PACE Trial and PACE Trial Protocol

[Dolphin]

Another witness account: CBT: fewer symptoms ... but able for fewer hours of work

A contact of mine from Sweden asked me to post this here which I am happy to do - he says he is too tired at the moment.

In an article in Daily Mail UK, I see a couple of comments that I find interesting.

One comment (#1 below) claims that only 6-8% improvement was achieved on the Chalder scale. Maybe the PACE trial does not use the classic invalidity scales for ME. Maybe the improvements are minimal on the classic scales.

The other comment (#2 below) seems to say that the patient had to decrease his working hours during the PACE trial. So, maybe the patients getting CBT actually decreased their working hours. If so, it is an important matter to know in order to interpret the results of the study.


DailyMail article
http://www.dailymail.co.uk/health/a...-exercise-best-hope-recovery-finds-study.html

Comment 1:
This research, reported in the article above, is nothing less than spin.
I have read the full study, and the press release about it does not reflect the PACE study, published in the Lancet. 1/ The people in the study were volunteers from the NHS ME/CFS clinics. These clinics offer Graded Exercise and CBT. They then had to conform to the Oxford Criteria, which excludes neurological disease. Myalgic Encephalomyelitis is a neurological disease. 2/ The "improvement" shown in the study was 6-8% on the Chalder scale. This was measured using a questionnaire, which is odd, because earlier in the study they used actometers to test functioning. So the very small improvement was subjectively measured. 3/ They considered people to be "recovered" if they attained the level of function of a 75 year old. Not my definition of full recovery. For this spin, we the British taxpayer shelled out 5,000,000. Very poor value, from a very poor study.
- Jace, Brighton, Sussex, 20/2/2011 17:50

Comment 2:
Part 2: 3.Contrary to the above article - read the Lancet to see how the above article misreads it - the PACE Trial CFS/ME experts/specialists recognise that there is currently no effective treatment for ME/CFS - how can there be when there is no clear and proven understanding of what causes it and what cures it! What the PACE Trial was testing was the effectiveness of techniques to help ME/CFS sufferers cope with their symptoms - the PACE Trial did NOT and was NOT INTENDED TO FIND A CURE for ME/CFS. 4.Did the PACE Trial/ CBT work for me? There's no easy answer - yes the ME/CFS symptoms have decreased. But at a price - all semblance of normal life - the decrease in symptoms was obtained solely by reducing my activities until I was only working a fraction of the hours with no social life. Since then, no matter how much pain & effort I put in, I can't get back to my pre-Trial activity levels. King's told me they didn't have a 'magic bullet', but I was hoping for more than this.
- PACE Trial Participant, London, 21/2/2011 1:27

Here's part 1 of what the participant said:

I took part in the PACE Trial under King's Hospital. I was allocated to CBT. 1. To those who say obtaining a diagnosis of ME/CFS is 'easy' and fakeable - I repeatedly raised the issue of my weird range of symptoms (including fatigue) with doctors for the best part of 18 years. I finally obtained a referral and a diagnosis of ME/CFS in 2007. 'Ease' was not a notable feature of my attempts to find out what was wrong! 2. To those who deny the existence of ME/CFS as a disease or syndrome - Until such time as the underlying cause(s) of ME/CFS are reliably isolated, I can see why you would doubt this - we are so used to being able to 'prove' illnesses exist. It's not that many of decades since many diseases that are now controllable could be identified but not effectively treated, and prior to that, some diseases were not individually identifiable. I personally find it difficult to believe that ME/CFS exists and affects me as badly as it does.
- PACE Trial Participant, London, 21/2/2011 0:48

 

[Dolphin]

6 minute walking test - results in some other areas

Somebody sent me this 16 hours ago.
I thought I'd share it.

Here's some good good good stuff- 6 minute walk tests (6 MWT) in different disease groups. Compare these results with the ones from the PACE Trial, it's a *(&^ing riot!

