PACE Trial and PACE Trial Protocol

[Bob]

Just some observations about the walking test... Apologies if they've all been made already...

After a year of GET patients improved from being able to walk 312 metres in 6 minutes, to 379 minutes in 6 minutes. Normal, steady walking speed is around 500 metres in 6 minutes, and this is the kind of speed that it should be possible to sustain for much longer. What it means is that patients improved from a slow amble to a slightly less slow amble, and this gives no indication of how long they could maintain that walking speed for, nor if there was a 'post-exertional malaise' reaction after the 6 mintute walking period.

 

[Bob]

A small private group would be different. I think one restrict who joins such private groups? i.e. somebody would have to be approved?

It's easy to set up a private group on the forum. And you can set them up to be either invite only, or just private (which means the group is accessible only if you join the group, but it's open to any forum member to join).
http://forums.aboutmecfs.org/group.php

 

[Dolphin]

Cella and Chalder (2010) - norms for the fatigue scales - data was collected in 90s

(Apologies if I or somebody else made this point before)

One thing I have found out from trying to find out more about this cohort was that this paper is based on data that was collected for studies that were published way back in 1995-1997.

It makes me suspicious that this data might have been published now (in 2010) with the intention that it could then be quoted in the main PACE Trial paper.

 

[Esther12]

re Cella and Chalder being written with Pace in mind: That was my thought on reading it too. Not sure it's anything we can use though.

 

[Marco]

As an aside to the 6MWT, something that had slipped my mind and might be worth discussing.

I don't have access to the full paper so have little knowledge of the degree of adverse effects recorded.

I've just remembered the Pacific Labs work and the finding that PEM, in reponse to physical exercise, seems to be triggered once the anaerobic threshold is exceeded.

Looking at the comparisons between the pace (no pun intended) attained during the PACE trial v normal healthy or even the aged, I'd be very surprised if, even though participants may have been restricted by muscle weakness or pain, gait problems, dizziness etc, they were not still operating within the anaerobic threshold.

The 6MWT (which is essentially self paced) may not have been sufficient to push the majority into PEM?

 

[alex3619]

Hi marco, for severe patients I think they would have driven us into PEM. But they only treat the mild to moderate, who may not even have what we would recognize as me/cfs so who knows. Where are the housebound and bedbound patients? Bye, Alex

 

[Bob]

Action for ME have asked for suggestions and comments with regards to their ongoing strategy in response to the PACE Trial...
They want responses before their policy meeting on the 3rd of March...

http://www.afme.org.uk/news.asp?newsid=1060

Suggestions and comments
Members and non-members who have suggestions for, or comments on, this emerging strategy should please forward their ideas to Policy Officer Tristana Rodriguez, ideally before the Policy Group meeting on 3 March.

 

[Marco]

Hi marco, for severe patients I think they would have driven us into PEM. But they only treat the mild to moderate, who may not even have what we would recognize as me/cfs so who knows. Where are the housebound and bedbound patients? Bye, Alex

I'm not sure its even that simple Alex. I have few problems walking, usually, and out of morbid curiousity I decided to time myself walking at a fairly brisk pace and clocked 330 paces up the lane and back in 3 minutes or a 6MWT of 660 paces. I was mildly puffed afterwards.

However, following unpredictable physical or cognitive triggers I am unable to walk more than a few paces at a very slow and unsteady shuffle. My subject feeling is that it is a problem with brain signalling as I'm far from 'deconditioned'. Perhaps this is the state the severe cases are in permanently?

It does mean however that for many patients, unless you are already in a PEM state, the 6MWT is unlikely to put you there.

Unfortunately, again it shows a complete misunderstanding of the range of symptoms and their affects on functioning, the fluctuating nature of the symptoms, and of the very nature of the type of fatigue experienced.

 

[anciendaze]

distributions

Amplifying my comments about distributions. A normal distribution is completely defined by two parameters: mean and variance. (Standard deviation is the square root of variance.) These two parameters tell you everything that can be known about a normal distribution. All remaining data are pure noise.

When researchers have trouble assigning consistent values to these fundamental parameters, it is a strong clue that they are either dealing with something other than a normal distribution, in which case other parametric statistics are inappropriate, or they are shopping for metrics. Because essential measures of success have been defined in terms of mean and standard deviation, these values are critical to understanding the results.

