PACE Trial and PACE Trial Protocol

[Snow Leopard]

Coming up next: CBT to cure fatigue in HIV-AIDS patients.

http://onlinelibrary.wiley.com/doi/10.1111/j.1468-1293.2005.00319.x/abstract

The presence of fatigue in HIV-infected patients is most strongly associated with psychological factors and not with more advanced HIV disease or the use of highly active antiretroviral therapy. This highlights the importance of investigation and management of underlying depression and anxiety in patients presenting with fatigue.

Either that, or maybe those so-called fatigue questionnaires lack specificity when they attempt to measure fatigue...

 

[oceanblue]

SF-36 and subjectivity: try it yourself

Lots of people have suggested that the improvements in the SF-36 Physical Function subscale (and Chalder Fatigue Scale too)for the CBT & GET groups are the result of a change in perception by participants, not a real change in activity levels (or fatigue). I thought I'd see how this might work out in practice for the SF-36 score for me and I think the results are illuminating - others might like to try it too.

How the SF-36 PF scale works:
There are ten questions asking what physical activity people can do. The answers to each question are scored:
Limited a lot=0 points
Limited a little=5 points
Not limited at all=10points

Max 100 points in total.

SF-36 Questions
- vigorous activities such as running
- Moderate activities, such as moving a table, pushing a vacuum cleaner, bowling, or playing golf (yes, weird)
- Lifting or carrying groceries
- Bending, kneeling, or stooping
- climbing several flights of steps
- Climbing one flight of stairs
- walking more than a mile
- Walking several hundred yards
- Walking one hundred yards
- Bathing or dressing yourself

For me, the first thing is that on 8 of these I'm clearly either a 0 (eg walking more than a mile)or a 10 (bending, kneeling).

However, for 'climbing one flight of stair' I would score me as a 5 (limited a little)in that usually I can do this fine but can struggle on bad days of if I've just done something else physical like walking round the house a bit. But maybe after a bit of CBT I'd focus more on what I can do and score a 10 (not limited at all); it wouldn't take a very big shift in perspective. The same applies to one other question where I could also pretty easily upgrade from a 5 to a 10.

Conclusion: I could easily add 10 points to my score just by taking a slightly more upbeat view of things, though it would be very hard to boost my score by more than 10 points, at least without the help of mind-altering drugs. Coincidentally, CBT and GET both came in with SF-36 scores about 10 points higher than the SMC group.

I'd be interested to know how this would work for other people. I'm sure most people won't want to discuss personal details of how their illness effects them, but it would be useful to know a likely 'change in score' due to a more upbeat perspective.

 

[Marco]

I'll play.

By the way, those questions are almost identical to the UK Incapacity Benefit form that has to be completed when applying for or being re-evaluated for IB. They do not account at all for the variable relapsing nature of ME/CFS.

SF-36 Questions
- vigorous activities such as running
- Moderate activities, such as moving a table, pushing a vacuum cleaner, bowling, or playing golf (yes, weird)
- Lifting or carrying groceries
- Bending, kneeling, or stooping
- climbing several flights of steps
- Climbing one flight of stairs
- walking more than a mile
- Walking several hundred yards
- Walking one hundred yards
- Bathing or dressing yourself


On a good day, the only ones I would check as limited a lot would be : 'vigorous activities such as running', 'climbing several flights of steps' and 'walking more than a mile'. The rest I would score as limited a lot or not limited at all depending on how upbeat I was feeling - so potentially a 35 points difference depending on how 'complaining' or realistic I was in answering the questions. The fact is that all of these activities are limited compared to a healthy normal because all have a cumulative 'cost'.

On a bad day I'm so dysfunctional that I would score a 0 on each of them. No ifs or buts, regardless of how upbeat I was trying to be I'd have to score them all at zero.

So potentially my score can vary from day to day from 0 to 70.

 

[Angela Kennedy]

Lots of people have suggested that the improvements in the SF-36 Physical Function subscale (and Chalder Fatigue Scale too)for the CBT & GET groups are the result of a change in perception by participants, not a real change in activity levels (or fatigue). I thought I'd see how this might work out in practice for the SF-36 score for me and I think the results are illuminating - others might like to try it too.

