Comparison of [CBT] versus activity management, both delivered remotely, to treat paediatric [CFS/ME]: the UK FITNET-NHS RCT 2024 Metcalfe et al

Andy

Andy

Senior Member (Voting rights)
Full title: Comparison of cognitive behaviour therapy versus activity management, both delivered remotely, to treat paediatric chronic fatigue syndrome/myalgic encephalomyelitis: the UK FITNET-NHS RCT

Authors:
Esther Crawley, Emma Anderson, Madeleine Cochrane, Beverly A Shirkey, Roxanne Parslow, William Hollingworth, Nicola Mills, Daisy Gaunt, Georgia Treneman-Evans, Manmita Rai, John Macleod, David Kessler, Kieren Pitts, Serena Cooper, Maria Loades, Ammar Annaw, Paul Stallard, Hans Knoop, Elise Van de Putte, Sanne Nijhof, Gijs Bleijenberg & Chris Metcalfe.

Abstract

Design
Parallel-group randomised controlled trial.

Methods
Participants
Adolescents aged 11–17 years, diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome and with no local specialist treatment centre, were referred to a specialist service in South West England.

Interventions
Fatigue In Teenagers on the interNET in the National Health Service is a web-based myalgic encephalomyelitis/chronic fatigue syndrome-focused cognitive–behavioural therapy programme for adolescents, supported by individualised written, asynchronous electronic consultations with a clinical psychologist/cognitive–behavioural therapy practitioner. The comparator was videocall-delivered activity management with a myalgic encephalomyelitis/chronic fatigue syndrome clinician. Both treatments were intended to last 6 months.

Objectives
Estimate the effectiveness of Fatigue In Teenagers on the interNET in the National Health Service compared to Activity Management for paediatric myalgic encephalomyelitis/chronic fatigue syndrome. Estimate the effectiveness of Fatigue In Teenagers on the interNET in the National Health Service compared to Activity Management for those with mild/moderate comorbid mood disorders. From a National Health Service perspective, estimate the cost-effectiveness of Fatigue In Teenagers on the interNET in the National Health Service compared to Activity Management over a 12-month horizon.

Primary Outcome
36-item Short Form Health Survey Physical Function subscale at 6 months post randomisation.

Randomisation
Web-based, using minimisation with a random component to balance allocated groups by age and gender.

Blinding
While the investigators were blinded to group assignment, this was not possible for participants, parents/carers and therapists.

Results
The treatment of 314 adolescents was randomly allocated, 155 to Fatigue In Teenagers on the interNET in the National Health Service. Mean age was 14 years old and 63% were female.

Primary outcome
At 6 months, participants allocated to Fatigue In Teenagers on the interNET in the National Health Service were more likely to have improved physical function (mean 60.5, standard deviation 29.5, n = 127) compared to Activity Management (mean 50.3, standard deviation 26.5, n = 138). The mean difference was 8.2 (95% confidence interval 2.7 to 13.6, p = 0.003). The result was similar for participants meeting the National Institute for Health and Care Excellence 2021 diagnostic criteria.

Secondary outcomes
Fatigue In Teenagers on the interNET in the National Health Service participants attended, on average, half a day more school per week at 6 months than those allocated Activity Management, and this difference was maintained at 12 months. There was no strong evidence that comorbid mood disorder impacted upon the relative effectiveness of the two interventions. Similar improvement was seen in the two groups for pain and the Clinical Global Impression scale, with a mixed picture for fatigue. Both groups continued to improve, and no clear difference in physical function remained at 12 months [difference in means 4.4 (95% confidence interval −1.7 to 10.5)].

One or more of the pre-defined measures of a worsening condition in participants during treatment, combining therapist and patient reports, were met by 39 (25%) participants in the Fatigue In Teenagers on the interNET in the National Health Service group and 42 (26%) participants in the Activity Management group.

