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Rethinking the treatment of chronic fatigue syndrome—A reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT

Authors:

Abstract

BACKGROUND: The PACE trial was a well-powered randomised trial designed to examine the efficacy of graded exercise therapy (GET) and cognitive behavioural therapy (CBT) for chronic fatigue syndrome. Reports concluded that both treatments were moderately effective, each leading to recovery in over a fifth of patients. However, the reported analyses did not consistently follow the procedures set out in the published protocol, and it is unclear whether the conclusions are fully justified by the evidence. METHODS: Here, we present results based on the original protocol-specified procedures. Data from a recent Freedom of Information request enabled us to closely approximate these procedures. We also evaluate the conclusions from the trial as a whole. RESULTS: On the original protocol-specified primary outcome measure - overall improvement rates - there was a significant effect of treatment group. However, the groups receiving CBT or GET did not significantly outperform the Control group after correcting for the number of comparisons specified in the trial protocol. Also, rates of recovery were consistently low and not significantly different across treatment groups. Finally, on secondary measures, significant effects were almost entirely confined to self-report measures. These effects did not endure beyond two years. CONCLUSIONS: These findings raise serious concerns about the robustness of the claims made about the efficacy of CBT and GET. The modest treatment effects obtained on self-report measures in the PACE trial do not exceed what could be reasonably accounted for by participant reporting biases.
R E S E A R C H A R T I C L E Open Access
Rethinking the treatment of chronic fatigue
syndromea reanalysis and evaluation of
findings from a recent major trial of graded
exercise and CBT
Carolyn E. Wilshire
1*
, Tom Kindlon
2
, Robert Courtney
3
, Alem Matthees
4
, David Tuller
5
, Keith Geraghty
6
and Bruce Levin
7
Abstract
Background: The PACE trial was a well-powered randomised trial designed to examine the efficacy of graded
exercise therapy (GET) and cognitive behavioural therapy (CBT) for chronic fatigue syndrome. Reports concluded
that both treatments were moderately effective, each leading to recovery in over a fifth of patients. However, the
reported analyses did not consistently follow the procedures set out in the published protocol, and it is unclear
whether the conclusions are fully justified by the evidence.
Methods: Here, we present results based on the original protocol-specified procedures. Data from a recent Freedom
of Information request enabled us to closely approximate these procedures. We also evaluate the conclusions from the
trial as a whole.
Results: On the original protocol-specified primary outcome measure - overall improvement rates - there was a
significant effect of treatment group. However, the groups receiving CBT or GET did not significantly outperform the
Control group after correcting for the number of comparisons specified in the trial protocol. Also, rates of recovery were
consistently low and not significantly different across treatment groups. Finally, on secondary measures, significant effects
were almost entirely confined to self-report measures. These effects did not endure beyond two years.
Conclusions: These findings raise serious concerns about the robustness of the claims made about the efficacy of CBT
and GET. The modest treatment effects obtained on self-report measures in the PACE trial do not exceed what could be
reasonably accounted for by participant reporting biases.
Keywords: Chronic fatigue syndrome, Myalgic encephalomyelitis, Graded exercise therapy, Cognitive behavioral therapy
Background
For some time now, the officially recommended treatments
for chronic fatigue syndrome (CFS) in many countries have
been graded exercise therapy (GET) and cognitive behav-
ioural therapy (CBT). In an effort to provide high quality
evidence of the efficacy of these treatments, White and
colleagues undertook a large randomised trial, informally
referred to as the PACE trial [1]. Reports from the PACE
trial concluded that GET and CBT were moderately
effective treatments for CFS, both leading to recovery in
over a fifth of patients [27]. The trialssizeanditspromo-
tion as a success have made it enormously influential in the
attempt to treat CFS [8].
However, there are some significant concerns with the
published reports of the trial. First, the outcomes and
analyses presented in these reports did not always follow
the procedures set out in the original published protocol
[1]. Since the purpose of a trial protocol is to prevent ad
hoc modifications that may unduly favour the study
hypotheses, it is important to carefully scrutinise the
justification for these changes and how they may have
influenced outcomes. Also, it is unclear whether some of
* Correspondence: Carolyn.Wilshire@vuw.ac.nz
1
School of Psychology, Victoria University of Wellington, New Zealand, P.O.
Box 600, Wellington, New Zealand
Full list of author information is available at the end of the article
© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Wilshire et al. BMC Psychology (2018) 6:6
https://doi.org/10.1186/s40359-018-0218-3
the trials conclusions about treatment efficacy were fully
justified by the evidence. Here, we present several new
analyses of the trial data, using methods that align with
those specified in the original trial protocol, and drawing
on data recently made available as part of a Freedom of
information application ([9]). This dataset, henceforth
referred to as the FOIA dataset, is available to the public
(see Declarations section for instructions on how to
download the dataset). We also explore several other
aspects of the findings not considered in the published
reports, and evaluate the conclusions from the trial as a
whole.
Summary of the PACE trial
PACE was a large randomised trial whose primary aim
was to assess the effectiveness of GET and CBT as treat-
ments for CFS (early publications refer to it as a rando-
mised controlled trial, but randomised trialis more
appropriate, given that several nuisance variables were
not fully controlled across trial arms, e.g., contact hours).
Participants were 641 adults with mild-to-moderate CFS
defined by the Oxford criteria [10]: the principal symp-
tom must be fatigue, which must have had a definite
onset, resulted in significant disability, and have
persisted for at least six months. Participants also had to
score 65 or less on the Short-Form Health Survey
Physical Function subscale [11]. Also, they had to report
experiencing at least six of the 11 fatigue items on the
Chalder Fatigue Questionnaire (CFQ [12]), as more
thanor much more thanthan prior to illness.
Participants were randomised into four groups. All were
offered at least three medical consultations. The first
group, which we will call Control, received no further
treatment (the trial publications use the term Specialised
Medical Care). The other groups received up to 15 ther-
apy sessions over 36 weeks. One group received CBT, one
GET, and the fourth group received a novel treatment,
Adaptive Pacing Therapy. Both the CBT and the GET
interventions were built upon a behavioural/decondition-
ing model of CFS. This model proposes that there is no
major ongoing disease process underlying CFS - only
deconditioning due to recent inactivity, and its various
consequences. When patients attempt to increase their
activity, they experience normal fatigue, stiffness and other
symptoms, which they misinterpret as signs of continuing
disease. The patients then become more focused on their
symptoms, and fearful of further activity, creating a self-
perpetuating cycle [2]. The GET programme was designed
to help CFS patients overcome this purported fear of exer-
cise and intense symptom-focusing through graded expos-
ure to exercise, and thereby also reverse any
deconditioning that had occurred. Participants were asked
to choose an aerobic activity they enjoyed, and to grad-
ually increase the duration and intensity of that activity
under the supervision of a therapist. The CBT programme
had similar aims, but addressed the fear of activity, mal-
adaptive illness beliefs and symptom focusing using a
combination of CBT and practical activities ([2], p. 825).
Participants were encouraged to view their symptoms as
arising from anxiety, intense symptom focusing and/or
deconditioning. The sessions addressed fears about exer-
cise and other unhelpful cognitionsthat may perpetuate
symptoms, and encouraged participants to try gradually
increasing their activity ([2], p. 825).
Adaptive Pacing Therapy, in which patients were
advised not to exceed a certain level of activity, was cre-
ated specifically for the trial. Results for this trial arm
did not differ significantly from those for the Control
arm for any of the outcomes considered in this article.
Consequently, we will not discuss them further here.
