruitment targets and extend the recruitment time by 6 months to enable the FITNET-NHS Trial to achieve the primary aim of testing the effectiveness (and costeffectiveness) of the FITNET-NHS treatment compared to Activity Management. The NIHR HTA gave their approval in principle of this change on 30 January 2019, subsequent to provision of documentation. Full NIHR HTA approval for revised recruitment target and the contract variation to include the 6-month extension to the project timeline was received on 24 April 2019. We will, therefore, recruit 314 children and recruitment will finish on 31 October 2020. Follow up will finish on 31 October 2021.
We have followed standard procedures to update all relevant organisations regarding these changes, including trial registration (ISRCTN, ID: 18020851: change accepted and records updated on 1 July 2019), and submitting as a substantial trial amendment to the Research Ethics Committee (REC, approved on 26 July 2019) and the Health Research Authority (HRA, approved on 10 July 2019).
With our revised recruitment target of 314 participants, the FITNET-NHS is still set to be the largest paediatric CFS/ME treatment trial in the UK and globally, the results of which will should the future of paediatric CFS/ME treatment delivery.

Funding
The trial is funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (14/192/109). The sponsor is the University of Bristol. The trial is monitored and audited in accordance with the sponsor's procedures. Indemnity for the trial is provided by the University of Bristol.

Availability of data and materials
The research staff will have access to the de-identified data during the project period, and 5 years following the completion of the trial for contributing to knowledge building through dissemination of research reports.

Ethics approval and consent to participate
The RCT protocol has been reviewed and approved by the South West -Frenchay Research Ethics Committee (16/SW/0268). Both the young person and their caregiver need to give consent/assent. Amendments to the trial protocol are approved by the sponsor (and the Research Ethics Committee if appropriate) prior to implementation.

Consent for publication Not applicable
Competing interests EC is a medical advisor for the Sussex and Kent ME Society. HK and GB received royalties for publication of treatment manual for CBT in CFS/ME in adults. Other than those stated, above, the remaining authors have nothing to declare.