How the SF-36 PF scale works:
There are ten questions asking what physical activity people can do. The answers to each question are scored:
Limited a lot=0 points
Limited a little=5 points
Not limited at all=10points

Max 100 points in total.

SF-36 Questions
- vigorous activities such as running
- Moderate activities, such as moving a table, pushing a vacuum cleaner, bowling, or playing golf (yes, weird)
- Lifting or carrying groceries
- Bending, kneeling, or stooping
- climbing several flights of steps
- Climbing one flight of stairs
- walking more than a mile
- Walking several hundred yards
- Walking one hundred yards
- Bathing or dressing yourself

For me, the first thing is that on 8 of these I'm clearly either a 0 (eg walking more than a mile)or a 10 (bending, kneeling).

However, for 'climbing one flight of stair' I would score me as a 5 (limited a little)in that usually I can do this fine but can struggle on bad days of if I've just done something else physical like walking round the house a bit. But maybe after a bit of CBT I'd focus more on what I can do and score a 10 (not limited at all); it wouldn't take a very big shift in perspective. The same applies to one other question where I could also pretty easily upgrade from a 5 to a 10.

Conclusion: I could easily add 10 points to my score just by taking a slightly more upbeat view of things, though it would be very hard to boost my score by more than 10 points, at least without the help of mind-altering drugs. Coincidentally, CBT and GET both came in with SF-36 scores about 10 points higher than the SMC group.

I'd be interested to know how this would work for other people. I'm sure most people won't want to discuss personal details of how their illness effects them, but it would be useful to know a likely 'change in score' due to a more upbeat perspective.

Well - Malcolm Hooper in Magical medicine has shown how those manuals demonstrated techniques of persuasion and frankly, manipulation of people's beliefs, including apparently telling them in advance that CBT/GET was efficacious and safe. I'm following up on that myself at the moment. If this is true- then Declaration of Helsinki and CONSORT standards would have been broken.

 

[wdb]

Lots of people have suggested that the improvements in the SF-36 Physical Function subscale (and Chalder Fatigue Scale too)for the CBT & GET groups are the result of a change in perception by participants, not a real change in activity levels (or fatigue).

I would argue that this alone is all that is required to explain the results.

It's well documented and accepted that if a group of patients is given a course of placebo treatment such as sugar pills or saline injections, particularly if patients are led to expect improvement, then many will report that their symptoms have improved.

If you ask someone to rate their symptoms, spend 12 weeks trying to convince them they have a condition which makes them unable to accurately rate their symptoms, their symptoms are not as severe as they feel, and actually they are capable of achieving a lot more than they think, then ask them to rate their own symptoms again, it seems pretty obvious what the result will be regardless of whether any actual objective improvement has occurred.

The APT group would not experience the same degree of effect as entirely different language is used in the APT training with the expectation being much more of avoidance of worsening/relapse rather than improvement.

It even perfectly explains why the subgroups did not show significant difference - because all we are looking at is change in perception, there is no significant therapeutic effect beyond placebo in any of the groups.

 

[Angela Kennedy]

I would argue that this alone is all that is required to explain the results.

It's well documented and accepted that if a group of patients is given a course of placebo treatment such as sugar pills or saline injections, particularly if patients are led to expect improvement, then many will report that their symptoms have improved.

If you ask someone to rate their symptoms, spend 12 weeks trying to convince them they have a condition which makes them unable to accurately rate their symptoms, their symptoms are not as severe as they feel, and actually they are capable of achieving a lot more than they think, then ask them to rate their own symptoms again, it seems pretty obvious what the result will be regardless of whether any actual objective improvement has occurred.

The APT group would not experience the same degree of effect as entirely different language is used in the APT training with the expectation being much more of avoidance of worsening/relapse rather than improvement.

It even perfectly explains why the subgroups did not show significant difference - because all we are looking at is change in perception, there is no significant therapeutic effect beyond placebo in any of the groups.

