Adverse events and deterioration reported by participants in the PACE trial of therapies for CFS

[Tom Kindlon]

Free full text: http://www.sciencedirect.com/science/article/pii/S0022399914001883

Journal of Psychosomatic Research

Available online 22 April 2014

In Press, Accepted Manuscript — Note to users

Adverse events and deterioration reported by participants in the PACE trial of therapies for chronic fatigue syndrome

Dominic Dougall a,
A.L. Johnson b,
K. Goldsmith c,
M. Sharpe d,
B. Angus e,
T. Chalder f,
P.D. White g, Corresponding author

a East London Foundation NHS Trust, London
b MRC Clinical Trials Unit at UCL, London
c Biostatistics Department, Institute of Psychiatry, King’s College London
d Psychological Medicine Research, Department of Psychiatry, University of Oxford, Oxford, UK
e Nuffield Department of Medicine, University of Oxford
f Academic Department of Psychological Medicine, King's College London
g Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London

Received 22 November 2013, Revised 31 March 2014, Accepted 8 April 2014, Available online 22 April 2014

________________________________

Highlights

• This study shows the distribution of adverse events in a trial of treatments for CFS.

• Non-serious adverse events were common, but no different between treatments.

• Non-serious adverse events were more related to ill health than treatments.

• Deterioration in physical function was more likely after adaptive pacing therapy.

• Differences between centres may be related to different ascertainment methods.

________________________________

Abstract

Objective

Adverse events (AEs) are health related events, reported by participants in clinical trials. We describe AEs in the PACE trial of treatments for chronic fatigue syndrome (CFS) and baseline characteristics associated with them.

Methods

AEs were recorded on three occasions over one year in 641 participants.

We compared the numbers and nature of AEs between treatment arms of specialist medical care (SMC) alone, or SMC supplemented by adaptive pacing therapy (APT), cognitive behaviour therapy (CBT) or graded exercise therapy (GET).

We examined associations with baseline measures by binary logistic regression analyses, and compared the proportions of participants who deteriorated by clinically important amounts.

Results

Serious adverse events and reactions were infrequent.

Non-serious adverse events were common; the median (quartiles) number was 4 (2, 8) per participant, with no significant differences between treatments (p = 0.47).

A greater number of NSAEs was associated with recruitment centre, and baseline physical symptom count, body mass index, and depressive disorder.

Physical function deteriorated in 39 (25%) of participants after APT, 15 (9%) after CBT, 18 (11%) after GET, and 28 (18%) after SMC (p < 0.001), with no significant differences in worsening fatigue.

Conclusions

The numbers of adverse events did not differ significantly between trial treatments, but physical deterioration occurred most often after APT.

The reporting of non-serious adverse events may reflect the nature of the illness rather than the effect of treatments.

Differences between centres suggest that both standardisation of ascertainment methods and training are important when collecting adverse event data.

Keywords

Adverse events;
body mass index;
chronic fatigue syndrome;
depression;
medically unexplained symptoms

 

[Tom Kindlon]

If anyone is considering a letter, here are the instructions:

Letters to the Editors
These normally refer to articles previously published in the journal. The Editors are also willing to consider letters on subjects of direct relevance to the journal's interest, including research letters. Letters should not exceed 1000 words, including references. Where appropriate, they should begin with a reference to the published article that is the subject of the letter. Research letters should be submitted as 'Letters to the Editors'

From: http://www.elsevier.com/journals/journal-of-psychosomatic-research/0022-3999/guide-for-authors

It is hard to keep a 1000 word letter tight so it might be better to aim for lower than the maximum.

 

[A.B.]

So why do these results seem to have no relationship to reality? How is deterioration of physical functioning defined?

 

[Dolphin]

Figure 1 shows that the distributions of NSAE counts had similar patterns across the treatment groups, but with more participants having no NSAEs in the CBT group (post hoc comparison of CBT participants versus all others combined: 6% versus 11%, chisquared = 4.65, 1 df, p = 0.03)

NSAE=Non-Serious Adverse Events

Possibly circumstantial evidence of response bias in CBT (or some who have done CBT) i.e. they don't report problems.

 

[Bob]

So they've published it at last. The abstract is meaningless. We need the full paper.

 

[Esther12]

I thought that this paper was also meant to be looking more generally at mediators for outcomes... when are we going to get those results - that's what I'd been waiting for! Ah well.