A small gain was observed for the Fatigue In Teenagers on the interNET in the National Health Service group compared to Activity Management in quality-adjusted life-years (0.002, 95% confidence interval −0.041 to 0.045). From an National Health Service perspective, the costs were £1047.51 greater in the Fatigue In Teenagers on the interNET in the National Health Service group (95% confidence interval £624.61 to £1470.41). At a base cost-effectiveness threshold of £20,000 per quality-adjusted life-year, the incremental cost-effectiveness ratio was £457,721 with incremental net benefit of −£1001 (95% confidence interval −£2041 to £38).

Conclusion
At 6 months post randomisation, compared with Activity Management, Fatigue In Teenagers on the interNET in the National Health Service improved physical function and school attendance. The additional cost of Fatigue In Teenagers on the interNET in the National Health Service and limited sustained impact mean it is unlikely to be cost-effective.

Open access, https://www.journalslibrary.nihr.ac.uk/hta/VLRW6701#/full-report
 
I don't plan to spend time analysing this but, skimming through, I noticed something of potential interest:
The TSC is referring to the seasonal pattern of referrals to ME/CFS services, rising in the winter and falling in the summer
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I wasn't aware there was a seasonal pattern to referrals. Does anyone know if this pattern is seen at other ME/CFS clinics?

If there is a seasonal pattern to onset, not just referral, that may tell us something useful.
 
There seems to be a large difference in treatment intensity between the two arms.

The activity management is described as also being called pacing, and then involved encouraging 10-20% increases in activity. "Participants were encouraged to increase activity until they were able to do up to 8 hours of cognitive and physical activity a day."
 
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A quote from a therapist delivering the intervention (p65):
I think the platform can say things that we can’t say out loud. The platform can say in black and white and I think in capitals in some places, if you don’t get your sleep sorted you’re not going to get better, in places where it is really quite like if you don’t do this you’re staying ill. You have to do this you need to
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I think it is completely unethical to tell a child that.
 
Nightsong said:
If there is a seasonal pattern to onset, not just referral, that may tell us something useful.
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It is interesting, but I wonder if long summer breaks in schools and universities have something to do with the reduced number of referrals?

Young people are less likely to struggle with attendance if they're either already on summer break, or there are more gaps in their normal timetable because of revision time and then exams.
 
Andy said:
The mean difference was 8.2 (95% confidence interval 2.7 to 13.6, p = 0.003).
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Haven't read the report yet but the research team of Crawley defined the minimal clinically important difference for this scale to be 10 points. So that would suggest that the effect they found was too small to be clinically significant. It also seems that it decreased to 4.4 points at the 12 month follow-up.
 
They define the control treatment as if it was similar to pacing:
Activity Management is a behavioural treatment offered throughout the UK in paediatric services. Patients and their families often call this Pacing. It was recommended by NICE in 2007 and in 2021.3,4
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But it seems more like graded exercise therapy (GET):
When participants managed the baseline for 1–2 weeks, they were encouraged to increase this gradually (by no more than 10–20%) each week in a flexible and individualised way. [...] Participants were encouraged to increase activity until they were able to do up to 8 hours of cognitive and physical activity a day
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The PACE trial also called all the active arms versions of pacing. GET was also called Simple incremental pacing and CBT was called Complex incremental pacing.
Edited to correct the above
See the Manual for therapists for CBT, pages 12, 13

What I don't understand with this trial design is that, given that PACE found no difference between CBT and GET, and it's so called efficacy was on the basis of comparing these with SMT and APT. Yet in this trial they set up what is effectively CBT versus GET, and expected to find a difference. The good thing about it is that they found no significant cost effective difference so that dumps both CBT and GET online versions in the bin.
 
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Harms
The small number of reports from participants and clinicians of a worsening condition at the point of reporting of an adverse event or treatment withdrawal were predominantly in the FITNET-NHS group (see Table 12), perhaps due to the more frequent contact in the FITNET-NHS intervention leading to the more adverse events being reported (one or more adverse events or serious adverse events reported for 28 participants in the FITNET-NHS group and 18 participants in the Activity Management group), and more treatment withdrawals (61 participants in the FITNET-NHS group and 12 participants in the Activity Management group). In contrast, participants meeting the pre-defined criteria for a worsening condition on the SF-36-PFS or CGI were evenly distributed between the two groups, with a composite of these different measures indicating about one-quarter of participants in each group experiencing a worsening condition at some point in the 12-month follow-up period.
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The number of participants with evidence of worsening condition from SF-36-PF or the Clinical Global Impression Scale (%) for the two treatments were: 39 (25%) and 42 (26%.