As presented, results force readers to speculate about questions like how measures used at the outset of the trial compare with those at the end. Inadvertently, I demonstrated the danger of doing so. The scale for measuring fatigue changed during the trial. The definition of an adverse event changed. It is hard to assign fixed meanings to words like: success, recovery, improvement, normal. Lacking these, it is not clear apparently solid numerical gains have any meaning at all.

The authors have demonstrated success in obtaining funding and publishing their own opinions. We await results more useful to others.

 

[Sean]

...or they are shopping for metrics.

He he.

Trying to torture the data into giving a result.

 

[Angela Kennedy]

He he.

Trying to torture the data into giving a result.

Heh heh.

Also - Sewing size 12 labels into size 18 garments - that's one for us ladies ; )

 

[alex3619]

It does mean however that for many patients, unless you are already in a PEM state, the 6MWT is unlikely to put you there.

Hi marco, like 99% of the research they ignore the research from the Lights and Pacific Labs. Then again they don't even do proper exercise testing in the first place - repeat testing requires that you understand even a little about PEM, and I am not sure they do.

However, try asking someone who is almost paralyzed with me/cfs - what would happen to their precious results if they had a lot of zeros? "The patients started at zero meters, and after twelve months of training they improved impressively to a total of zero meters".

Bye
Alex

 

[Dolphin]

IACFS/ME Statement on the PACE Trial: The Issue of Illness "Reversal"

FWIW

http://www.iacfsme.org/PACETrial/tabid/450/Default.aspx

IACFS/ME Statement on the PACE Trial:
The Issue of Illness "Reversal"
February 24, 2011


The much publicized UK-based PACE trial (Lancet, Feb. 18th; http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60096-2/fulltext) reported positive outcomes for patients with CFS/ME who were treated with cognitive-behavior therapy (CBT) or graded exercise therapy (GET) in comparison to a standard medical care condition or an adaptive pacing condition. The adaptive pacing condition was intended to help patients adjust their activity levels according to their available energy (based on envelope theory). The findings were similar to previous CBT and GET studies in CFS. This trial was unique in incorporating a pacing condition and recruiting a very large sample. That said, we have concerns about how the trial was reported.

We certainly support any effective treatment for CFS/ME, medical or behavioral. Behavioral interventions are helpful for a number of major medical conditions (cardiovascular disease, diabetes).

Illness Reversal and Behavioral Intervention

The most fundamental concern we have is focused on the type of causal model that was linked to the CBT and GET conditions in this study. The model, based on the application of cognitive-behavioral and physical conditioning principles, predicts that properly designed behavioral or exercise interventions will reverse the CFS illness. Not improve symptoms/functioning or provide better management, but reverse the illness. This term implies that the illness can be cured (or something close to it) with behavioral techniques.

If one assumes such a direct correspondence between behavioral treatment and curative outcomes, then the illness is by implication a psychiatric condition. Once this assumption is made, then research efforts to assemble a biomedical model of CFS are more likely to be delegitimized. And the publics perception of the illness as simply being tired is again reinforced. Perhaps this is the most unfortunate aspect of the PACE trial: The omission of any reference to the medical complexity of this illness.

Furthermore, when one compares the study goal of illness reversal to the reported outcomes, the support for such reversal is modest at best: 30% of GET and CBT patients achieved normative physical functioning-- but the 30% figure was in comparison to 15% who achieved such normative function in the standard medical care control condition.

Thus a more accurate statement of this finding would be: An additional15% of patients in the CBT and GET conditions achieved normal functioning in comparison to standard medical care. The critical standard of clinical significance is that a therapy results in restoration of normal function. But their own data do not support reversal outcomes above and beyond standard medical care for the vast majority of their subjects in the CBT and GET conditions.

Question of CFS/ME Diagnosis

In addition, the 15% advantage over standard care for patients in CBT and GET can be further questioned given that at least 1/3 of all patients did not meet the strict international criteria for CFS (Table 1 in study)the diagnostic protocol most often used in published studies. Strict criteria for CFS are linked to poor prognosis and conversely, subjects who dont meet strict criteria for CFS have better outcomes. So the PACE trial folded in a significant number of subjects who do not have CFS according to standard criteria. Again this dilutes the significance of their findings as it makes it more difficult to generalize to the population of people who do have CFS.

To put behavioral approaches in contextthey can be quite helpful, but they hardly meet the standard of clinical significance that would elevate them to curative interventions. If this had been made clear in the study, it would have provoked far less controversy and debate.