Primary outcomes
The primary outcome for the trial, as specified in the
trial protocol published in 2007, was the percentage of
patients who fulfilled the specified criteria for overall
improvement 52 weeks after randomisation [1]. Two
measures contributed to the definition of improvement:
self-rated fatigue, measured using the Chalder Fatigue
Questionnaire [12], and self-rated disability, measured
using the SF-36 Physical Function subscale [11]. The
minimum levels of improvement required on each of
these two measures are given in Table 1(Definition A).
However, in May 2010, several months after data collec-
tion was complete, this primary outcome measure was
replaced with two continuous measures: fatigue and
physical function ratings on the two scales described
above (see [13,14] for details). According to the
researchers, the changes were made before any examin-
ation of outcome data was started...([13], p. 25).
In 2011, the first major publication from the trial
reported results based on this new primary outcome
[2]. It was found that, following treatment, scores on
both these continuous measures improved in all
groups, but significantly more so in the CBT and
GET groups than in the other groups. In the 2011
publication, rates of overall improvement were also
reported; however, these were not based on the
protocol-specified definition, but rather on a very dif-
ferent, and much more generous, one: Definition B in
Table 1.Bythisnewdefinition,59%ofCBTpartici-
pants and 61% of GET participants were classed as
having improved overall [2]. However, 45% of Con-
trol participants did so too. Results for the original
protocol-specified definition of improvement - Defin-
ition A in Table 1do not appear in any peer
reviewed publications from the trial (which number
in the double digits [15]).
Wilshire et al. BMC Psychology (2018) 6:6 Page 2 of 12
Rates of recovery
An important secondary outcome specified in the trial
protocol was the proportion of patients who met the
specified definition of recovery at the end of the trial [1].
The definition of recovery presented there considered
each participants scores on two key self-rated measures
(fatigue, physical function), one further measure of overall
self-rated improvement and finally, whether the partici-
pant still met various CFS case definitions. The complete
definition of recovery is given in Table 1(Definition A).
However, results for this outcome never appeared in
published reports. Instead, a 2013 paper reported recovery
rates based on a much more generous definition of recov-
ery (Definition B in Table 1)[4]. According to these new
criteria, 22% of patients in each of the CBT and GET
groups qualified as recovered, but only 7% in the Control
group. The difference in recovery rates between the CBT/
GET groups and the Control group was statistically signifi-
cant. The PACE investigators have not specified when the
decision to change the definition of recovery was made,
except to say it was before the analysis occurred[16];
the change does not appear in any documentation prior to
the final publication, and there is no published evidence
that it was approved by the trial steering committee.
Other outcome measures
A number of other secondary outcome measures were
collected at 52 weeks, including several additional
subjective outcomes, and also four objectively scored
measures, which are described further below. During
the course of the trial, data for a range of adverse
events and outcomes were also collected; these are
also described briefly below.
The four objectively scored measures examined at
52 weeks were: 1) distance walked in six minutes; 2)
fitness (VO
2
max, estimated using the step-test method);
3) days lost from work during the six-month period
following the primary endpoint; and 4) the percentage of
participants receiving illness/disability benefit during
that same period. In the 2011 primary trial report, only
one of these outcomes was reported: walking speed [2].
Here, 69% of the GET group completed the test, and
walked approximately 1012% farther in six minutes
than the 74% of Controls who completed the test. This
small difference was statistically significant (based on an
available case analysis), but given the high and uneven
drop-out rate for these outcome measures, this result
should be treated with caution. The CBT group did not
walk significantly farther than Controls. Results for the
other objective outcomes were not reported until some
years later, and then only in summary form [3,6].
H.owever, none appear to be associated with significant
treatment effects. For the fitness measure, a simple one-
way analysis of variance performed on the summary data
extracted from ([6], Figure 2) failed to reveal a significant
effect of treatment group, F(3,425) = 0.368, ns. For the
employment loss measure, a similar analysis of the sum-
mary data in ([3], Table 2) also failed to reveal a significant
treatment effect, F(3, 636) = 0.23, ns.Finally,forillness/
disability benefit data, a binary logistic regression
performed using the summary data in ([3], Table 3) did
not reveal any significant treatment effect, χ
2
(3) = 0.00, ns.
The adverse events measures collected during the trial
included: serious adverse events (death, hospitalisation,
etc.); serious deterioration (a broader category that
included a serious adverse event, sustained decrease in
Table 1 Definitions of improvement and recovery specified in the trial protocol [1], and those used in the final trial reports [2,4].
Improvement was the primary outcome measure specified in the protocol. Recovery was a secondary measure
Definition A: Specified in trial protocol Definition B: Used in published reports
Overall
Improvement
Minimum score of 75 on the 100-point SF-36 physical
function scale or a score increase of 50% or more.
At least an 8 point increase in the 100-point SF-36 physical
function scale.
Of the 11 fatigue items on the Chalder Fatigue Questionnaire
(CFQ), three or fewer rated as worse/much worse than prior to
illness OR the total items rated worse/much worse dropped by
at least a 50%.
At least a 2 point decrease on the 33-point CFQ (Likert scoring
method).
Recovery Minimum score of 85 on the 100-point SF-36 physical function
scale.
Minimum score of 60 on the 100-point SF-36 physical function
scale.
Of the 11 items on the CFQ, three or fewer rated as worse/much
worse than prior to illness.
Maximum score of 18 on the 33-point CFQ.
Overall health self-rated as very much betteron the Clinical Global
Impression scale [50].
Overall health self-rated as much betteror very much better
on the Clinical Global Impression scale.
The final casenesscriterion was met if the patient no longer
fulfilled: The Oxford case definition of CFS; the CDC criteria [51];
AND the London ME criteria [52]. (As determined by a non-blinded
assessor).
The revised casenesscriterion was met if ANY of the following
applied: a) the patient did not meet the standard Oxford case
definition; OR b) on the CFQ, they rated less than six of the 11
fatigue items as being worse than prior to illness; OR c) their
SF-36 Physical Function score was greater than 65.
CFQ Chalder Fatigue Questionnaire
Wilshire et al. BMC Psychology (2018) 6:6 Page 3 of 12
self-reported physical function or overall health, or with-
drawal due to worsening); and non-serious adverse
events. Serious adverse events were significantly more
prevalent in the GET group (8%) than in the Control
group (4%); there were no other statistically significant
group differences.
Long-term follow-up
A mail survey was conducted at least two years after
randomisation (median 31 months [7]:). Survey response
rates were 72%, 74% and 79% for the Control, CBT and
GET groups respectively. Participants were again asked
to complete the trials primary fatigue and physical
rating scales, and several other questionnaires. A 2015
paper reported the results for the fatigue and physical
function measures, again treating them as separate, con-
tinuous variables [7]. Analyses of these measures, based
on an available case approach, failed to yield any signifi-
cant effects of treatment group. However, the investiga-
tors did not view this negative result as a cause for
concern at all. They argued that many patients in the
Control and Adaptive therapy trial arms had received
some CBT or GET after the conclusion of the main trial,
and this could explain why they had since improved to
the level of the other patients.
Current analyses
The primary objective of our reanalyses was to exam-
ine how the trial outcomes would have looked if the
investigators had adhered to their published protocol.
Specifically, we were interested in analysing results
for the primary outcome set out in that document:
overall improvement rates. We also calculated recov-
ery rates based on the definition outlined in the
protocol. Results from this latter analysis have been
published elsewhere [17,18],butherewepresent
more complete details of our method and findings.
Finally, we explored the published data on long-term
outcomes to examine whether they had been contam-
inated by patientspost-trial therapy experiences, as
the PACE researchers hypothesised.