 

[Countrygirl]

So they've published it at last. The abstract is meaningless. We need the full paper.

The full paper is there........or am I hallucinating????

Discussion
There were no important differences between treatment arms in any of the adverse events, however they were measured or classified. Most importantly there was no evidence of more frequent adverse events after either CBT or GET. The factors associated with a higher number of NSAEs were the centre where the participant was seen, followed by the number of physical symptoms at baseline, having a depressive episode, and higher body mass index. Those variables associated with CFS related NSAEs were centre, CFS symptom count and a depressive episode. The common baseline associations in both models were centre, depressive disorder and physical symptom count. Those who received APT were most likely to deteriorate by a clinically important amount in physical function, with those in receipt of CBT being least likely to deteriorate.

The substantial variation in the frequency of the reporting of NSAEs between centres is our most unexpected finding, although variation between centres is not uncommon in multi-centre trials [32], and this did not influence treatment response [17]. We found statistically significant linear associations between centres stratified by NSAE counts and a number of baseline variables, but the differences between centres were small, and nothing like the size of differences in NSAE frequency across centres. ThIs suggests that the large differences in NSAE numbers between centres is unlikely to be related to the small differences found between centres in baseline factors. Although the research assessments across centres were standardised and training was provided at the start of the trial, it might be that the differences were due to different methods of ascertainment. This apparent variation in recording NSAEs, despite a standard protocol for doing so, has important implications for recording adverse events in future trials.

Having more symptoms at baseline, particularly those associated with CFS, predicted subsequent NSAEs in general and also NSAEs attributed to CFS. This replicates previous work [5]. Higher symptom counts are associated with somatoform disorders in secondary care [33], and may reflect a general tendency to report symptoms, which is associated with, but also independent of, mood disorders [34]. The specificity of CFS symptoms at baseline being associated with NSAEs attributed to CFS suggests a specific tendency to report these symptoms, rather than a generic influence of reporting any symptom. It may also reflect the relapsing and remitting nature of CFS.

Our finding that a diagnosis of a depressive disorder at baseline predicted increased reporting of NSAEs is consistent with previous studies that found negative affect to be associated with NSAEs specifically[1] and [3], and somatic symptoms in general [6], [7], [8], [9], [10] and [35]. This association remained significant for both NSAEs as a whole and for CFS attributed NSAEs in one regression model. Unlike some previous studies, we did not find an association with anxiety, either with the HADS score or through the SCID interview. One other trial failed to find an association between anxiety and adverse events [5].

We found that a higher BMI was associated with NSAEs in general. This observation may have several explanations; obese people generally report both more physical and mental health related problems [36], and our sample included 123 (19%) participants who were morbidly obese. We were not able to replicate a previous research finding that female participants are more likely to report adverse events [4].

The strengths of this paper are that it used data from a large trial from multiple centres. The assessment of NSAEs on three occasions improved sensitivity. The limitations include the difference in frequency of NSAE reporting between centres, implying variation in ascertainment, although controlling for centre did not significantly affect our main findings. We only measured deterioration using self-ratings, rather than objective measures. We were unable to model the full distribution of NSAEs, which may have limited the power of our regression models.

Conclusions
We found that there were no important differences in any of the adverse events between treatment arms, and no excess associated with either CBT or GET. Clinically important deterioration occurred least often after CBT and GET; APT may be associated with more frequent deterioration in physical functioning. We also noted that the reporting of non-serious adverse events in a clinical trial of treatment for CFS varied by recruitment centre, perhaps related to the method of ascertainment. This important finding has implications for the design of future trials. Research assessors need clear manualised guidance on the various definitions of adverse events, and specific training and supervision in order to implement them. We also found that baseline symptom count, having a depressive disorder and BMI were significantly associated with a greater number of NSAEs, independently of the treatment arms. This has both research and clinical implications for clinicians running trials, particularly those including patients with CFS. Adverse events in trials may more accurately reflect fluctuations in a condition, rather than reactions to interventions.

 

[Bob]

The full paper is there........or am I hallucinating????

lol, no you're not hallucinating. It wasn't available earlier.

It's suddenly become open access!

A nice bit of bedtime reading!

 

[Countrygirl]

lol, no you're not hallucinating. It wasn't available earlier.