I can't send you all the links, but if you go to this article and go to the references they reference lots of studies in lots of different patient groups which have used the 6 MWT. It's a smorgasbord extravaganza of hilarity when you consider the PACE Trial authors claiming that +/- 300, 350 meters or so is indicative of the 'normal functioning' that they returned patients to.

(paper with lots of references to lots of different studies using 6 MWT) American Journal of Respiratory and Critical Care Medicine Vol 166. pp. 111-117, (2002)
Guidelines for the Six-Minute Walk Test
American Thoracic Society
http://ajrccm.atsjournals.org/cgi/content/full/166/1/111

More 6 minute walk test links- http://scholar.google.com/scholar?q=6+minute+walk+test&hl=en&as_sdt=0&as_vis=1&oi=scholart

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(below are samples of different papers- have highlighted relevant parts)

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BMC Pulmonary Medicine 2010, 10:31
The six minute walk test accurately estimates mean peak oxygen uptake
http://www.biomedcentral.com/1471-2466/10/31
http://www.biomedcentral.com/1471-2466/10/31/table/T1 (shows lots of 6-min walk tests for lots of different disease groups with heart and lung disorders such as COPD, chronic heart failure, primary pulmonary hypertension, etc . Mean distance for the different disease groups, comprising over 1,000 patients, was 393m.)

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http://www.ncbi.nlm.nih.gov/pubmed/9087875?dopt=Abstract

J Heart Lung Transplant. 1997 Mar;16(3):313-9.
The six-minute walk test: a guide to assessment for lung transplantation.
Kadikar A, Maurer J, Kesten S.

Toronto Hospital, University of Toronto, Ontario, Canada.

Abstract

BACKGROUND: A window of opportunity exists with regard to optimal timing for lung transplantation. Performance of a transplantation too early may rob the patient of months to years of survival, whereas waiting too long increases the risk of death before transplantation. Several studies have examined specific lung function tests as predictors of death, but none have been shown to be useful across the various disorders leading to end-stage lung disease. We therefore sought to examine the usefulness of the 6-minute walk test as a guide to assessment for transplantation.

METHODS: We conducted a retrospective chart review of patients who were assessed and either were accepted or died waiting acceptance by the Toronto Lung Transplant Program between January 1991 and June 1995. One hundred forty-five patients with the following lung diseases were included: emphysema (n = 38), alpha-1-antitrypsin deficiency (n = 20), idiopathic pulmonary fibrosis (n = 26), primary pulmonary hypertension (n = 10), Eisenmenger's syndrome (n = 9), and cystic fibrosis (n = 41). The sensitivity, specificity, and positive and negative predicted values for a 6-minute walk distance of 300 and 400 m as a predictor of death were calculated.

RESULTS: Mortality rates were as follows: emphysema (7.9%), alpha-1-antitrypsin deficiency (15%), idiopathic pulmonary fibrosis (42.3%), primary pulmonary hypertension (50%), Eisenmenger's syndrome (11%), and cystic fibrosis (24.4%). A 6-minute walk distance of less than 400 m had the following characteristics for prediction of death: sensitivity 0.80, specificity 0.27, positive predictive value 0.27, and negative predictive value 0.91. Similar findings for a 6-minute walk distance of less than 300 m were as follows: 0.52, 0.80, 0.38, and 0.88, respectively.

CONCLUSION: The 6-minute walk test is a useful tool in the assessment of when to list patients for transplantation. A 6-minute walk test result of less than 400 meters appears to be a reasonable marker with regard to when a patient should be listed for transplantation.
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http://171.66.122.149/cgi/content/full/161/2/487

Am. J. Respir. Crit. Care Med., Volume 161, Number 2, February 2000, 487-492
Clinical Correlates and Prognostic Significance of Six-minute Walk Test in Patients with Primary Pulmonary Hypertension
Comparison with Cardiopulmonary Exercise Testing
SHOICHI MIYAMOTO, NORITOSHI NAGAYA, TORU SATOH, SHINGO KYOTANI, FUMIO SAKAMAKI, MASATOSHI FUJITA, NORIFUMI NAKANISHI, and KUNIO MIYATAKE

"Distance walked in 6 min was significantly shorter in patients with PPH than in age- and sex-matched healthy subjects (297 188 versus 655 91 m, p < 0.001)... Patients walking < 332 m had a significantly lower survival rate than those walking farther, assessed by Kaplan-Meier survival curves (log-rank test, p < 0.01)."