Methods
Using the FOIA dataset, we first calculated rates of
improvement at the primary 52-week endpoint according
to the definition specified in the trial protocol (Definition A
in Table 1). We used an intent-to-treat approach, again as
specified in the protocol: if the 52-week score was missing,
that case was counted as a non-improver (there were no
missing scores at baseline; missing scores had been replaced
with scores at screening as described in [14]). However, for
comparison, we also repeated the analysis based on an
available case sample: participants with missing scores at
52 weeks were simply excluded from the dataset.
Based on the methods stipulated in the published
protocol, we performed a logistic regression analysis on
the binary outcome data from all four treatment arms.
Where appropriate, we also performed pairwise compar-
isons between each of the two key treatment groups
(CBT and GET), and the Control group, correcting for
the total number of planned comparisons. The trial
protocol lists six planned comparisons [1]. The statistical
analysis plan, published some years later, lists only five
[14]. Here, we report outcomes based on both scenarios.
No method of correction was specified in the trial proto-
col, but in the statistical analysis plan, the Bonferroni
method was stipulated [14], so this was the method we
applied. All omnibus analyses (that is, all analyses exam-
ining the overall effect of treatment group on outcomes)
included the adaptive pacing therapy group, because it
forms part of the trial design. However, specific results
for this group are not detailed here.
The protocol specified that various stratification
variables would also be included in the primary out-
come analysis (e.g., treatment centre, therapist, pres-
ence/absence of co-morbid depression). These
variables were not available in the FOIA dataset, so
we were unable to include them. Nonetheless, they
were approximately evenly distributed across groups,
and therefore their inclusion would be unlikely to
change outcomes substantially [2]. Also, our team has
previously shown that for one of the published logis-
tic regression analyses (that for recovery rates based
on Definition B in Table 1), replicating the analysis
Table 2 Outcomes at 52 weeks and long-term follow-up, excluding patients who completed any additional sessions of GET or CBT.
Confidence intervals were only available for the follow-up phase
Measure Group N 52 weeks (mean scores for subgroup) Long-term follow-up (means, 95%CIs)
SF-36 Physical Function Scale Control 49 56.8 62.6 (54.6, 70.6)
CBT 88 61.5 64.2 (58.6, 69.8)
GET 95 62.8 62.5 (57.1, 67.9)
Chalder Fatigue Scale
(Likertscoring method)
Control 49 22.6 18.7 (16.2, 21.2)
CBT 88 20 17.9 (16.1, 19.7)
GET 95 19.7 18.7 (17.1, 20.3)
CIs confidence intervals
Wilshire et al. BMC Psychology (2018) 6:6 Page 4 of 12
without the stratification variables had a negligible
effect on the outcome of the analysis [18].
We also calculated recovery rates based on the defin-
ition specified in the trial protocol (Definition A in Table
1). Results from this analysis have been published else-
where [17], but here we present more complete details
of our method and findings. In the published protocol, it
was not explicitly specified that an intent-to-treat ap-
proach would be applied, so we present results based on
both an intent-to-treat approach (according to the defin-
ition above) and an available case approach (again, ac-
cording to the definition above). Our definition of
recovery closely approximated Definition A from the
trial protocol, but may have been marginally more gen-
erous: in determining whether the final CFS caseness
criterion was met, we considered only the Oxford case
definition (the other case definitions were not available
in the FOIA dataset). However, it is unlikely that this
change impacted substantially on recovery rates, and if it
had, its likely effect would have been to further reduce
recovery rates for the CBT and GET groups relative to
the other two groups (the maximum effect it could pos-
sibly have had was to exclude a further three individuals
each from the CBT and GET recoveredgroups, and
none from the Control group. This is the number of in-
dividuals that were excluded from the recoveredgroup
when these two alternative caseness criteria were
added to the recovery definition used in [4]). We
then performed a logistic regression analysis incorpor-
ating the binary recovery data from all four treatment
arms. Where appropriate, we performed planned pair-
wise comparisons according to the procedures set out
above for the primary outcome analysis.
Finally, to explore the PACE investigatorshypothesis
that long-term treatment effects may have been
obscured by patientspost-trial treatment choices, we
isolated the long-term self-rated fatigue and physical
function scores for those patients who did not receive
any post-trial CBT or GET. The relevant individual
patient data are not available in the FOIA dataset, so a
systematic reanalysis could not be performed. However,
since the relevant summary data are reported in [7], see
Supplementary materials, Table C], we were able to per-
form a simple one-way analysis of variance examining
the effect of original treatment allocation on long-term
outcomes in this subgroup.
Results
Figure 1shows intent-to-treat means and confidence
intervals for the two self-rated measures that contrib-
uted to the definition of improvement, alongside esti-
mates of performance in healthy controls. A number of
the Chalder Fatigue Questionnaire scores needed to cal-
culate these rates of improvement were missing from
the FOIA dataset; however, in every such case, the out-
come could be inferred from other data available in the
FOIA set. Based on the protocol-specified definition of
improvement, 20% of CBT patients and 21% of GET
patients improved, and 10% of the Control patients.
These percentages accord with those calculated by the
investigators and posted to the Primary Investigators
institutional website shortly after the researchers were
directed to release the data under FOI legislation ([19];
these results were never formally published and the stat-
istical analyses specified in the original trial protocol
were never performed).
There was a statistically significant effect of treatment
on improvement rates, χ
2
(3) = 14.24, p= .003. The p-
value associated with the contrast between CBT and
Control was p= .015 and that for the contrast between
Fig. 1 Intent-to-treat means for fatigue and physical function ratings, the two measures that contributed to the criterion for improvement specified in
the published protocol (Definition A in Table 1). Estimates of healthy performance for the fatigue and physical function measures are based on
previously published samples that further excluded the elderly (over 60), and those with a significant medical condition (95% CI bands = upper and
lower bounds of 95% confidence interval). The relevant normative data for the Chalder Fatigue Questionnaire were obtained from [48], and those for
the SF-36 physical function scale were obtained from [49]. In the case of the SF-36 scale, the healthy sample was highly negatively skewed, so medians
are reported. The median score for this sample was 100 (95% confidence intervals: 100,100)
Wilshire et al. BMC Psychology (2018) 6:6 Page 5 of 12
GET and Control was p= .010. If we take into account
all six planned comparisons listed in the protocol, the
Bonferroni-adjusted pthreshold for both pairwise com-
parisons is 0.008. Neither comparison reaches this
threshold. The situation is not much improved if we
consider only the five planned comparisons listed in the
subsequent statistical analysis plan ([14]); the pthresh-
old is 0.010. The comparison between GET and Control
just reaches this threshold, but the comparison between
CBT and Control does not.
The percentage of participants with missing outcomes
at 52 weeks was small (5.2% across all trial arms). Never-
theless, to explore the impact of counting drop-outs as
non-improvers, we repeated our calculations based on an
available case sample. Using this definition, 11% of Con-
trol participants improved, compared to 22% and 21% of
CBT and GET participants respectively. There was again a
statistically significant overall effect of treatment group on
improvement rates, χ
2
(3) = 15.02, p=.002.Thep-value as-
sociated with the contrast between CBT and Control was
p= .010 and that for the contrast between GET and Con-
trol was p= .011. However, once more, neither of these
outcomes survives Bonferroni correction based on the
number of planned comparisons specified in the trial
protocol (corrected threshold pvalue = .008). Even using
the looser criterion based on the statistical analysis plan
(p= .010), the comparison between CBT and Control only
just reaches the threshold of 0.01 and the comparison
between GETand Control does not.