It's suddenly become open access!

A nice bit of bedtime reading!

I've scanned it, Bob.................from under the safety of the duvet. Now I have the thoughts of the infernal trio bedding down with me tonight and it will take a whole zopiclone and more to beat them down..

This irrelevant twaddle really is enough to make a man eat his young. Just how much longer do we have to put up with this disgraceful situation? At this rate, I shall have fallen off my perch long before we receive that heartfelt apology from the UK medical profession for their half-century of neglect and abuse of the ME community. It is my ambition to live long enough to savour that moment. Will I make it?

C.G.

 

[minkeygirl]

I think that it was put out by the Journal of Psychosomatic Research says it all.

 

[Dolphin]

So why do these results seem to have no relationship to reality? How is deterioration of physical functioning defined?

To answer your second question, a deterioration of physical functioning required a decrease of 8 or more points on a questionnaire, the SF-36 physical functioning subscale (many CBT and GET investigators/authors tend to talk about "physical functioning" without making it clear they're talking about a questionnaire).

This questionnaire involves 10 questions about activity where people are asked to say one of the following regarding certain activities: "Yes, limited a lot", "Yes, limited a little" or "no, not limited at all". There is a difference of 10 points between "Yes, limited a lot" and "no, not limited at all" and 5 points between the two smaller changes. So the deterioration required was two small steps or one larger steps.

It seems possible that somebody who became more cautious about not overdoing it, as encouraged by APT, might report this sort of level of change, without it necessarily representing a true deterioration.

 

[Bob]

Table 5 seems the most relevant, in terms of how CBT/GET affected patients:
http://www.sciencedirect.com/science/article/pii/S0022399914001883#t0025

They looked at deterioration, at one year, as an equivalent measure to improvement (as reported in the main Lancet paper) for self-reported fatigue and physical function, and other measures.

Roughly 10% reported deterioration in physical function after CBT+SMC (9%) and GET+SMC (11%).
But this needs to be compared with the SMC-alone group for which the deterioration rate was 18% for physical function.
So there was roughly an 8% lower deterioration rate in the CBT/GET groups than in the SMC-alone control group. So CBT/GET compare favourably with the control in this paper.

Self-reported fatigue has fairly similar difference between groups.

There were 2 or 3 "serious adverse reactions" in each group, out of roughly 160 participants in each group. I can't see what the threshold for a serious reaction was.

 

[biophile]

So why do these results seem to have no relationship to reality?

I think there are a number of reasons for the discrepancy.

Clinical trials are generally much better organized and controlled than routine clinical practice. One of the main aims of the PACE Trial was to test the safety of these therapies. The principal authors were already proponents of CBT/GET and convinced these were safe (based on clinical experience and small trials which showed no major worsening in group average scores), so one could say they were motivated to prove that their position and role in the ongoing controversy about safety was justified by evidence. So extra care was put into harms prevention and safety monitoring.

CBT and GET groups were encouraged to carefully increase activity and tolerate a degree of symptom exacerbations for a week or so as long as the activity levels were sustainable and did not lead to a relapse or reduction in function. This safety net is an important factor when considering that the objective evidence suggests that CBT and GET does not lead to clinically significant improvements in total activity levels, total service use, employment hours, walking distances, welfare dependency etc. There was encouragement to test the boundaries, but no evidence that the boundaries were actually expanded in a sustainable manner, something which CBT/GET proponents tend to spin doctor or gloss over.

The 'safety' of CBT/GET seems to depend on not actually achieving what proponents claim to achieve with it. CBT/GET outside a RCT may be less respectful with patients and this is what proponents and an AfME survey blame for the adverse effects universally reported in patient surveys. I also think Dolphin's point about response/reporting bias is important if patients were told that they focus too much on symptoms and that they exaggerate the seriousness of symptoms etc.

Other explanations include the recruitment process. 80% of candidates who were provisionally or definitely diagnosed with CFS before referral were excluded from the trial. The most common reason for exclusion was not meeting Oxford criteria for CFS. This criteria allowed multiple symptoms but demands that fatigue to be the only principal symptom. Some candidates refused to participant or were excluded because they had a preference for one of the therapies. I think it is a safe bet that some candidates did not want to do CBT/GET because they thought it was useless or harmful. The medical assessment may have also excluded ME/CFS patients with organic dysfunction.