Media Mis-reports

Finally, the media message from this study has often been: Exercise is good; Rest is bad. Although the PACE trial authors did not issue such a statement, I think there is some responsibility to explain to the media that this type of recommendation is simplistic and potentially harmful for patients with CFS/ME. Activity and exercise recommendations must be based on a thorough evaluation and a sensitive individualized approach, not the broad brush that has become the take home message of this study.

Fred Friedberg, PhD
President
IACFS/ME

 

[Dolphin]

How similar do letters have to be for it to be a problem? Empirical evidence ideally

I (and I imagine some others) would be interested to know has anyone looked through past Lancet letters, or even letters in other journals. to see how much overlap there can be. I imagine some of the time, there is at least some overlap in points as generally letter writers won't have worked together.

If people come across two or more letters with some similar posts, it'd be good if they posted them.

 

[Bob]

The best recorded measurements seem to be with the "short form-36 physical function subscale score":

GET showed a 27.63% improvement over SMC-alone.

CBT showed a 19.64% improvement over SMC-alone.

Can anyone points me towards anything that might undermine these results in any way?
e.g. is it a fair scale to use to measure fatigue?
(sorry if i'm repeating stuff here... This thread is so long to check back over now!)

 

[OverTheHills]

Lovely stuff, Anciendaze

Amplifying my comments about distributions. A normal distribution is completely defined by two parameters: mean and variance. (Standard deviation is the square root of variance.) These two parameters tell you everything that can be known about a normal distribution. All remaining data are pure noise.

When researchers have trouble assigning consistent values to these fundamental parameters, it is a strong clue that they are either dealing with something other than a normal distribution, in which case other parametric statistics are inappropriate, or they are shopping for metrics. Because essential measures of success have been defined in terms of mean and standard deviation, these values are critical to understanding the results.

As presented, results force readers to speculate about questions like how measures used at the outset of the trial compare with those at the end. Inadvertently, I demonstrated the danger of doing so. The scale for measuring fatigue changed during the trial. The definition of an adverse event changed. It is hard to assign fixed meanings to words like: success, recovery, improvement, normal. Lacking these, it is not clear apparently solid numerical gains have any meaning at all.

The authors have demonstrated success in obtaining funding and publishing their own opinions. We await results more useful to others.

The elegance of your prose makes me smile (was it you who admires the master, Woodhouse?) (favourite bits in bold). I am really hoping that you plan to send something to the Lancet. :victory:

OTH

 

[OverTheHills]

Dolphin et al

Thanks for posting the IACFS/ME statement, it makes many good points that we are all aware of but I notice they don't seem to have picked up that patients claimed as recovered/improved were not returned to normative function for their age group but were tottering along at a pace appropriate to an 80 year old.

"30% of GET and CBT patients achieved normative physical functioning-- but the 30% figure was in comparison to 15% who achieved such normative function in the standard medical care control condition."

I wonder whether it would be worthwhile someone sending a letter to the IACFS/ME about that (I would myself but I understand very little about statistics and the same about science, I can follow less than 50% of this thread). I don't trust the Lancet to publish much correspondence/ analysis.

In fact this thread looks so impressive to me I wonder if anyone could get Lenny Jason interested in co-authoring something. HE has no trouble getting things published and it seems right up his street; he also has the right letters after his name for a rebuttal paper to count.

Thanks for this thread guys, I hope it bears fruit
OTH

 

[Dolphin]

Thanks OTH

I would be hopeful the Lancet would publish some letters. This week they published 5 letters in reply to one article (and then the authors' reply). Not the same thing necessarily of course.

A letter can only be 250 words and a max. of 5 refs (which is really 4 as one has to quote the paper and down to 3, if one also quotes the protocol paper) so it's not a huge commitment for somebody to try their luck. If people have a draft letter that they'd like one or more people to look over, let me know as I know a few people who are willing to help. :Retro smile:

People can see what can be done with the points that weren't published after that.

 

[oceanblue]

The best recorded measurements seem to be with the "short form-36 physical function subscale score":
Can anyone points me towards anything that might undermine these results in any way?
e.g. is it a fair scale to use to measure fatigue?

You can take the SF-36 here, nb in the UK version a "block" is a hundred yards. More info on the scale. Nb it measures physical activity (/disability), not fatigue. It's been widely used in ME research by researchers of all persuasions.