Yes. 'placebo effect' here is merely one of reporting positively after being persuaded to - but is not in any way a psychogenic therapeutic 'effect'/ 'mind over body' effect usually attributed to 'placebo effect' - i'm aware of the over-use of the word 'effect' there! apologies : )

Issues like deference are also in the mix.

 

[Orla]

Yes. 'placebo effect' here is merely one of reporting positively after being persuaded to - but is not in any way a psychogenic therapeutic 'effect'/ 'mind over body' effect usually attributed to 'placebo effect' - i'm aware of the over-use of the word 'effect' there! apologies : )

Issues like deference are also in the mix.

Yes, agree with you totally on this.

Orla

 

[biophile]

I just wish to say thankyou to everyone who has been discussing the PACE trial. It wasn't that long ago on another thread a few of us were defending the importance of probing the psychological research. I bet now more people can see the value of this. I haven't seen anyone complaining since about all the precious time and effort that has gone into this thread.

I was not able to contribute in the short-term, but I have been taking notes for the long-term, which itself has been overwhelming. I am impressed with what others have written and the leads they have provided, there isn't really anything important I can add to the discussion right now.

The news press hyperbole and ignorant reader comments were disappointing. I cringe when I read comments about how "well-designed" and "robust" the PACE trial is. Upon close examination it appears to have more holes in it than swiss cheese, and even has a XMRV-immune mouse running through it!

I showed and explained to a friend of mine (who doesn't know much about ME/CFS) the unusually low threshold for "normal" physical functioning and the histogram of the skewed distribution which distorts the standard deviation. That was enough for him to become suspicious about the rest of the study.

 

[Angela Kennedy]

I just wish to say thankyou to everyone who has been discussing the PACE trial. It wasn't that long ago on another thread a few of us were defending the importance of probing the psychological research. I bet now more people can see the value of this. I haven't seen anyone complaining since about all the precious time and effort that has gone into this thread.

I was not able to contribute in the short-term, but I have been taking notes for the long-term, which itself has been overwhelming. I am impressed with what others have written and the leads they have provided, there isn't really anything important I can add to the discussion right now.

The news press hyperbole and ignorant reader comments were disappointing. I cringe when I read comments about how "well-designed" and "robust" the PACE trial is. Upon close examination it appears to have more holes in it than swiss cheese, and even has a XMRV-immune mouse running through it!

I showed and explained to a friend of mine (who doesn't know much about ME/CFS) the unusually low threshold for "normal" physical functioning and the histogram of the skewed distribution which distorts the standard deviation. That was enough for him to become suspicious about the rest of the study.

Hey biophile,

Firstly your contributions in previous discussions have always been extremely useful I find in particular, and will have indirectly contributed to the general level of analysis this thread has generated.

Secondly, I think your comment about long-term contributions is important. After we see the results of the Lancet correspondence publication process, there are going to have be other, more long-term strategies, especially as the glaring flaws of this study have not stopped the outrageous (egregious?) spin about safety and efficacy at various levels.

 

[oceanblue]

Comments for media about PACE - why we need to expose the flawed findings

Personally, I find reading this kind of misrepresentation rather upsetting, but here are some highlights of 'Expert Opinion' put out by the Science Media Centre:

Dr Derick Wade, Consultant and Professor in Neurological Rehabilitation, Oxford

The trial design in this study was very good, and means that the conclusions drawn can be drawn with confidence.

every patient who wishes to be helped should be willing to try one or both of the treatments... Further research should identify ways that treatments derived from these may deliver greater benefits.
[er, maybe with such modest results it's time to look elsewhere for effective therapies?]

...and proving a treatment is effective starts to give clues about causative factors.
[er, the biopsychosocial model predicted great things of CBT/GET, and they didn't materialise; that's bad news for the biopsychosocial model, not evidence for it]

Prof Willie Hamilton, GP in Exeter and Professor of Primary Care Diagnostics, Peninsula College of Medicine and Dentistry, said:

At least half of patients improved with CBT or GET...
[45% of SMC patients reported rather modest improvements in fatigue and activity levels, against around 60% of those with CBT/GET in addition to SMC - which is not qute the same thing as our expert says]
This study matters: it matters a lot. At a patient level, I now know what to suggest to my patients...