 

[Esther12]

The oversight and safety provisions built into PACE were good. If similar provisions were in place for these treatments in routine practice, and if patients were provided access to unspun data on efficacy (like Pace's protocol defined outcomes, with information on problems with response bias in unblinded trials and the info we have from more objective measures of outcome), then I wouldn't have a problem with them.

I thought that GET could have more fluctuations in reported symptoms, but overall, I'm not surprised by these results (although i've not read the paper properly, so could well be missing something important).

 

[biophile]

While CBT and GET were designed to be rehabilitative, the goal of APT was to optimise adaptation to the illness by planning and pacing activities to avoid or reduce fatigue [17].

No objective evidence that CBT and GET are actually rehabilitative.
APT had a 70% rule which is not part of general pacing.

We have already reported that there were few serious adverse events (SAEs) and even fewer serious adverse reactions (SARs), the numbers of which did not differ significantly across treatment arms [17].

It may not be obvious in the sentence quoted above, but in the Lancet paper there were about twice as many SAEs in the GET group and the difference was statistically significant. It was only after the assessors were unblinded to group allocation that these were judged unrelated to treatment, which seems awfully arbitrary. Maybe it should be the participants judging whether their symptom exacerbations were related to GET?

This paper reports the more commonly reported non-serious adverse events (NSAEs), compares their frequency between treatment arms, and also identifies baseline factors associated with reporting larger numbers of NSAEs [17] and [19].

Readers may be unaware that the full trial protocol also graded NSAEs by severity, which is not reported in this paper. These could be graded Mild / Moderate / Severe. There has been no attempt to explore the difference.

http://www.meactionuk.org.uk/FULL-Protocol-SEARCHABLE-version.pdf

This is important because a NSAE may range somewhere between say, a minor annoyance, to, being bedridden for several weeks. "Transient exacerbation of fatigue or pain, expected as a normal reaction to CBT or GET in patients with CFS/ME, which does not have significant impact upon function (see 14.1.1 (a))"

Their definition of a non-significant impact upon function is essentially anything that is not a serious adverse event (SAE), which is described in the paper and quoted below, so I will not repeat again here. It is strict and patients may not agree that anything less than a SAE is not a significant impact upon function.

Unless I misread something, the specific reference to part (a) of 14.1.1 rather than the whole subsection must be a typo because it is "death", which is an absurd threshold for a significant impact upon function!

This report uses data from the PACE trial, relevant aspects of which are described; more comprehensive accounts are available in the protocol [19], and the primary paper [17].

They do not seem to mention that they changed the definition of serious deterioration since the protocol was published? i.e. reduction of SF-36 score by 20 or more points from one assessment to two consecutive assessments.

The PACE trial recruited 641 patients from secondary care clinics with a diagnosis of CFS, using the Oxford criteria, which require six or more months of disabling fatigue, with fatigue being the principal symptom, and no alternative, explanatory diagnosis [20].

Once again, overemphasis on fatigue, which is not required of any other CFS or ME definition. Even the CDC criteria does not require fatigue to be the principal symptom.

Two consultant physicians and a consultant liaison psychiatrist, all experienced in CFS, were appointed as independent scrutineers and were masked to the participants’ allocated treatment group. They determined whether each AE was serious or non-serious. A serious adverse event (SAE) was an event that resulted in one of the following outcomes: a) death, b) threat to life (i.e., an immediate, not hypothetical, risk of death at the time of the event), c) required hospitalisation except for elective treatment of a pre-existing condition, d) increased severity and persistent disability, defined as: (i) severe, i.e. significant deterioration in the participant’s ability to carry out their important activities of daily living (e.g. employed person no longer able to work, caregiver no longer able to give care, ambulant participant becoming bed bound); and (ii) symptom and disability persistent, i.e. of at least 4 weeks continuous duration, e) any other important medical condition which, though not included in the above, might require medical or surgical intervention to prevent one of the outcomes listed, f) any episode of deliberate self-harm. For any AE established as serious, the scrutineers were unmasked to treatment allocation to establish whether or not the event was a serious adverse reaction (SAR). A serious adverse reaction was considered to be a reaction to one of the supplementary therapies or a drug prescribed as part of SMC [19]. All those judged as definitely, probably, or possibly related were considered to be SARs.