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http://jama.ama-assn.org/content/270/14/1702.full.pdf+html

(JAMA. 1993;270:1702-1707)

Prediction of Mortality and Morbidity With a 6-Minute Walk Test in Patients With Left Ventricular Dysfunction

Vera Bittner, MD; Debra H. Weiner, MPH; Salim Yusuf, MBBS, DPhil; William J. Rogers, MD; Kevin M. McIntyre, MD; Shrikant I. Bangdiwala, PhD; Marvin W. Kronenberg, MD; John B. Kostis, MD; Robert M. Kohn, MD; Maureen Guillotte, RN; Barry Greenberg, MD; Patricia A. Woods, RN; Martial G. Bourassa, MD; for the SOLVD Investigators

Endpoint results were initially analyzed in terms of the proportion of patients in each quartile of walk-test performance who experienced an event (quartile 1- less than 308 m; quartile 2- 308 to 372 m; quartile 3- 374 to 446 m; and quartile 4- greater than 446 m)... Distance walked was inversely related to mortality (P<.02). Compared with those walking at least 450 m, patients walking less than 300 m had a 3.7-fold risk of dying (95% confidence interval [CI], 1.44 to 9.55), and those in level 2 had a 2.78-fold risk of dying (95% CI, 1.09 to 7.11); the risk of death was not significantly increased in patients in level 3 (OR, 1.42; 95% CI, 0.50 to 4.06).

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http://www.bmj.com/content/284/6329...bffaf7ce4a38600f8812d79c&keytype2=tf_ipsecsha

Two-, six-, and 12-minute walking tests in respiratory disease

Study 2. Comparison of two-, six-, and 12-minute tests-Thirty patients of mean age 61 (12) years with stable chronic respiratory disability owing to various diseases were studied (forced expiratory volume in one second = 1-28 0-66 1, forced vital capacity= 2-29 0-78 1). Twelve-minute walking distances ranged from 345 to 1215 m. Each patient performed one two-minute, one six-minute, and one 12-minute test in a randomised cross-over design. The walks were made on three consecutive days but at the same time of day. The mean distances walked during the tests were 14935 m, 413107 m, and 774229 m, respectively.

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http://www.bmj.com/content/292/6521/653.abstract

Six minute walking test for assessing exercise capacity in chronic heart failure.
Br Med J (Clin Res Ed) 1986; 292 : 653 doi: 10.1136/bmj.292.6521.653 (Published 8 March 1986)

"There were significant differences in the distance walked in six minutes between normal subjects, patients with heart failure, class II, and those with class III heart failure (683 m, 558 m, and 402 m, respectively."
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http://physicaltherapyjournal.com/content/82/2/128.full

Physical Therapy February 2002 vol. 82 no. 2 128-137
Age- and Gender-Related Test Performance in Community-Dwelling Elderly People: Six-Minute Walk Test, Berg Balance Scale, Timed Up & Go Test, and Gait Speeds
Teresa M Steffen, Timothy A Hacker and Louise Mollinger

Table 2- Six-Minute Walk Test Distances: Means, Standard Deviations, and Confidence Intervals by Age and Gender (in Meters) http://physicaltherapyjournal.com/content/82/2/128/T2.expansion.html

Ages 60-69, 70-79, 80-89 / Means 572, 527, 417

 

[Dolphin]

Any normative data for 6 minute walking test for "non-older" healthy adults?

As I recall, most/all the data so far is for older adults with or without health problems.

The average age of the participants in the PACE Trial was 38 (SD=12). It'd be good if anyone had could find numbers for that sort of age range.