I would like to know what "evidence of worsening condition from SF-36-PF or the Clinical Global Impression Scale" means.

And I'm wondering whether it can be excluded that the higher dropouts in the FITNET-NHS arm are inflating the average scores. The average health of the group will go up if the sickest are more likely to be dissatisfied or harmed by the treatment and decide to drop out.
 
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InitialConditions said:
A 166-page report, in an NIHR journal. How strange.

It seems they've not bothered to plot up the results for the primary outcome and instead have presented the results in a table.
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I did wonder whether this journal was actually peer-reviewed, as I wasn't aware NIHR had their own journals — but it is. So it's unlikely these results will be written up elsewhere.
 
I recall this paper was also published like this:

O'Dowd H, Gladwell P, Rogers C, Hollinghurst S, Gregory A. Cognitive behavioural therapy in chronic fatigue syndrome: a randomised controlled trial of an outpatient group programme. Health Technol Assess 2006;10(37)
https://www.journalslibrary.nihr.ac.uk/hta/hta10370/#/abstract

It is probably a better way of doing things versus the PACE Trial where the data was released across lots of different papers.
 
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These look like the main results. The Clinical Global Improvement Score and quality of life (EQ-5D-Y) are not shown but also showed no significant differences.

The only results that point to a consistent effect is (self-reported) school attendance which was about 12% higher in the FITNET group.

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Plain language summary
Why did we do the study? The best evidence for the treatment of adolescents with myalgic encephalomyelitis/chronic fatigue syndrome is cognitive–behavioural therapy for fatigue delivered in person. In the United Kingdom, most adolescents with myalgic encephalomyelitis/chronic fatigue syndrome cannot get this specialist treatment where they live. Fatigue In Teenagers on the interNET in the National Health Service is an online treatment using cognitive–behavioural therapy designed for myalgic encephalomyelitis/chronic fatigue syndrome, which has been shown to work in the Netherlands. To find out if Fatigue In Teenagers on the interNET in the National Health Service would be beneficial in the United Kingdom, we compared Fatigue In Teenagers on the interNET in the National Health Service to Activity Management. Activity Management is the treatment most often offered to children and young people with myalgic encephalomyelitis/chronic fatigue syndrome in the United Kingdom, and aims to avoid peaks in activity (sometimes called ‘pacing’).

What was the question? Does Fatigue In Teenagers on the interNET in the National Health Service lead to greater improvements in children and young people with myalgic encephalomyelitis/chronic fatigue syndrome when compared to Activity Management, when both interventions are delivered remotely?

What did we do? We compared Fatigue In Teenagers on the interNET in the National Health Service and Activity Management in two comparable groups of children, and measured physical function at 6 months as the main indication of improvement. We measured how much the treatments cost and we asked children and young people, their parents and treatment providers what they thought about the two interventions.

What did we find? At 6 months, adolescents saw greater improvements in physical function, and attended half a day more school per week, with Fatigue In Teenagers on the interNET in the National Health Service compared to Activity Management. Both interventions were associated with improvements over 12 months, with there being no clear difference between them after that time. However, the Fatigue In Teenagers on the interNET in the National Health Service treatment was more expensive.

What does this mean? We have shown that cognitive–behavioural therapy for fatigue can be provided online to children as Fatigue In Teenagers on the interNET in the National Health Service, leading to faster improvement in physical function and greater school attendance compared to Activity Management. However, Fatigue In Teenagers on the interNET in the National Health Service is expensive and is unlikely to be good value for money.

https://twitter.com/user/status/1852725480778014925
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When I got sick, trying to maintain higher school attendance destroyed me, but it took 1-2 years before it could no longer be denied. The desire to believe in a positive story of self-improvement is very strong and children don't have the permission to go against adult's views.

These children are trying to protect themselves from deterioration by limiting activity. The instinct to do less is correct and not a flaw.
 
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