In other words, definition of SAE was strict, and there was room for interpretation when judging whether it was a reaction to treatment (therapy or medication). @Bob . A SAR is just a SAE that was judged to be related to treatment.

The distribution of NSAEs across trial participants was non-normal, and attempts to normalise the distribution by transformation were unsuccessful, so we used non-parametric comparisons, such as Kruskal-Wallis tests.

No such consideration for non-normal distribution of physical function scores in the population data when questionably and controversially changing the thresholds for "normal" and "recovered".

Approximately half of participants were educated to A-level or degree level standard (Appendix A Table A).

So, smart enough to realize that they were probably conned on the issue of "recovery".

There were no important differences between treatment arms in any of the adverse events, however they were measured or classified.

Again, they failed to look at the grading of NSAEs (mild / moderate / severe).

Most importantly there was no evidence of more frequent adverse events after either CBT or GET. The factors associated with a higher number of NSAEs were the centre where the participant was seen, followed by the number of physical symptoms at baseline, having a depressive episode, and higher body mass index.

The substantial variation in the frequency of the reporting of NSAEs between centres is our most unexpected finding, although variation between centres is not uncommon in multi-centre trials [32], and this did not influence treatment response [17].

Maybe some centres / therapists were better at convincing participants that symptoms aren't as serious or severe as they thought? Again, Dolphin's point about response bias is important here. Nevertheless, variations of ascertainment between centres is also an plausible contributing factor.

Having more symptoms at baseline, particularly those associated with CFS, predicted subsequent NSAEs in general and also NSAEs attributed to CFS. This replicates previous work [5]. Higher symptom counts are associated with somatoform disorders in secondary care [33], and may reflect a general tendency to report symptoms, which is associated with, but also independent of, mood disorders [34]. The specificity of CFS symptoms at baseline being associated with NSAEs attributed to CFS suggests a specific tendency to report these symptoms, rather than a generic influence of reporting any symptom. It may also reflect the relapsing and remitting nature of CFS.

Or it may reflect illness characteristics which are incompatible with CBT/GET.

The limitations include the difference in frequency of NSAE reporting between centres, implying variation in ascertainment, although controlling for centre did not significantly affect our main findings. We only measured deterioration using self-ratings, rather than objective measures. We were unable to model the full distribution of NSAEs, which may have limited the power of our regression models.

Cue CPET for future studies? They could have included 6MWD deterioration in this paper.

Adverse events in trials may more accurately reflect fluctuations in a condition, rather than reactions to interventions.

Especially when the assessors are unblinded to allocation before arbitrarily deciding whether SAEs are SARs.
There is no mention of non-serious adverse reactions, which is also mentioned in the trial protocol!

"Non-serious adverse events or reactions will be assessed by the RN at each follow-up assessment interview. A risk assessment has been undertaken, and we have concluded that the therapies are of low risk to participants. Non-serious adverse events will be reported according to the usual regulatory requirements."

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

Clinically important deterioration occurred least often after CBT and GET; APT may be associated with more frequent deterioration in physical functioning.

Can't say I'm surprised, given APT's questionable 70% rule.

 

[Dolphin]

I came across one participant from the GET arm of the trial on another forum.

She said the physiotherapist (=physical therapist) said to her that she could use housework to replace exercise on some days if she wasn’t feeling so good, or something along those lines.

This is not part of the philosophy of GET which is about adding exercise on top of daily activities.

Also, housework can be of varying intensities including very low intensity. This is not how GET is supposed to be: the exercise session is supposed to be of the same intensity and either the same length or a bit longer.

If such measures to “play it safe” were more common across the trial, one could see how fewer adverse events would be reported than with a more rigorous program including one that stuck rigidly to the manuals.

 

[Valentijn]

Follow-up assessment interviews were conducted by the RA at each centre on three occasions: 12, 24 and 52 weeks after randomisation. At each of these time points the RA asked participants whether any new events or illnesses had taken place since the last assessment including any events for which the participant visited the GP or hospital department, or took medication. [19] AEs were also recorded by treating specialist doctors and therapists if spontaneously reported to them during the trial.

So they only looked for adverse events at three points, with a HUGE gap of 7 months between the 2nd and 3rd assessment. Without being asked at other appointments, and with CBT and GET involving a healthy dose of brainwashing, that seems pretty scanty.