Dr Brian John Angus, Clinical Tutor in Medicine and Honorary Consultant Physician, University of Oxford and Centre Leader for the PACE Trial in Oxford, said:

This study is the largest ever done in CFS/ME and as such is critically important. The study should reassure patients that there is an evidence based treatment that can help them to get better and there is no need to worry about harm from the treatment.

It was extremely rigorous. It was large and it was randomised... As a trial this involved a huge amount of checking and cross checking.
[extremely rigorous trials do not, as a rule, change their primary outcomes before publication; they definitely don't fail to report recovery rates promised in the protocol, and generlally they include plenty of objective measures alongside subjective measures (and don't hold back data on some of the objective measures)]

 

[Enid]

Scary how they rush to defend !. Must remember not to see any of them and add to my "don't touch with a bargepole list"

 

[Dolphin]

Thanks for the SMC quotes, oceanblue.

The one from AfME's (newish) medical advisor can be found here: http://forums.aboutmecfs.org/showth...s-CBT-and-GET)&p=162845&viewfull=1#post162845 as part of a thread on him.

It is lucky we didn't leave replying to PACE to him!

 

[anciendaze]

I ran that distribution past someone who really knows statistics and is experienced in psychological research. My observation on kurtosis, an extended left tail and meaningless parameter values was repeated. The idea of people 4 SD below the mean having negative physical activity got a laugh. Changing criteria in mid-study didn't seem as funny. The main question was "How did they get this published?"

Don't expect statistical experts to run to the defense of this group.

 

[oceanblue]

I ran that distribution past someone who really knows statistics and is experienced in psychological research. My observation on kurtosis, an extended left tail and meaningless parameter values was repeated. The idea of people 4 SD below the mean having negative physical activity got a laugh. Changing criteria in mid-study didn't seem as funny. The main question was "How did they get this published?"

Don't expect statistical experts to run to the defense of this group.

Thanks for this. A friend of mine who uses stats (properly) in his research made similar comments to me.

As pure speculation, I did wonder if the reason publication was delayed so much was that they originally submitted to a different journal that wouldn't let them pull the 'within the normal range' stunt, so they found a journal that would.

 

[Dolphin]

As pure speculation, I did wonder if the reason publication was delayed so much was that they originally submitted to a different journal that wouldn't let them pull the 'within the normal range' stunt, so they found a journal that would.

One possibly way to tell that might be to find out the date submitted. Most articles that I see these days say this.

 

[Dolphin]

Lots of people have suggested that the improvements in the SF-36 Physical Function subscale (and Chalder Fatigue Scale too)for the CBT & GET groups are the result of a change in perception by participants, not a real change in activity levels (or fatigue). I thought I'd see how this might work out in practice for the SF-36 score for me and I think the results are illuminating - others might like to try it too.

How the SF-36 PF scale works:
There are ten questions asking what physical activity people can do. The answers to each question are scored:
Limited a lot=0 points
Limited a little=5 points
Not limited at all=10points

Max 100 points in total.

SF-36 Questions
- vigorous activities such as running
- Moderate activities, such as moving a table, pushing a vacuum cleaner, bowling, or playing golf (yes, weird)
- Lifting or carrying groceries
- Bending, kneeling, or stooping
- climbing several flights of steps
- Climbing one flight of stairs
- walking more than a mile
- Walking several hundred yards
- Walking one hundred yards
- Bathing or dressing yourself

For me, the first thing is that on 8 of these I'm clearly either a 0 (eg walking more than a mile)or a 10 (bending, kneeling).

However, for 'climbing one flight of stair' I would score me as a 5 (limited a little)in that usually I can do this fine but can struggle on bad days of if I've just done something else physical like walking round the house a bit. But maybe after a bit of CBT I'd focus more on what I can do and score a 10 (not limited at all); it wouldn't take a very big shift in perspective. The same applies to one other question where I could also pretty easily upgrade from a 5 to a 10.