In addition to overall improvement rates, the trial
protocol identifies rates of improvement on each of the
two major contributing criteria self-rated fatigue and
physical function - as primary outcomes in their own
right. So we analysed these outcomes in the same man-
ner as above, using an intent-to-treat approach as speci-
fied in the protocol. Rates of protocol-specified
improvement on the SF36 physical function criterion
were 44% for the Control group, 48% for the CBT group,
and 61% for the GET group. The overall effect of treat-
ment arm was significant, χ
2
(3) = 16.31, p= .001. The p-
value associated with the contrast between CBT and
Control was p= .34 and that for the contrast between
GET and Control was p= .002. The comparison between
GET and Control survives correction for multiple com-
parisons (irrespective of whether one assumes five or six
planned comparisons) but that between CBT and Con-
trol does not.
Rates of protocol-specified improvement on the CFQ cri-
terion were 13% for the Control group, 26% for the CBT
group, and 24% for the GET group. There was also a statis-
tically significant effect of treatment on rates of improve-
ment on the fatigue criterion, χ
2
(3) = 13.19, p= .004. The p-
value associated with the contrast between CBT and Con-
trol was p= .004 and that for the contrast between GET
and Control was p= .015. The former remains after correct-
ing for multiple comparisons, but the latter does not.
Recovery rates
Using the protocol-specified definition of recovery, and ap-
plying an intention-to-treat approach, the rates of recovery
were 7%, 4% and 3% for the CBT, GET and Control groups
respectively. Applying an available-case approach, these
rates were 8%, 5%, and 3% respectively. In neither instance
was there a statistically significant effect of treatment on re-
covery rates (pvalues were 0.14 and 0.10, respectively, for
the intent-to-treat and available case approaches).
Long-term outcomes
Out of those who responded to the long-term follow-up,
43% of the Control participants had received no further
CBT or GET after the completion of the trial. This was
also the case for 74% and 75% of the respondents from
the CBT and GET arms respectively. Considered together,
this subset of participants was perhaps slightly less
severely affected than the remaining patients: they scored
slightly better on the primary physical function and fatigue
scales at 52 weeks than those who opted for further treat-
ment (physical function: 61.3 vs. 48.1; fatigue: 23.9 vs.
25.9). However, at 52 weeks, the pattern of scores across
treatment arms was the same as for the sample as a whole:
the CBT and GET participants in our subset rated their fa-
tigue as slightly lower and their physical function slightly
higher at 52 weeks than the Control participants. In this
respect, our subsample may be considered reasonably rep-
resentative of the sample as a whole.
Table 2provides arithmetic means for the two major
self-report outcome measures for this subset of patients
(i.e., those who received no further treatment). The pat-
tern of results presented here mirrors that obtained for
the entire cohort: the small group differences apparent
on these measures at 52 weeks are no longer evident at
long-term follow-up. A one-way analysis of variance
revealed that there were no statistically reliable effects of
treatment group on either outcome measure (Physical
function: F(3,291) = 0.70, ns; Fatigue F(3,291) = 0.17, ns).
If we repeat the analyses, adding in those cases who
received some additional therapy sessions, but less than
the minimum 10 considered by the investigators to be
an adequatedose ([7], p.1071), the outcome does not
change (Physical function: F(3,384) = 1.85, ns; Fatigue
F(3,384) = 0.86, ns). Consequently, the disappearance of
group differences at long-term follow-up cannot be
attributed to the effects of additional post-trial therapy.
Discussion
Discussion of new results
Our reanalyses of the trial data based on the published
protocol generated some troubling findings. First, scores
Wilshire et al. BMC Psychology (2018) 6:6 Page 6 of 12
on the protocol-specified primary outcome measure
improvement in self-reported fatigue and physical
function were numerically higher for the CBT and the
GET groups than for the Control group. However, these
differences did not pass the threshold for statistical sig-
nificance after correcting for the number of planned
comparisons specified in the trial protocol. Using a more
lenient correction (assuming only five planned compari-
sons), outcomes are only marginally more positive: the
comparison between GET and Control just reaches this
threshold, but the comparison between CBT and Control
does not. Of course, our analyses did not incorporate a
number of important stratification variables that were
unavailable in the FOIA dataset. However, it appears
unlikely that their inclusion would substantially alter the
result, and our analyses remain the closest approxima-
tion to the originally specified one that has ever been
published. Our findings suggest that, had the investigators
stuck to their original primary outcome measure, the out-
comes would have appeared much less impressive.
Improvement rates for self-rated fatigue and physical
function considered individually did yield some statisti-
cally significant findings, which suggests that the inter-
ventions were somewhat specific in the way they altered
patientsillness perceptions. Self-rated physical function
scores showed greater improvement in the GET group
than in the Control group but not self-rated fatigue
scores which suggests GET had a modest effect on
patientsperceptions of their physical function, but did
not do much to alter symptom perceptions. Conversely,
self-rated fatigue showed greater improvement in the
CBT group than in Controls but not physical function
which suggests CBT elicits modest reductions in
symptom-focusing, but does not do much to improve
patientsconfidence in their physical capacities.
Second, when recovery rates were calculated using the
definition specified in the published protocol, these were
extremely low across the board, and not significantly
greater in the CBT or GET groups than in the Control
group. Neither an intent-to-treat nor an available case
analysis yielded a significant benefit for these therapies
over conventional medical care. Again, we were unable
to incorporate a number of stratification variables into
this analysis, but it is unlikely that the result would be
different had we done so.
With respect to long-term outcomes, the investigators
original analysis did not reveal any significant effects of
treatment allocation on self-reported fatigue and physical
function at long-term follow-up [7]. They suggested this
null effect may have been due to the confounding effects
of post-trial therapy. Our informal re-examination of the
long-term follow-up results provide no support for this
suggestion. We found that even when patients who
received post-trial CBT or GET are excluded, there is still
no evidence of any long-term treatment-related benefits
not even a trend in the hypothesised direction. Of course,
our analyses were informal. Ideally, we would have repli-
cated the analysis reported in [7] for this patient subset,
which included all the covariates listed in that analysis
([7], p. 1068), such as fatigue and physical function scores
at 52 weeks, time of follow-up, trial centre and disease
caseness. This was not possible on the data available.
However, until better evidence becomes available, there is
no reason to believe that post-trial therapy can offer a
viable explanation for the absence of treatment effects at
long-term follow-up.
One major problem for the PACE trial is that it was
originally designed around a highly optimistic view of
the therapeutic benefits of CBT and GET. Drawing on
results from previous, smaller trials, the PACE investiga-
tors estimated that CBT would be likely to yield an
improvement rate some six times greater than medical
care alone, and GET would yield a rate five times greater
[20]. These expectations formed the basis of the power
calculations for the trial. But unfortunately, the improve-
ment rates for CBT and GET participants - when com-
pared with Control participants - fell markedly short of
those expectations. So it is perhaps not surprising that
an analysis of the binary improvement data alone was in-
sufficient to detect any statistically reliable effects. In this
context, it would have been perfectly acceptable first to
report the protocol-specified primary outcome analysis,
and then to explore the data using methods that are
more sensitive to smaller effects for example, analysis
of the individual, continuous outcome measures. How-
ever, instead, the researchers chose to omit the former
analysis altogether, and report only the latter. They then
reported improvement rates based on an entirely new,
and much more generous, definition of improvement. In
sum, the analyses that were the least complimentary to
CBT and GET never appeared in the published reports;
the analyses that showed these interventions in a more
favourable light were the only ones to be published.
As we have already pointed out, the timing of the
change to the primary outcome several months after
trial completion - was highly problematic. There was also
insufficient independent justification for making the
change. For reasons that are never made clear, investiga-
tors had suddenly taken the view that “…a composite
measure would be hard to interpret, and would not allow
us to answer properly our primary questions of efficacy
(i.e. comparing treatment effectiveness at reducing fatigue
and disability).([13], p. 25). Certainly, the separate ana-
lysis of the two continuous measures provides useful add-
itional information, but this does not justify abandoning
the originally planned outcome. Further, the protocol
already included measures of specific improvement rates
in self-rated fatigue and physical function, and it is not
Wilshire et al. BMC Psychology (2018) 6:6 Page 7 of 12
clear why these were abandoned in favour of the new
measure.