For any AE established as serious, the scrutineers were unmasked to treatment allocation to establish whether or not the event was a serious adverse reaction (SAR). A serious adverse reaction was considered to be a reaction to one of the supplementary therapies or a drug prescribed as part of SMC [19]. All those judged as definitely, probably, or possibly related were considered to be SARs.

While they are blinded in determining if an adverse event is serious, it's not clear who is making this determination. If it's anyone involved in the research, or friendly CBT/GET practitioners, there's a general interest in showing no serious adverse events in any arm of the trial. And then they are unblinded to determine if the event is a reaction to the treatment. So basically they get to determine if their pet therapy caused a severe adverse event. Can anyone say "Bias"?

In contrast, there were significant associations between increased reporting of NSAEs and several baseline variables: the numbers of both physical symptoms in general and symptoms of CFS, higher BMI, worse physical function, avoidance due to embarrassment, more fatigue, and HADS depression (table 3). The mean (standard deviation) BMI was 25.5 (4.97) for all 640 participants. Some 123 (19%) participants were morbidly obese (BMI ≥ 30).Significant associations were also found between reporting more NSAEs and having any psychiatric disorder, particularly depressive disorder, dysthymia, and major depressive disorder (table 4).

This ties into the statement at the beginning of the paper, that women and neurotics report more adverse events than manly sane types. Basically, if you report adverse effects, they're implying it's because you're more psychosomatic, female, fat, shy, neurotic, and/or depressed.

Also they've made a clear error in labeling obese patients: a BMI of greater than 30 represents mere obesity, not "morbid obesity". Morbid obesity requires a BMI of at least 35 AND obesity-caused health problems. If health problems aren't a result of the obesity (there's no indication here that they are), then a BMI of at least 40 is required for the label of "morbidly obese".

The substantial variation in the frequency of the reporting of NSAEs between centres is our most unexpected finding, although variation between centres is not uncommon in multi-centre trials [32], and this did not influence treatment response [17].

Basically different clinics reported vastly different amounts of non-serious adverse events per patient. If I'm reading the table right, Kings, Oxford, and Bart's reported them at about half the rate as Edinburgh, Royal Free, and Bristol. Aren't Kings, Oxford, and Bart's the more hardcore centers, with heavy involvement by the PACE authors?

Higher symptom counts are associated with somatoform disorders in secondary care [33], and may reflect a general tendency to report symptoms, which is associated with, but also independent of, mood disorders [34].

Ah, they finally come out and say it in the Discussion: having too many symptoms means you're psychosomatic. Nice theory, but do they have any proof? Nope, not a single shred of evidence supporting it.

Our finding that a diagnosis of a depressive disorder at baseline predicted increased reporting of NSAEs is consistent with previous studies that found negative affect to be associated with NSAEs specifically [1,3], and somatic symptoms in general [6-10, 35].

This part is complete trash, resulting from their insistence in using questionnaires which are grossly inappropriate for patients with physical disability. Apparently not being capable of doing things we used to do, even if we want to do them, means we're depressed. Whoops! Or it just means they're a bunch of idiots. I favor the "idiot" theory - it's much better supported by the available data.

The strengths of this paper are that it used data from a large trial from multiple centres. The assessment of NSAEs on three occasions improved sensitivity.

Indeed, the size is the only strength of the study - but that pretty much disappears when you study fatigue patients instead of ME patients, in addition to all of the other problems. I guess 3 NSAE assessments are an improvement over 0, but it's still pretty damned pathetic.

The limitations include the difference in frequency of NSAE reporting between centres, implying variation in ascertainment, although controlling for centre did not significantly affect our main findings. We only measured deterioration using self-ratings, rather than objective measures.

Well, at least they admit that the lack of objective outcomes is a weakness. Too bad they never consider it to be big enough of a weakness to rectify it with objective measurements. And frankly, if they did, they'd just take the Nijmegen model and explain that lack of objective improvement simply proves that objective improvement is irrelevant, since the subjective measurements say they must be cured.

...

This is the bit where they completely fail to discuss the Serious Adverse Events which they decided, when unblinded, are not reactions to the therapy. They talk about Non-serious Adverse Events at great lengths, give lip service to Serious Adverse Reactions, and do not mention how GET had twice as many Serious Adverse Events as the "controls". Naturally they do not explain how that difference disappeared when the researchers were unblinding to the treatment and realized it was their money-making therapy involved. Oops.