The question on moderate acitvity

Moderate activities, such as moving a table, pushing a vacuum cleaner, bowling, or playing golf

is bizarre: vacuuming and a round of golf in the same statement? but other Qs I think are fair enough.

The biggest issue with the SF36 is that it is a subjective measure, ie it's what people report they can do, which might not be quite the same as what they can do and could be influenced by a desire to please researchers and/or a strong relationship with their therapist, or even an over-optimistic viewof what they can do as a result of 'successful' CBT.

 

[Dolphin]

SF-36 and fatigue scores vs actometer readings

Although Wiborg et al. (2010) paper is seen as being about fatigue scores, two of the three papers also used the SF-36:

New paper lists 3 CFS studies where there was no improvement in the actometer readings but an improvement was reported in subjective outcome measures

http://www.biomedcentral.com/1471-2377/7/6/comments#387679

I know it might perhaps have seemed to some who have read these posts that I might be concerned about something that was not important (when I was calling for actometers to be used if possible for at least some of the patients at the end of the trial). So I feel "vindicated" in a way by a review[1] that has just been published. It found that in the three Dutch CFS trials looked at, studies which all found improvements in fatigue[2-4], there was no statistically significant increase in physical activity levels as measured by actometers.

The review also found that "changes in physical activity were not related to changes in fatigue."

The authors of the review (who include people who were involved in all the studies) say that, in the three studies, "treatment was based on the manual of CBT for CFS described in detail by Bleijenberg et al. (2003)" [5]. This form of CBT is comparable to the form of CBT being assessed in the PACE Trial [6].

It is useful to point out that fatigue wasn't the only subjective outcome measure that was said to have improved (in these trials where there was no increase in physical activity).

In all of the three studies [2-4], improvements were reported in functional impairment (as measured by questionnaires). In two of the studies [2,3], improvements in physical functioning as measured by the SF-36 physical functioning subscale were reported (this questionnaire does was not used in the third study[4]). So the patients reported improvements in "physical functioning" (as measured by the SF-36 physical functioning subscale) but there was no improvement in physical activity as measured by the actometers. The SF-36 physical functioning subscale is one of the primary outcome measures in the PACE Trial[6].

This discrepancy between objective measures of activity and questionnaire is similar to data I have previously drawn attention to[7] in a study by Friedberg and Sohl[8].

References:

[1] Wiborg JF, Knoop H, Stulemeijer M, Prins JB, Bleijenberg G. How does cognitive behaviour therapy reduce fatigue in patients with chronic fatigue syndrome? The role of physical activity. Psychol Med. 2010 Jan 5:1 -7. [Epub ahead of print]

[2] Stulemeijer M, de Jong LW, Fiselier TJ, Hoogveld SW, Bleijenberg G (2005). Cognitive behaviour therapy for adolescents with chronic fatigue syndrome: randomised controlled trial. British Medical Journal 330. Published online : 7 December 2004. doi:10.1136/bmj.38301.587106.63.

[3] Knoop H, van der Meer JW, Bleijenberg G (2008). Guided self-instructions for people with chronic fatigue syndrome: randomised controlled trial. British Journal of Psychiatry 193, 340–341.

[4] Prins JB, Bleijenberg G, Bazelmans E, Elving LD, de Boo TM, Severens JL, van der Wilt GJ, Spinhoven P, van der Meer JW (2001). Cognitive behaviour therapy for chronic fatigue syndrome: a multicentre randomised controlled trial. Lancet 357, 841–847.

[5] Bleijenberg G, Prins JB, Bazelmans E (2003). Cognitive-behavioral therapies. In Handbook of Chronic Fatigue Syndrome (ed. L. A. Jason, P. A. Fennell and R. R. Taylor), pp. 493–526. Wiley: New York.

[6] White PD, Sharpe MC,Chalder T, DeCesare JC and Walwyn R for the PACE trial group. Protocol for the PACE trial: A randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurology 2007, 7:6

[7] Kindlon T. Further evidence showing why objective measures are preferable in CFS trials particularly where cognitions could be changed following the intervention http://www.biomedcentral.com/1471-2377/7/6/comments#333618

[8] Friedberg F, Sohl S. Cognitive-behavior therapy in chronic fatigue syndrome: is improvement related to increased physical activity? J Clin Psychol. 2009 Feb 11.