Conclusion: I could easily add 10 points to my score just by taking a slightly more upbeat view of things, though it would be very hard to boost my score by more than 10 points, at least without the help of mind-altering drugs. Coincidentally, CBT and GET both came in with SF-36 scores about 10 points higher than the SMC group.

I'd be interested to know how this would work for other people. I'm sure most people won't want to discuss personal details of how their illness effects them, but it would be useful to know a likely 'change in score' due to a more upbeat perspective.

Thanks oceanblue.

In:

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.

the headline figures (abstract) were:

An intention-to-treat analysis showed a significant decrease in fatigue and
disability after self-instruction.

Actometer readings: (CBT and Control group)
Baseline: 63.1 (23.5) 63.5 (21.8)
Second assessment 67.3 (22.5) 67.8 (21.4)

SF-36: (CBT and Control group)
Baseline: 52.3 (20.4) 54.1 (21.1)
Second assessment 65.9 (23.2) 60.2 (23.7)
Significant difference in change and also final scores

While I'm at it, CIS-fatigue scores. (This scale is scored 0-56 with 56 being the worst)
(CBT and Control group)
Baseline: 49.1 (5.2) 49.9 (5.6)
Second assessment: 38.9 (12.1) 46.4 (8.7)

 

[Dolphin]

I decided to read Kathy Fulcher's PhD to try to get a handle on the area (I don't know much about exercise physiology and I also wanted to see all the results for Fulcher & White (1997)). I read the first 100 pages before the PACE Trial came out and read the rest today. It can be downloaded for free from: http://ethos.bl.uk/ (just like lots of other PhDs).

Anyway, for the moment, perhaps all we need is the results that were in

Fulcher KY, White PD. Randomised controlled trial of graded exercise in patients with the chronic fatigue syndrome. BMJ. 1997 Jun 7;314(7095):1647-52. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2126868/pdf/9180065.pdf

Main outcome measure: The self rated clinical global impression change score, “very much better” or “much better” being considered as clinically important.

(same as the PACE Trial)

RESULTS: Four patients receiving exercise and three receiving flexibility treatment dropped out before completion. 15 of 29 patients rated themselves as better after completing exercise treatment compared with eight of 30 patients who completed flexibility treatment. Analysis by intention to treat gave similar results (17/33 (51.52%) v 9/33 (27.27%) patients better) (these are the results after 12 weeks). Fatigue, functional capacity, and fitness were significantly better after exercise than after flexibility treatment. 12 of 22 (54.55%) patients who crossed over to exercise after flexibility treatment rated themselves as better after completing exercise treatment 32 of 47 (68%) patients rated themselves as better three months after completing supervised exercise treatment (approx. 25 weeks) 35 of 47 (74.47%) patients rated themselves as better one year after completing supervised exercise treatment. (approx. 64 weeks) (it was 35 of 56 (63%) by intention to treat)

Compare those results with Table 5!! The results from the PACE Trial are much worse.

The clinical global impression (CGI) might be something some people might concentrate on. Peter White and others would be taking a big chance criticising it given how they depended on it before.

BTW, on p145 of the PhD, Kathy Fulcher gives her reasons why the CGI is the most important measure; also on page 167.

 

[urbantravels]

Coming up next: CBT to cure fatigue in HIV-AIDS patients.

"The presence of fatigue in HIV-infected patients is most strongly associated with psychological factors and not with more advanced HIV disease or the use of highly active antiretroviral therapy. This highlights the importance of investigation and management of underlying depression and anxiety in patients presenting with fatigue."

http://onlinelibrary.wiley.com/doi/10.1111/j.1468-1293.2005.00319.x/abstract

Either that, or maybe those so-called fatigue questionnaires lack specificity when they attempt to measure fatigue...

I just had a flashback to a visit I had with an infectious disease doctor, at the start of my illness, before I had been diagnosed and while I was still being sent around to various specialists.

This particular ID doctor expressed his opinion that CFS doesn't even really exist, and that it's just a wastebasket diagnosis, and that there was no possible way for any infection to persist this long in a person without either killing them, going away, or...( I think the third thing was showing up in abnormal liver function tests. Perhaps it was hepatitis he was referring to.)