 

[Valentijn]

A bit more about "Serious Adverse Events" versus "Serious Adverse Reactions":

The trial measures of safety included systematic assessments of adverse events (AE), which occur uncommonly in trials of behavioural interventions [18]. We have already reported that there were few serious adverse events (SAEs) and even fewer serious adverse reactions (SARs), the numbers of which did not differ significantly across treatment arms [17].

I think the 2nd sentence was deliberately written to imply that there was no significant difference between SAEs or SARs per treatment. But I'm doubting that is accurate regarding the SAEs.

From the initial PACE trial, there were 17 SAEs among 13 of the 161 GET patients (some of the 13 had multiple SAEs). This compares to 7 SAEs among 7 of the 160 SMC patients (each of the 7 had 1 SAE). They don't examine that data too closely, but I can't imagine that having 243% of the SAE rate (2.4 times as many) wouldn't be statistically significant, especially in such a big trial.

In the Deterioration paper, they completely omit the total number of SAEs per group, but only report the number of patients per group with SAEs. They show the number of participants who had SAEs (13 GET, 7 SMC), and say it isn't statistically significant, with a p-value of 0.15. This seems a little fishy even with those numbers ... any stasticians who can comment?

They are also being quite dishonest in mentioning "Serious Adverse Events" in the paper, but then displaying the number of participants with such events, rather than the number of events. Even the table which shows the data for participants with SAEs (table 5) does not specify that they're showing the number of participants with SAEs, rather than the number of SAEs. In fact, the label is simply "Serious Adverse Events", which I would think is major error in their paper.

I'm also rather disappointed in the lack of detail regarding SAEs and SARs. Non-serious Adverse Events are broken down by category, but there is 0 data about the serious events and reactions.

 

[alex3619]

Crashes with ME are often temporary, though they don't have to be. For some of us that is a few days to a week or two. This will downplay the impact and in most cases they probably will fail to detect it if measured at two time points.

Again the PACE papers fail to come to grips with the exercise physiology. I would like to know how their patients fair now using a 2 day CPET, and its a shame we were not aware of CPET much earlier. I think CPET results will probably blow their research into the deep cold of space. It would be nice to see.

 

[biophile]

@Valentijn. Yes, 7 months is a long time between assessments. I struggle to remember how many non-serious adverse events have occurred in the last 7 months or much detail about them, just that some have occurred.

Re "independent assessors of the trial safety data", from the Lancet paper:
Hiroko Akagi, Alastair Miller, and Gavin Spickett.

Good point about the questionable definition of morbid obesity used.

"Basically, if you report adverse effects, they're implying it's because you're more psychosomatic, female, fat, shy, neurotic, and/or depressed [...] having too many symptoms means you're psychosomatic [...] [diagnosis of depression] resulting from their insistence in using questionnaires which are grossly inappropriate for patients with physical disability".

Indeed. It doesn't seem to occur to them at all that having more symptoms could alternatively reflect a more severe illness. All the stuff about somatization and depression is a tad circular. As you said, "not being capable of doing things we used to do, even if we want to do them, means we're depressed" (or at least counts towards it).

Re SAE vs SARs again. I haven't looked at the numbers in closer detail, but I remember last year when they had to comment on the PACE Trial during the NHS online clinic week last year when the experts got too many questions. They tried to claim that were no significant differences in "any" of the safety measures across the four trial arms (except for the measure of satisfaction in the SMC-alone group), which presumably also includes "serious adverse events" (SAEs) since they listed it in the same paragraph among the other safety measures.

However, this contradicts their 2011 Lancet paper which states that "There were more serious adverse events in the GET group than there were in the SMC group (p=0·0433)." An effect size for this statistically significant difference is not given, but when looking at Table 4, it appears that SAEs were roughly 2.4 times more common (as you said) for +GET, a difference which just happens to disappear when the assessors were unblinded.

I think someone mentioned this potentially relevant systematic review paper on another thread:
http://www.bmj.com/content/344/bmj.e1119

On average, non-blinded assessors of subjective binary outcomes generated substantially biased effect estimates in randomised clinical trials, exaggerating odds ratios by 36%. This bias was compatible with a high rate of agreement between blinded and non-blinded outcome assessors and driven by the misclassification of few patients.