Turning now to the recovery rates, the late changes to
the definition of recovery made it much easier for a
patient to qualify as recovered. These changes were quite
substantial. For example, the minimum physical function
score required to qualify as recovered was reduced from
85 to 60, which is close to the mean score for patients
with Class II congestive heart failure (57/100 [21]), and
lower than the score required for trial entry (65/100).
Also, on the fatigue criterion, a patient could now count
as recovereddespite reporting continuing fatigue on as
many as seven out of the 11 fatigue questionnaire items,
a level that substantially overlaps with that required for
trial entry. Again, these changes operated to favour the
study hypotheses. They enabled the researchers to make
the claim that CBT and GET were significantly more
likely to lead to recovery than conventional medical care
(the original recovery definition would have yielded a
null result), and to declare that at least a fifthof partic-
ipants recover with CBT and GET [4,22]. Neither claim
could have been made if the original definition of recov-
ery had been used.
Again, the timing of the change to the recovery defin-
ition over a year after the trial was completed - is
highly problematic. Also, an adequate justification for
the change is yet to be provided. In their 2013 publica-
tion on recovery rates, the researchers argued that the
normal ranges for some key scores were wider than pre-
viously thought, which would justify classing more par-
ticipants as recoveredon these measures [4]. However,
we have recently shown that when the chronically ill and
the very old were excluded from the relevant reference
samples, and where correct statistics were applied to de-
termine appropriate cut-off values, the normal ranges
are, if anything, narrower than previously believed [17].
Consequently, this argument does not stand up to scru-
tiny (see [17] for further details).
Several other arguments have been presented in de-
fence of these changes [23,24]. One was that since there
is no agreed definition of recovery, the new modified
one is just as good as the original (the original definition
simply makes different assumptions[24], p. 289). This
argument fails to explain why the definition was changed
in the first place. If both definitions are indeed equally
good, then the one to be preferred is surely the one that
was specified in advance, before any of the results were
known. Another argument was that the recovery rates
obtained with the modified definition were numerically
similar to those found in some previous trials of CBT for
CFS [23]. However, these other trials used entirely differ-
ent definitions of recovery, so are not relevant here. One
final argument was that the original definition of recov-
ery was simply too stringent to capture clinically
meaningful recovery[23]. However, the only supporting
evidence for this statement comes from the disappoint-
ing recovery rates in the PACE trial itself; no independ-
ent justification is offered. Clearly, a strong concept like
recovery must be operationalised carefully. Physicians
and lay people understand this term to mean a return to
good health [25], and any definition must preserve this
core meaning. If anything, the original protocol-specified
definition was rather generous, and may have identified
some individuals that had not recovered in the plain
English sense of the word. For example, on the primary
physical function measure (the SF36), it was possible to
score in the bottom decile for working age individuals
with no long-term illness or disability, and still count as
recovered on that criterion [17]. The definition also did
not require evidence of an ability to return to work or
other premorbid activities, even though these are very
important components of what recovery means to
patients. There was certainly no justification for further
loosening that definition. In sum, none of the trial inves-
tigatorsarguments adequately justified the late changes
to the recovery definition. More detailed discussion of
these issues can be found elsewhere [26].
Turning now to long-term follow-up, the original pub-
lication of the long-term follow-up data reported no sig-
nificant differences amongst treatment groups at this
time point [7]. However, the authors dismissed their
own finding, arguing that many participants received
additional post-trial therapy which might have operated
to obscure group differences. Instead, they based their
main conclusion on comparisons between time points.
For example, the first line of the Discussion reads: The
main finding of this long-term follow-up study of the
PACE trial participants is that the beneficial effects of
the rehabilitative CBT and GET therapies on fatigue and
physical functioning observed at the final 1 year out-
come of the trial were maintained at long-term follow-
up 2·5 years from randomisation.([7] p. 1072, Italics
added). This conclusion is repeated in the Abstract. The
decision to lead with this conclusion again operated to
show the findings in a more positive light than would have
been possible based on their own primary between-groups
analysis. The informal analyses we presented here provide
no support for the investigatorsclaim that post-trial ther-
apy contaminated the long-term outcome data. Of course,
our analyses did not include important potentially con-
founding variables that might differ amongst trial arms,
and such a comprehensive analysis might possibly produce
a different result. However, until there is positive evidence
to suggest that this is the case, the conclusion we must
draw is that PACEs treatment effects are not sustained
over the long term, not even on self-report measures. CBT
and GET have no long-term benefits at all. Patients do just
as well with some good basic medical care.
Wilshire et al. BMC Psychology (2018) 6:6 Page 8 of 12
Overall evaluation of the trial
Some notable strengths of the PACE study included the
large sample size (determined a priori using power ana-
lysis [1]), the random allocation of patients to treatment
arms, the use of a well-formulated protocol to minimise
drop-outs, and the reporting of the full CONSORT trial
profile (including detailed information about missing
data). The incorporation of an active comparison group -
Adaptive Pacing Therapy - also provided a useful second-
ary control for factors such as overall therapy time and
patient-therapist alliance. It is worth pointing out that re-
sults for this group were not significantly different from
those for the Control group on any of the measures con-
sidered in this paper. Other strengths were that each ther-
apy group received a substantial dose of therapy, and
standardised manuals ensured comparability of treatments
across centres and therapists. Finally, a wide range of out-
comes was measured, including several objective mea-
sures, as well as various adverse events measures.
However, despite these strengths, the design, analysis
and reporting of the results introduced some significant
biases. We have already discussed some of the biases
that were introduced at the analysis and reporting stage.
Several key results that showed CBT and GET in less
than favourable light were omitted and replaced with
new ones that appeared more favourable to the treat-
ments. These changes were made at a late stage in the
trial, and we have argued here that none had sufficient
independent justification. In reality, the effects of CBT
and GET were very modest - and not statistically reliable
overall if we apply procedures very close to those speci-
fied in the original published protocol.
Another source of bias arose from the trials heavy reli-
ance on self-reports from participants who were aware of
their treatment allocation. Clearly, in a behavioural inter-
vention trial, full blinding is not possible. Nevertheless, it
is the researchersresponsibility to consider the possible
effects of lack of blinding on outcomes, and to ensure
such factors are insufficient to account for any apparent
benefits. A trial that is not blinded, self-reported outcomes
in particular can produce highly inflated estimates of
treatment-related benefits [27,28]. A recent meta-analysis
of clinical trials for a range of disorders found that when
patients were not blinded to their treatment allocation,
their self-reported improvement on the treatment of inter-
est was inflated by 0.56 standard deviations, on average,
when compared to a corresponding blinded phase of the
same trial [29]. In contrast, observer-rated measures of
improvement were not significantly affected by blinding.
Given this discrepancy in the effects of blinding on sub-
jective and objective measures, it appears unlikely that
these effects reflect genuine health benefits. Amore plaus-
ible explanation is that they are expectation-related arte-
facts for example, they reflect the operation of
attentional biases that favour the reporting of events con-
sistent with ones expectations [30], or recall/confirmation
biases that enhance recollection for expectation-
consistent events [31].
The PACE investigators have argued that expectancy
effects alone cannot account for the positive self-reported
improvements, because at the start of treatment, patients
expectations of improvement were not greater in the CBT
and GET groups than in the other groups [2,23]. How-
ever, they fail to point out that CBT and GET participants
were primed during treatment to expect improvement.
