[Just a registration] Paediatric immune dysregulation disorders - FITNET plus from Elise van de Putte ISRCTN12612526

I was searching for CFS FITNET stuff, and found this:
http://www.isrctn.com/ISRCTN12612526

All outcomes look like self report, and "The follow-up duration is four weeks and will be measured by weekly questionnaires and finished by a follow-up assessment." Four weeks is not long, and looks likely to maximse potential problems with bias for self-report outcomes.

No results published yet, but I thought I'd post anyway just in case it was of interest to anyone.

The researcher running it, Elise van de Putte, had this to say about the Dutch Health Council ME/CFS advisory report:

https://www.nrc.nl/nieuws/2018/03/26/frustratie-over-me-spreekt-uit-advies-gezondheidsraad-a1597158

 

The registration for the study contains the phrase "There are no anticipated risks involved with participating in this study". Will this mean that the researchers are repeating the trend in [the parallel] ME/CFS GET studies of failing to adequately record any harms or adverse reactions, clearly demonstrated by Vink and Vink-Niese in their excellent recent paper (plug, plug)? Let's hope the researchers read and absorb the Vink and Vink-Neise review, though the almost invariable tendency of researchers in this field to ignore anything that does not confirm their pre judgements and/or prejudices does not make this likely. [For the Vink and Vink-Neise review see http://journals.sagepub.com/doi/full/10.1177/2055102918805187 ]

The registration fails to define the theoretical basis (or bias) behind the CBT offered, but it implies it is linked to the belief that ongoing increasing activity levels will be an effective treatment of the 'chronic fatigue', which makes meaningful recording of harm or adverse reactions essential, over and above the need for objective outcome measures raised above by @Esther12 .

It looks like we are seeing yet another study involving subjective outcomes in an unblinded trial, where the research's inherent confirmation biases makes any results totally meaningless, even before any data has been collected or analysed.

What will it take for researchers in this area to abandon this irrevocably flawed methodology and for ethics committees and peer reviewers to adequately do their job? Without objective outcome measures or meaningful recording of harms, especially when the intervention is not face to face, we have yet another example of unpoliced research misconduct, that potentially amounts to medically sanctioned child abuse.

Even if the real risk of harm from the intervention is ignored, the subjecting of children and young adults to a psychological intervention in a research context that inherently due to its design can not provide any meaningful conclusions must surely constitute a form of abuse.

[added later: Had this been a drug trial the initial research proposals would have been rightly ridiculed and failed to attract any funding or institutional support. When will psychological interventions be held up to the same basic standards for clinical trials?]

 

Re reading this retrospective registration of this feasibility study, the 'secondary study design' is described as a 'randomised controlled trial'.

Interestingly the subjects are their own controls, being assessed over different pre treatment periods without intervention and 'randomised' to eight distinct periods of between seven and twenty four weeks waiting time. However, given there is not a clear pattern to these control periods in practice with seven of the ten subjects having different unevenly spread waiting times and three the same, it would seem that this was not a prospective randomisation but rather a retrospective post hoc analysis. Further with the small size of these eight control groups, seven having only one subject, any inter group comparison will be statistically limited. Consequently I would question how meaningful it is to describe this at present as a randomised trial. It looks like trying to after the fact make use of existing data, using historical accident as an unreliable proxy for prospective randomisation.

Also during the waiting period participants are to be (or were) assessed on a weekly basis. This seems a very time intensive process and one wonders what if any are the implications of so much interaction during a no intervention control period. Time wise how does this compare with the interaction during the active treatment phase, are there any consequences of so much testing and retesting and of subjects becoming so familiar with these subjective assessments? Further with weekly testing the different pre treatment control periods have uncontrolled for differences in total interaction time.

Given the shortness of the waiting times in comparison to the potential duration of the intervention of up to six months, I would also question how meaningful this controlling is. How meaningful is it to compare an average passive wait of thirteen weeks to an up to six month active treatment phase? In practice is it even reasonable to describe this as a control group or as control groups?

Surely for any meaningful conclusions to be made there needs to be a control group with a pretreatment phase of the same duration as the active treatment phase, otherwise how is any effect of the passage time alone to be controlled for? A short pretreatment control followed by a much longer active treatment phase undoubtedly would increase the likelihood of any time dependant spontaneous improvement being misinterpreted as a treatment effect.

With the follow up assessments only occurring after four weeks as already pointed out by @Esther12, the whole time scale of the project feels very messy and unthought out. For symmetry alone surely there needs to be a six month follow up?

In relation to the outcomes, the primary measure and two of the secondary measures are subjective self ratings, but to be fair the third secondary measure 'school presence' has the potential to be objective, though unfortunately they do not indicate how it is to be (or was) recorded.

Increasingly I am wondering if this is a retrospective recasting of analysis of previous and/or ongoing intervention as an experimental design. So are we not only are we looking at retrospective registration, but also retrospective experimental design? Do we have here not an experimental design, but clinical evaluation of existing treatment? There is nothing wrong with doing this as long as the researchers are open and honest about what they are doing.

Presumably the intention is to use this study as the basis for the application for funding for a full prospective study. Given the confusion in this 'feasibility study' and the possible lack of openness in the design process, the prospective study should it be realised needs very very careful scrutiny. However given the lack of objective measures and the historical design failures and ethical failures of researchers advocating this approach I do not have any confidence that a meaningful study will emerge.

 

Perhaps of interest to @dave30th ans @Mark Vink as it seens to repeat issues highlighted with other paediatric studies.

 

There are several similarities to studies we have seen from Esther Crawley. It is interesting that this is a study of juvenile chronic arthritis, which was Crawley's previous area of research. There is the similar use of 'feasibility studies'.

I find it very hard o see how this study can make sense. Juvenile chronic arthritis is rare, so there would be just enough patients in Holland to make up a study cohort if they all satisfied the entry criteria. Other immunodeficiencies are pretty uncommon too, quite apart from being completely unrelated to juvenile arthritis.

So it looks as if the assumption is that all fatigue in juvenile arthritis is amenable to encouragement to exercise. Yet it is pretty clear that in most cases it is due to cytokine production! Drugs like tocilizumab make these children well. And these children have had encouragement by physiotherapists for decades now, with no suggestion that it does more than maintain range of movement, and it may not do that very well. Is it really being suggested that most of the fatigue in these children is 'psychosomatic'?

And fatigue in juvenile arthritis bears little or no resemblance to ME as far as I am aware.

One gets the clear impression of a research industry supported by healthcare research bodies like NIHR where nobody involved has any idea what they are doing. I also note that Dr van de Putte is chairman of a research ethics committee.

It seems that the situation in Bristol has at least changed in terms of public presentation. Rather than regular lectures on malicious patients there has been a stony silence for nearly a year now. Hopefully, we will eventually get a recognition from Archives of Disease of Childhood that concerns have been legitimate. The adult MUS situation may be a Canute and the sea situation but it really does seem important and potentially feasible to get the need for some sort of transparency recognised with the paediatric situation.

 

Thank's for this professional perspective which greatly helps us lay people see issues in a holistic and balanced way.

Shame that those in Bristol don't appear to have that benefit..........or the benefit of hindsight....?

 

Wow, she really does not like us at all. The funny thing is, quite a few people on this forum have likely read far more scientific research than she has and I bet they can can more accurately describe all the possible biases of such research.