 

[Mark]

I can see what you're saying, but I don't think that's actually the case.

You're right that the trial is designed so that it will give statistically significant results for the primary outcomes (at least the original ones, not the new ones they switched to!).

However, there are separate statistical tests that will be applied to each of the additional measures and it's implicity accepted that it may turn out the sample size isn't big enough for some of these measures to be significant - these measures will then have to be dropped. Also, they explicitly made the CBT/GET groups bigger than statistically required to help with significance of the additional measures.

It's also not quite the same as post-hoc testing, in that the researchers have specified in advance which measures/predictors they are looking at and how they will analyse them. mind you, they did that for the primary measures too, and still changed their minds afterwards.

I agree; my comment that you quoted was trying to understand what their (spurious) theoretical justification for moving the goalposts was...not agreeing that it was valid! Not sure if I was even right that this was their argument...hard to figure out what on earth this garbage is all about...they must have had some alleged justification, but so far, it seems to be so complicated that nobody understands what it actually was...though it seems perfectly obvious what the real reason was...

 

[Marco]

As I recall, most/all the data so far is for older adults with or without health problems.

The average age of the participants in the PACE Trial was 38 (SD=12). It'd be good if anyone had could find numbers for that sort of age range.

Reference Equations for the Six-Minute Walk in Healthy Adults
PAUL L. ENRIGHT and DUANE L. SHERRILL

Respiratory Sciences Center, University of Arizona, Tucson, Arizona


Data and age v distance scattergraphs for healthy 40 to 80 year olds


http://171.66.122.149/cgi/content/full/158/5/1384#F1

 

[oceanblue]

Reference Equations for the Six-Minute Walk in Healthy Adults
PAUL L. ENRIGHT and DUANE L. SHERRILL
Respiratory Sciences Center, University of Arizona, Tucson, Arizona
Data and age v distance scattergraphs for healthy 40 to 80 year olds
http://171.66.122.149/cgi/content/full/158/5/1384#F1

Just to summarise from figure 2, for women only, the typical 6MWD for those aged around 45 (it doesn't go much younger than that) is 600m. Yes, that's a lot more than the sub-400 managed by all the PACE groups at 52 weeks.

 

[anciendaze]

repeated tests + encouragement

Just in case anyone missed it, the data in the Enright and Sherrill paper refer to 40 to 80 year-olds. The mean age for PACE was 38. There is no reason to expect younger patients to perform more poorly.

In the summation we find this nugget:

Caution should be exercised when applying our regression equations to patients who have characteristics which fall outside our cohort, including non-Caucasians and those younger than 40 yr or older than 80 yr. Larger values may be expected from those who have previously performed 6 min. walk tests and those to whom non-standardized encouragement is given.

You can get higher results just by repeating the test! This could account for about 20 m. improvement across the board.

As for non-standardized encouragement, wasn't that the point of the PACE study? It looks like all PACE data can be explained by subjective changes. The only objective measure was subject to subjective distortion without any real change in condition.

 

[Dolphin]

Also: the full protocol document makes clear that this is the 3rd test patients would have done: at assessment, at 24 weeks (we're not given that data) and at 52 weeks.

 

[Marco]

In the summation we find this nugget:


You can get higher results just by repeating the test! This could account for about 20 m. improvement across the board.

As for non-standardized encouragement, wasn't that the point of the PACE study? It looks like all PACE data can be explained by subjective changes. The only objective measure was subject to subjective distortion without any real change in condition.

Isn't that the crux.

CBT and GET groups are told repeatedly that they will get better. SMT and APT groups are not.

Any wonder the CBT and GET groups do better on the subjective self report 'happy sheets' and a case could certainly be made that the CBT and GET arms both received 'non standard encouragement' prior to the 6MWT.