The manual given to CBT participants at the start of treat-
ment proclaimed CBT to be a powerful and safe treat-
ment which has been shown to be effective in... CFS/ME
([32], p. 123). The GET participantsmanual described
GET as one of the most effective therapy strategies cur-
rently known([33], p. 28). Both interventions emphasised
that faithful adherence to the programme could lead to a
full recovery. Such messages from an authoritative
source are likely to have substantially raised patients
expectations of improvement. Importantly, no such state-
ments were given to the other treatment groups. When we
add to this the fact that the CBT programme, and to a
lesser extent GET, was designed to reduce symptom
focusing, which may have further influenced self-report
behaviour in the absence of genuine improvement [27,34],
these findings start to look very worrying indeed.
A further cause for concern in the PACE trial was that
the two primary self-report measures appear to behave
in different ways depending upon the intervention. Our
analysis based of the protocol-specified outcomes indi-
cated that GET produces modest enhancements in
patientsperceived physical function, but has little effect
on symptom perception. Conversely, CBT improved
symptom perception specifically, self-rated fatigue
scores but had little effect on perceived physical func-
tion. If these interventions were operating to create a
genuine underlying change in illness status, we would
expect change on one measure to be accompanied by
change on the other.
Given the high risk of participant response bias in this
study, it was therefore crucial to demonstrate
accompanying improvement on more objective measures.
However, only one such measure showed a treatment ef-
fect. On the six-minute walking test, the originally-
reported available case analysis found that GET partici-
pants walked reliably farther than Control participants at
the primary, 52-week endpoint. However, after an entire
year, this group walked an average of just 67 m farther
than baseline, and around 30 m farther than Controls. To
put this in context, a sample of Class II chronic heart fail-
ure patients with similar baseline walking distances
increased their distance by an average of 141 m after only
three weeks of a gentle graded exercise programme [35].
Wilshire et al. BMC Psychology (2018) 6:6 Page 9 of 12
No other objective measures yielded significant
treatment effects. Most notably, treatment did not
affect aerobic fitness, measured using a step test. If
GET had genuinely improved participantsphysical
function and levels of activity, these improvements
should have been clearly evident on fitness measures
taken a full year after trial commencement. Treatment
also did not affect time lost from work [3]. There
was ample opportunity for improvement here: during
the six months preceding the trial, 83% of partici-
pantswereeitherinworkorwouldhaveworkedif
able (based on the number reporting lost work days).
This suggests they could have immediately increased
their hours if their health had permitted. Finally, the
percentage of participants receiving government bene-
fits or income protection actually increased over the
treatment period for all groups [3]. It is concerning that
these negative findings were not even published until
years after the primary results had been reported, so these
inconsistencies are not immediately apparent to the
reader. For example, the crucial fitness results were not
published until four years after the primary outcomes.
The investigators dismissed most of these measures as un-
important or unreliable; they did not consider them valu-
able as a means of estimating the degree of bias inherent
in their self-report outcomes.
The absence of evidence for treatment-related
recovery is an additional, serious concern for the trial.
CBT and GET were not seen as adjunct treatments that
might relieve a little distress. Rather, they were seen as
capable of reversing the very behaviours and cognitions
responsible for CFS. The behavioural-deconditioning
model, on which the treatments were based, assumes
that there is no underlying disease process in CFS,
and that patientsconcerns about exercise are merely
fearful cognitionsthat need addressing ([36], p.
478). Participants in some trial arms were even told
that there is nothing to stop your body from gain-
ing strength and fitness([32], p. 31). If this model
of CFS were correct, and if the treatments were
operating as hypothesised, then some participants that
duly followed the programme should have returned to
the levels of health and physical function, that they
enjoyed prior to illness onset. Therefore, the rates of
recovery in the CBT and GET groups should have
been significantly and reliably higher than in the Con-
trol group, irrespective of the method used to define
recovery. This was not the case.
The failure of CBT and GET to reverseCFS is per-
haps not so surprising when we consider recent exercise
physiology studies. CFS patients have shown various
physical abnormalities when tested 24 h after exertion
(reduced VO
2
max and/or anaerobic thresholds; for a
review, see [37]). These abnormalities are not seen in
sedentary, healthy adults or even in patients with cardio-
vascular disease, and therefore cannot be attributed to
deconditioning alone. Such findings call into question
the core assumption of the behavioural/deconditioning
model that there is no ongoing disease process. If there
is a rational basis for patientsconcerns over exercise,
encouraging them to push through symptoms may be
harmful, and recasting patientsconcerns as dysfunc-
tional may cause additional, psychological harm.
Turning now to safety issues, there were few group dif-
ferences in the incidence of adverse events, and the
researchers concluded that both CBT and GET were safe
for people with CFS. This finding particularly that
relating to GET - contrasts markedly with findings from in-
formal surveys conducted by patient organisations [38,39].
In these surveys, between 33% and 79% of respondents re-
port worsened health as a result of having participated in
some form of graded exercise programme (weighted aver-
age across 11 different surveys: 54% [39]). Of course, in
such surveys, participant self-selection may operate to en-
hance the reporting rates for adverse outcomes. However,
this finding is so consistent, and the number of participants
surveyed is so large (upwards of 10,000 cases), that it can-
notbeentirelydismissed.Onelikelyreasonforthediscrep-
ancy between PACEs findings and those of patient surveys
is the conservative approach used in PACEsGET
programme. Patients were encouraged to increase activity
only if it provoked no more than mild symptoms [40]. Un-
fortunately, compliance with the activity recommendations
was not directly assessed: actigraphy data were collected
only at trial commencement [1] and never reported. This
is a significant omission, since there is evidence that graded
exercise therapies are not always successful in actually in-
creasing CFS patientsactivity levels [41]. Even those
who comply with exercise goals may reduce other ac-
tivities to compensate [42]. The lack of improvement
in fitness levels in PACEs GET group does suggest
that participants may not have substantially increased
their activity levels, even over the course of an entire
year. Also, even though the majority of GET partici-
pants chose walking as their primary activity [2], this
group demonstrated an average increase in walking
speed of only 10% after an entire year (increases of
50% or more have been observed in other patient
populations [35]). Given these features, it is inappro-
priate to generalise the safety findings from PACE to
graded activity programmes more widely, especially as
they are currently implemented in clinical settings.
Conclusion
In conclusion, the various treatment effects reported
in the PACE trial were modest, almost entirely con-
fined to self-report measures, and did not endure be-
yond two years. If one were to ask, Given the
Wilshire et al. BMC Psychology (2018) 6:6 Page 10 of 12
procedures used here, what pattern of results would
we expect if these therapies did not produce genuine
change?the answer would be, Modest, short-lived
changes in self-report behaviour unaccompanied by
objectively measurable changes”—apatternmuch
like the one obtained. Given the size and power of the
PACE trial, it seems unlikely that further research based on
these treatments will yield more favourable results. Indeed,
another large parallel trial that involved home-based ther-
apy, described as PACEssister trial([43]), also yielded null
outcomes at its primary endpoint [44,45]. The time has
come to look elsewhere for effective treatments. Current
major NIH research initiatives include a large intramural
study of post-infectious CFS, which aims to examine the
pathophysiology of this phenotype specifically [46], and a
systematic investigation of inflammatory markers (both per-
ipheral and CNS) in CFS, and how they are influenced by
exertion [47]. Such initiatives have the potential to play a
key role in generating new treatment paradigms.
