A general thread on the PACE trial!

One justification given by the PACE investigators, and also separately by Wessely, for the changes was that it made the results consistent with those from both the previous trials and their 'clinical experience', and that otherwise no PACE patient would be classed as improved, let alone recovered.

But the whole point of PACE, its justification, was to provide a "definitive" test of those previous underpowered non-definitive trials and clinical experience. So they can't use them as the benchmark for PACE results. It is the other way around. PACE was the benchmark, and it failed to validate those previous methodologically inferior results.

Furthermore, how did they know that the results from the original protocol didn't validate those previous results, and hence claim that as a justification for weakening the protocol, if they had not seen the results before they changed the protocol?

https://bmcpsychology.biomedcentral.com/articles/10.1186/s40359-018-0218-3
https://bmcpsychology.biomedcentral.com/articles/10.1186/s40359-019-0288-x
https://bmcpsychology.biomedcentral.com/articles/10.1186/s40359-019-0296-x

 

Not even proof of that.

The main PACE trial paper shows that 160 people were in the GET group at baseline, at 24 weeks there were only 150. I assume you are talking about differences in fatigue as measured by the Chalder Fatigue Questionnaire and physical function as measured by the SF-36. Both of those are subjective measures, so really biased by the nature of the interventions, especially when we are only talking about small differences over the SMC control, which we are. GET encouraged people to make light of their symptoms and suggested that getting better was the result of effort - so we would expect people to report that their capacity had improved after the intervention, somewhat regardless of how they were.

We have also heard that people cut out some of their pre-existing activities in order to be able to do the GET activities, so there was not necessarily any improvement in fitness. The six minute walking test is quite subject to bias too, with results depending on different levels of effort and familiarity. The improvement reported for that test at 52 weeks was modest and for only 110 people. I don't think we can say that the PACE trial is proof that GET made people with CFS fitter, up to some limit imposed by ME/CFS.

The APT was not pacing. It was a complicated lot of joy-sapping scheduling. It didn't work either of course. It had the expectation that participants would increase their activity as they were able. So, actually it was quite similar to the symptom-contingent Graded Activity Therapy interventions that are currently being promoted at NIH clinics (and that have also been shown not to work e.g. recently in the Gaunt et al paediatric trial).

I am by no means an expert in the PACE trial, others here might want to correct what I have written or add to it.

 

The Self-Paced Step Test in PACE also gave a null result, as did employment and welfare use.

Every objective measure in PACE was null, except the GET arm on the 6MWT, which did not reach clinical significance, barely increased the absolute distance patients could walk after a year of therapy, still leaving them scoring down among the worst of all medical conditions, and had a significant drop out rate. IOW, it is not even clear that single, extremely modest result was real, let alone of practical meaningful benefit to patients.

Total score on objective measures in PACE was effectively zero, and using the original protocol the results on the self-report measure were null as well.

Even if you accept the initial results on self-report measures according to the post-hoc modified protocol used in the published paper, the long-term follow-up (LTFU) results at 2.5 years were still null (no significant difference between any of the arms on the two primary measures).

Furthermore, an interesting feature of the response curves revealed at LTFU is that extrapolating the curve slopes suggests that the SMC & APT arms were continuing to improve, while the GET & CBT arms had tapered off in an asymptotic fashion, with no further gains, as you would expect from natural decay curves.

The PACE authors of course couldn't admit that, so they described the LTFU results not as null (no advantage for CBT or GET over APT or SMC) as they should have, but instead as CBT & GET 'maintaining their initial benefit'. Which is just not how comparative trials work at all.

In short, PACE showed no meaningful objective or sustained benefit from CBT or GET over APT or SMC. Even by PACE's own problematic standards the psycho-behavioural model it was testing failed completely.

And that is before we get into other serious issues with PACE, such as patient selection, harms reporting, dropping actimeters for outcome, and no doubt others I can't recall offhand.

 

Also, the PACE data that was released (and only when ordered to by a court) was only partial, and the authors have flatly refused to release the rest of it, despite legitimate requests for it from established researchers.

Which is about as unscientific, disgraceful, and cowardly as it gets in science.

 

I thought it was a platform where one could apply to be given the data, and the application needed you to write a valid reason or some such thing (+ I think it helped to have an affiliation with a university or other institution). There was the two data sleuths that didn't get access since reproducing analyses was not good enough?

 

If I understand it correctly, the mandatory retention period for the PACE data is 20 years, after which it can be destroyed. It is now 13 years since the publication of the main PACE paper (Feb 2011), so that leaves only 7 years for anybody to be able to access it before there can be no more re-assessment based on the unreleased data, nor hence on the full data set.

That is a situation that should never be allowed to occur. There needs to be serious pressure, particularly from within the medical scientific community, for that data to be secured and made available.

 

Yes, Vivli is the one they have been promoting.

It's important to note they have not released data as if it were in response to an FOI. They have released data for researchers only.

As @Midnattsol points out, some highly qualified researchers have tried and then gave up.

This is what one of them said to me after he gave up:

Getting the data from Vivli seems like a very convoluted process. I'm not surprised the PACE authors put it there... [his ellipsis]
Yeah, it's just gatekeeping. The opposite of OSF and proper open science
I have since found a bit more. It's like it was designed by a particularly sadistic bureaucrat. I'm trying to imagine who would put their data on there who didn't have something to hide.