 

[Angela Kennedy]

Has anybody noticed this little gem from the PACE article about adverse outcomes? (page 12 of the pdf)

There were no differences between groups in the
proportions with serious deterioration or serious adverse
reactions. The increased rate of serious adverse events
with GET compared with SMC is unlikely to be important
because serious adverse events were not thought by the
independent scrutinisers to be related to treatment.
Consequently, if these treatments are delivered as
described, by similarly qualified and trained clinicians,
patients need not be concerned about safety.

So, we have a rather ad hoc analysis of serious adverse events that 'independent scrutinisers' did not BELIEVE were related to treatment. This needs further investigation.

On the basis of this vague allusion, ME patients are to accept, on faith, from researchers who do not believe in their illness or the cardiovascular, mitochondrial and neurological impairments that contra-indicate CBT/GET (and ignore the evidence of that completely in their article for that matter), that CBT/GET is safe, and must stop worrying their pretty little heads about it.

I will look myself anyway- but if anybody can point me towards something I'd be grateful - were treatment drop-outs included in negative outcome figures?

 

[Angela Kennedy]

A separate thread has developed here about Oxford (and other) criteria, their exclusionary capacity and use in the PACE trial:

http://forums.aboutmecfs.org/showthread.php?10219-PACE-study-and-oxford-criteria

I don't want to necessarily drag all that information onto this thread as it might become unmanageable. Therefore, I'm just posting that the above thread exists.

The issue of criteria is very important, and has been since the beginning of the PACE trial. I'm certainly doing some work on it, in addition to: issues of adverse outcome and what I see are discrepant relating of those (leading to this terribly unsafe assertion of safety and efficacy which could have disastrous consequences for many people and must be objected to strenuously in due course); and various other ethical problems (that's a wide ranging group of issues!)

 

[Bob]

Has anybody noticed this little gem from the PACE article about adverse outcomes? (page 12 of the pdf)

There were no differences between groups in the
proportions with serious deterioration or serious adverse
reactions. The increased rate of serious adverse events
with GET compared with SMC is unlikely to be important
because serious adverse events were not thought by the
independent scrutinisers to be related to treatment.
Consequently, if these treatments are delivered as
described, by similarly qualified and trained clinicians,
patients need not be concerned about safety.

So, we have a rather ad hoc analysis of serious adverse events that 'independent scrutinisers' did not BELIEVE were related to treatment. This needs further investigation.

On the basis of this vague allusion, ME patients are to accept, on faith, from researchers who do not believe in their illness or the cardiovascular, mitochondrial and neurological impairments that contra-indicate CBT/GET (and ignore the evidence of that completely in their article for that matter), that CBT/GET is safe, and must stop worrying their pretty little heads about it.

Yes, it's outragious isn't it.


Here's the figures for adverse events:

Serious adverse events

SMC 7

GET 17 (This is a 243% increase in adverse events, as compared to the SMC-alone group.)


Participants with Serious Adverse events

SMC 4%

GET 8% (This is a 100% increase in participants with serious adverse events, as compared to the SMC-alone group.)

 

[Bob]

I will look myself anyway- but if anybody can point me towards something I'd be grateful - were treatment drop-outs included in negative outcome figures?

This is something i've been trying to get my head around...
I haven't read the whole paper, or the exact methodology, but it looks to me like they haven't included the dropouts in the figures, because in the Chalder scale figures for CBT, for example, the baseline number of patients was n=161, and then at 52 weeks n=148. So the results were recorded for n=148, not n=161.

I think that they might also have added more patients to each group, as patients dropped out, so the difference between 161 and 148 might not be the true drop-out rate. I'm not clear on that. Does anyone know about this?

I've worked out for the chalder scores in the GET group, that if there were only 6 drops outs, as is apparent from the figures in the table 3 (I'm not clear on the number due ot the point i made above), and if we were to assume that each of these drop-out patients recorded a maximum score of 33, then this only changes the total average score by 0.465. But the chalder scale is skewed in favour of the recovering patients, because 33 is the maximum score that extremely ill patients can get anyway, so they only increase their scores by a couple of points if they relapse, whereas those who improve can drop by many points.