Abbreviations
CBT: Cognitive behavioural therapy; CDC: US Centers for Disease Control;
CFQ: Chalder Fatigue Questionnaire; CFS: Chronic fatigue syndrome;
CI(s): Confidence interval(s); CNS: Central nervous system;
CONSORT: Consolidated Standards of Reporting Trials; FOI(A): United
Kingdom Freedom of Information (Act); GET: Graded exercise therapy;
ME: Myalgic encephalomyelitis; NIH: US National Institutes of Health; SF-
36: Short-form; VO2max: Maximal oxygen uptake
Acknowledgements
None.
Funding
We would like to thank the UK ME Association for their contribution towards
the article processing fee for the pulication of this open access article. DTs
position at UC Berkeley is part funded by a public crowdfunding campaign
in support of his work on chronic fatigue syndrome. KG receives part
funding from the UK ME Association.
Availability of data and materials
The datasets analysed during the current study are available in the PACE-
FOIR Google Sites repository, at https://sites.google.com/site/pacefoir/pace-
ipd_foia-qmul-2014-f73.xlsx. A readme file is available at https://sites.google.-
com/site/pacefoir/pace-ipd-readme.txt
Authorscontributions
CW wrote the manuscript, and contributed to the statistical analyses, the
review of background literature and the development of key arguments. AM
contributed to statistical analyses, and BL advised on statistical procedures.
TK, AM, RC, and DT contributed to the review of background literature and
to the development of key arguments. TK, BC, AM, DT, KG and BL all
commented on previous versions of the manuscript. All authors read and
approved the final manuscript.
Ethics approval and consent to participate
Not applicable. The research reported in this article utilises data already
available in the public domain.
Consent for publication
Not applicable.
Competing interests
All authors have read the competing interests statement, and declare no
competing interests. TK is a (volunteer) committee member of the Irish ME/
CFS Association.
PublishersNote
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Author details
1
School of Psychology, Victoria University of Wellington, New Zealand, P.O.
Box 600, Wellington, New Zealand.
2
Irish ME/CFS Association, Dublin, Ireland.
3
London, UK.
4
Perth, Australia.
5
School of Public Health, University of
California, Berkeley, California, USA.
6
School of Health Sciences, University of
Manchester, Manchester, UK.
7
Department of Biostatistics, Columbia
University, New York, USA.
Received: 29 May 2017 Accepted: 22 February 2018
References
1. White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R. Protocol for the
PACE trial: a except to say it was before the analysis occurredcognitive
behaviour therapy, and graded exercise as supplements to standardised
specialist medical care versus standardised specialist medical care alone for
patients with the chronic fatigue syndrome/myalgic encephalomyelitis or
encephalopathy. BMC Neurol 2007;7:1.
2. White PD, Goldsmith KA, Johnson AL, Potts L, et al. Comparison of adaptive
pacing therapy, cognitive behaviour therapy, graded exercise therapy, and
specialist medical care for chronic fatigue syndrome (PACE): a randomised
trial. Lancet. 2011;377(9768):82336.
3. McCrone P, Sharpe M, Chalder T, Knapp M, Johnson AL, Goldsmith KA,
White PD. Adaptive pacing, cognitive behaviour therapy, graded exercise,
and specialist medical care for chronic fatigue syndrome: a cost-
effectiveness analysis. PLoS One. 2012;7:e40808. http://www.plosone.org/
article/info:doi/10.1371/journal.pone.0040808
4. White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M. Recovery from
chronic fatigue syndrome after treatments given in the PACE trial. Psychol
Med. 2013;43(10):222735.
5. Dougall D, Johnson A, Goldsmith K, Sharpe M, Angus B, Chalder T, White P.
Adverse events and deterioration reported by participants in the PACE trial of
therapies for chronic fatigue syndrome. J Psychosom Res. 2014;77(1):206.
6. Chalder T, Goldsmith KA, White PD, Sharpe M, Pickles AR. Rehabilitative
therapies for chronic fatigue syndrome: a secondary mediation analysis of
the PACE trial. Lancet Psychiatry. 2015;2(2):14152.
7. Sharpe M, Goldsmith KA, Johnson AL, Chalder T, Walker J, White PD.
Rehabilitative treatments for chronic fatigue syndrome: long-term follow-up
from the PACE trial. Lancet Psychiatry. 2015;2(12):106774.
8. United Kingdom National Institute for Health and Care Excellence, Centre for
Clinical Practice (2011). Review of clinical guideline (CG53) chronic fatigue
syndrome/ myalgic encephalomyelitis. https://www.nice.org.uk/guidance/
cg53/evidence/review-decision-2011-546258781.Accessed1Oct2016.
9. Queen Mary University of London (QMUL): Statement: disclosure of PACE
trial data under the freedom of information act. 2016. http://www.qmul.ac.
uk/media/news/items/smd/181216.html Accessed 1 Oct 2016.
10. Sharpe MC, Archard LC, Banatvala JE, Borysiewicz LK, Clare AW, David A,
Edwards RH, Hawton KE, Lambert HP, Lane RJ. A reportchronic fatigue
syndrome: guidelines for research. J R Soc Med. 1991;84(2):118.
11. Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36):
I. Conceptual framework and item selection. Med Care. 1992;30:47383.
12. Chalder T, Berelowitz G, Pawlikowska T, Watts L, Wessely S, Wright D, Wallace
EP. Development of a fatigue scale. J Psychosom Res. 1993;37(2):14753.
13. White PD, Chalder T, Sharpe M. The planning, implementation and
publication of a complex intervention trial for chronic fatigue syndrome:
the PACE trial. BJPsych Bull. 2015;39(1):247.
14. Walwyn R, Potts L, McCrone P, Johnson AL, DeCesare JC, Baber H, Goldsmith K,
Sharpe M, Chalder T, White PD. A randomised trial of adaptive pacing therapy,
cognitive behaviour therapy, graded exercise, and specialist medical care for
chronic fatigue syndrome (PACE): statistical analysis plan. Trials. 2013;14(1):386.
15. Queen Mary University of London (QMUL): Pace trial - published papers.
2016. http://www.wolfson.qmul.ac.uk/current-projects/pace-trial#published-
papers Accessed 6 Dec 2017.
16. Queen Mary University of London (QMUL): Pace Trial. 2016. http://www.
wolfson.qmul.ac.uk/current-projects/pace-trial#patients Accessed 23 Sept 2017.
17. Wilshire C, Kindlon T, Matthees A, McGrath S. Can patients with chronic
fatigue syndrome really recover after graded exercise or cognitive
Wilshire et al. BMC Psychology (2018) 6:6 Page 11 of 12
behavioural therapy? A critical commentary and preliminary re-analysis of
the PACE trial. Fatigue. 2017;5:14.
18. Matthees A, Kindlon T, Maryhew C, Stark P, Levin B. A preliminary analysis of
recoveryfrom chronic fatigue syndrome in the PACE trial using individual
participant data. Virology Blog. 2016; http://www.virology.ws/wp-content/
uploads/2016/09/preliminary-analysis.pdf. Accessed 1 Oct 2016
19. Goldsmith KA, White PD, Chalder T, Johnson AL, Sharpe M. The PACE trial:
analysis of primary outcomes using composite measures of improvement:
Unpublished report, Queen Mary University of London; 2016. http://www.
wolfson.qmul.ac.uk/images/pdfs/pace/PACE_published_protocol_based_
analysis_final_8th_Sept_2016.pdf. Accessed 1 Oct 2016
20. White et al. PACE trial protocol: Final version 5.0, 01.02.2006. http://www.
meactionuk.org.uk/FULL-Protocol-SEARCHABLE-version.pdf. Accessed 1 Oct 2016.
21. Juenger J, Schellberg D, Kraemer S, Haunstetter A, Zugck C, Herzog W,
Haass M. Health related quality of life in patients with congestive heart
failure: comparison with other chronic diseases and relation to functional
variables. Heart. 2002;87(3):23541.