Anyway, he then went on to explain (kindly, it seemed at the time) that he sees mostly HIV patients, because at my HMO, HIV patients are assigned to ID doctors as their primary care providers. He described a situation where an HIV patient is treated with retrovirals to the point where their viral load is undetectable and for all intents and purposes they are "well," and should feel well, but they don't get better. He then explained that this is because of anxiety, and that I seemed like an anxious person, and that treatment with antidepressants would cure such patients. (I *am* kind of an anxious person, but you can imagine how anxious I was seeing all these doctors, having recently been clobbered by a completely horrible, disabling, and mysterious illness.) He confidently told me that if I sought out help from the psychiatry department, that I would feel completely better within six months.

Now I wonder if that particular doctor was talking about this research referenced above by Snow Leopard. And it makes me wonder what's *really* going on with those fatigued HIV patients. I'm not saying they have CFS or XMRV; I have no idea; but I now have a fundamental doubt about ANY physical manifestation of disease that can't be "objectively" measured being assigned to the "psychological factors" wastebasket. Perhaps someone ought to look a little harder into why those patients are fatigued when they "should" be well.

End digression.

 

[urbantravels]

Well - Malcolm Hooper in Magical medicine has shown how those manuals demonstrated techniques of persuasion and frankly, manipulation of people's beliefs, including apparently telling them in advance that CBT/GET was efficacious and safe. I'm following up on that myself at the moment. If this is true- then Declaration of Helsinki and CONSORT standards would have been broken.

I'd like to get a professional medical bioethicist to take a look at this whole question. In many comments I've made about PACE I've said it just seems to me tantamount to brainwashing. What exactly are the ethical standards regarding testing, or even using, this kind of "therapy" that is designed to tell the patient they are mistaken regarding the severity of their physical symptoms?

I know there are psychological treatment approaches being used for things like pain - to help people not focus on their pain and what-not, to perhaps alleviate the severity of what they feel. But this seems to me like a horse of a different color. You wouldn't try to treat heart disease patients on this basis, to encourage them to get up and exercise at times when it is dangerous for them to do so - or to encourage them that those chest pains are the result of "mistaken beliefs."

What do the CONSORT standards say about what patients in a trial can and cannot be told about the treatments they are undergoing?

 

[Dolphin]

Results for CBT in PACE Trial worse than Sharpe et al. (1996)

This was the RCT that "launched" CBT for CFS in a big way around the world:

Sharpe M, Hawton K, Simkin S, Surawy C, Hackmann A, Klimes I, Peto T, Warrell D, Seagroatt V. Cognitive behaviour therapy for the chronic fatigue syndrome: a randomized controlled trial. BMJ. 1996 Jan 6;312(7022):22-6. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2349693/pdf/bmj00523-0026.pdf

It included some 6 minute walk data:

Distance walked in 6 minutes (m)t
(CBT & Control group)
Baseline: 424 435
5 months: 467 436 Change: 43 1 Difference: 42 (95% CI: 8 to 76)
8 months: 476 436 Change:52 1 Difference: 51 (95% CI: 14 to 88)
12 months: 481 437 Change: 57 2 Difference: 55 (95% CI: 17 to 94)

PACE Trial (they omit to tell us the figures at 24 weeks)

6-min walking test
APT CBT GET SMC
Baseline distance (m) 314 (90) 333 (86) 312 (87) 326 (95)
52-week distance (m) 334 (117) 354 (106) 379 (100) 348 (108)
Comparison with SMC –57; p=055 –15; p=087 353; p=00002
Comparison with APT 42; p=065 410; p<00001

CGI results (compare to Table 5):

At the final assessment (at 12 months) significant subjective
improvement ("much improved" or "very much
improved") was reported by 60% (18/30) of the
patients who received cognitive behaviour therapy and
23% (7/30) of the patients who had only medical
care. Deterioration ("worse" or "much worse") was
reported by 13% (4/30) of the cognitive behaviour
therapy group and 10% (3/30) of the medical care only
group. Two patients given cognitive behaviour therapy
attributed their deterioration to the treatment and two
experienced only temporary benefit.