 

[anciendaze]

statistical & medical significance

314 333 312 326 * Baseline
334 354 379 348 * 52 weeks
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20 21 67 22 gain

If we assume 20 meters improvement is merely the result of retest familiarity, or a Hawthorne effect which would not transfer to practice, adjusted scores are less impressive:

0 1 47 2 adjusted

What is considered significant improvement on this test for patients with other conditions serious enough to put them in this performance range?

For COPD patients, 70 meters is suggested (by the ATS guidelines) as showing an intervention produces significant improvement with 95% confidence. For older patients with heart failure, 43 meters was considered significant, though in this case the results proved more responsive to deterioration than improvement.

The only objective measure, (other than cost,) does not show significant improvement by the standards applied to medical interventions for other conditions which put patient performance in this range. It does show subjective distortion, as should be expected.

I would like to estimate the effect of parts of the protocol not considered treatment. Adverse events needed to be investigated and reported. Patients were encouraged to remain in the trial, if this did not present a threat to their health -- in the opinion of those running the trial.

I believe there is a better correlation between these unconsidered interventions and test results than with the treatments under official test. Anyone agree?

 

[Bob]

The patients in this study had far more input than any patients would ever have in a normal NHS setting.
I'm sure that they had many hours of one to one encouragement, that you wouldn't get in a normal setting.
Does anyone have any insight into how many hours of SMC, GET, CBT and other instructions or encouragement that they had?
It would be interesting to find out.

 

[Angela Kennedy]

Yes, it's outragious isn't it.


Here's the figures for adverse events:

Serious adverse events

SMC 7

GET 17 (This is a 243% increase in adverse events, as compared to the SMC-alone group.)


Participants with Serious Adverse events

SMC 4%

GET 8% (This is a 100% increase in participants with serious adverse events, as compared to the SMC-alone group.)

Ooh- thanks for this Bob.

 

[oceanblue]

I'm sure that they had many hours of one to one encouragement, that you wouldn't get in a normal setting.
Does anyone have any insight into how many hours of SMC, GET, CBT and other instructions or encouragement that they had?
It would be interesting to find out.

From memory, there were up to 15 1 hour sessions of CBT, GET or APT, plus I think an average of 3 consultations with the specialist SMC doctor, though I'm not sure if these were also one hour long.

 

[oceanblue]

Just in case anyone missed it, the data in the Enright and Sherrill paper refer to 40 to 80 year-olds.

You can get higher results just by repeating the test! This could account for about 20 m. improvement across the board.

As for non-standardized encouragement, wasn't that the point of the PACE study?

Very interesting about higher results on repetition. For the record, the protocol does instruct assessors not to encourage patients during the walk itself.

 

[Sean]

Bedtime here so don't have time to check it further right now, but there seems to be two different tests: a 6 minute walking test (6MWT), and a 6 minute walking distance (6MWD) test. If so then we had better be careful not to mix them up.

 

[anciendaze]

The best match I get for this cohort to patients with other illnesses is from the JAMA paper Dolphin quoted: left ventricular dysfunction

If I assume the entry criteria selected patients in the first and second quartiles of that group, this looks like a very good comparison. The patients in that referenced study had a mixture of systolic and diastolic dysfunction. Diastolic dysfunction has been reported in long-term ME/CFS patients.

I need to make it clear that I am not saying any of the PACE patients had congestive heart failure, serious hypertension, ischemic heart disease, etc. If such conditions were known they would have been excluded. I can't say what their ejection fraction (EF) was because this was not measured, since they had passed ordinary screening tests for heart conditions. A standard 6-wire EKG will not normally show diastolic dysfunction with the patient supine. Echocardiograms were not performed, because they were not thought necessary. Similarly, Holter monitoring for 24 hours was not performed.

If I assume these patients had significant diastolic dysfunction while upright, but did not show other classic signs of heart conditions, this looks like a viable interpretation. I am suggesting they were not merely like patients with left ventricular dysfunction, I am saying they look exactly like a subset of these. Fatigue and dizziness are prominent symptoms for such patients.