22. Kings College London. CBT for chronic fatigue syndrome. https://www.kcl.
ac.uk/ioppn/about/difference/22-CBT-for-chronic-fatigue-syndrome.aspx.
Accessed 23 Sept 2017.
23. Sharpe M, Chalder T, Johnson AL, Goldsmith KA, White PD, et al. Fatigue.
2017;5(1):5761.
24. Chalder T, White PD, Sharpe M, Mitchell AJ. Controversy over exercise
therapy for chronic fatigue syndrome: continuing the debate. BJPsych
Advances. 2017;23(5):28891.
25. Devendorf AR, Jackson CT, Sunnquist M, A Jason L. Defining and measuring
recovery from myalgic encephalomyelitis and chronic fatigue syndrome: the
physician perspective. Disabil Rehabil. 2017;5:18.
26. Wilshire C, Kindlon T, McGrath S. PACE trial claims of recovery are not
justified by the data: a rejoinder to Sharpe, Chalder, Johnson, goldsmith and
white (2017). Fatigue. 2017;5(1):627.
27. Lilienfeld SO, Ritschel LA, Lynn SJ, Cautin RL, Latzman RD. Why ineffective
psychotherapies appear to work: a taxonomy of causes of spurious
therapeutic effectiveness. Perspect Psychol Sci. 2014;9(4):35587.
28. Hróbjartsson A, Kaptchuk TJ, Miller FG. Placebo effect studies are susceptible to
response bias and to other types of biases. J Clin Epidemiol. 2011;64(11):12239.
29. Hróbjartsson A, Emanuelsson F, Thomsen AS, Hilden J, Brorson S. Bias due
to lack of patient blinding in clinical trials. A systematic review of trials
randomizing patients to blind and nonblind sub-studies. Int J Epidemiol.
2014;43(4):127283.
30. Allan LG, Siegel S. A signal detection theory analysis of the placebo effect.
Eval Health Prof. 2002;25(4):41020.
31. Rothbart M, Evans M, Fulero S. Recall for confirming events: memory
processes and the maintenance of social stereotypes. J Exp Soc Psychol.
1979;15(4):34355.
32. Burgess M, Chalder T. PACE manual for participants: cognitive behavioural
therapy. 2004. http://www.wolfson.qmul.ac.uk/images/pdfs/4.cbt-participant-
manual.pdf. Accessed 1 Oct 2016.
33. Bavinton J, Dyer N, White, PD. PACE manual for participants: graded
exercise therapy. 2004. http://www.wolfson.qmul.ac.uk/images/pdfs/6.get-
participant-manual.pdf. Accessed Oct 1, 2016.
34. Howard GS. Response-shift bias: a problem in evaluating interventions with
pre/post self-reports. Eval Rev. 1980;4:93106.
35. Meyer K, Schwaibolda M, Westbrook S, Beneke R, Hajric R, Lehmann M,
Roskamm H. Effects of exercise training and activity restriction on 6-minute
walking test performance in patients with chronic heart failure. Am Heart J.
1997;133(4):44753.
36. Burgess M, Chalder T. PACE manual for therapists: cognitive behavioural
therapy. 2004. http://www.wolfson.qmul.ac.uk/images/pdfs/5.get-therapist-
manual.pdf. Accessed 1 Oct 2016.
37. Keller BA, Pryor JL, Giloteaux L. Inability of myalgic encephalomyelitis/
chronic fatigue syndrome patients to reproduce VO2peak indicates
functional impairment. J Transl Med. 2014;12:104.
38. Kindlon T. Reporting of harms associated with graded exercise therapy and
cognitive behavioural therapy in myalgic encephalomyelitis/chronic fatigue
syndrome. Bull IACFS ME. 2011;19(2):59111.
39. Geraghty K, Hann M, Kurtev S. Myalgic encephalomyelitis/chronic fatigue
syndrome patientsreports of symptom changes following cognitive
behavioural therapy, graded exercise therapy and pacing treatments:
analysis of a primary survey compared with secondary surveys. J Health
Psychol. 2017;1:1359105317726152.
40. Bavinton J, Darbyshire L, White PD. PACE manual for therapists: graded
exercise therapy for CFS/ME: manual for therapists. 2004. http://www.wolfson.
qmul.ac.uk/images/pdfs/3.get-therapist-manual.pdf.Accessed1Oct2016.
41. Wiborg JF, Knoop H, Stulemeijer M, Prins JB, Bleijenberg G. How does
cognitive behaviour therapy reduce fatigue in patients with chronic fatigue
syndrome? The role of physical activity. Psychol Med. 2010;40(8):12817.
42. Friedberg F. Does graded activity increase activity? A case study of chronic
fatigue syndrome. J Behav Ther Exp Psychiatry. 2002;33(3):20315.
43. PACE ParticipantsNewsletter Issue 1. 2006. http://www.wolfson.qmul.ac.uk/
images/pdfs/participantsnewsletter1.pdf. Accessed 1 Oct 2016.
44. Wearden AJ, Riste L, Dowrick C, Chew-Graham C, Bentall RP, Morriss RK,
Peters S, Dunn G, Richardson G, Lovell K, Powell P. Fatigue intervention by
nurses evaluationthe FINE trial. A randomised controlled trial of nurse led
self-help treatment for patients in primary care with chronic fatigue
syndrome: study protocol. [ISRCTN74156610]. BMC Med. 2006;4(1):9.
45. Wearden AJ, Dowrick C, Chew-Graham C, Bentall RP, Morriss RK, Peters S,
Riste L, Richardson G, Lovell K, Dunn G. Nurse led, home based self help
treatment for patients in primary care with chronic fatigue syndrome:
randomised controlled trial. BMJ. 2010;340:c1777.
46. National Institutes of Health. NIH intramural study on Myalgic
encephalomyelitis/chronic fatigue syndrome. 2016. http://mecfs.ctss.nih.gov.
Accessed 1 Oct 2016.
47. National Institutes of Health. Project information: project 1U54NS10554101.
2016. https://projectreporter.nih.gov/project_info_description.cfm?aid=
9479859&icde=36166731&ddparam=&ddvalue=&ddsub=&cr=3&csb=
default&cs=ASC&pball=. Accessed 20 Dec 2017.
48. Loge JH, Ekeberg Ø, Kaasa S. Fatigue in the general Norwegian population:
normative data and associations. J Psychosom Res. 1998;45(1):5365.
49. Bowling A, Bond M, Jenkinson C, Lamping DL. Short form 36 (SF-36) health
survey questionnaire: which normative data should be used? Comparisons
between the norms provided by the omnibus survey in Britain, the health
survey for England and the Oxford healthy life survey. J Public Health. 1999;
21(3):25570.
50. Guy W. Clinical global impression scale. The ECDEU assessment manual
for psychopharmacology-revised Volume DHEW Publ No ADM. 1976;
76(338):218212.
51. Reeves WC, Lloyd A, Vernon SD, et al. Identification of ambiguities in the
1994 chronic fatigue syndrome research case definition and
recommendations for resolution. BMC Health Serv Res. 2003;3:25.
52. Tyrrell DAJ. Report from the National Task Force on chronic fatigue
syndrome (CFS), post viral fatigue syndrome (PVFS) and myalgic
encephalomyelitis (ME). Bristol: Westcare; 1994.
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Wilshire et al. BMC Psychology (2018) 6:6 Page 12 of 12
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Purpose: To inform an operationalised definition of recovery from myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) for research and practice. Without a consensus on defining and measuring recovery, there will continue to be controversy amongst researchers, clinicians, and patients when interpreting treatment outcomes. Method: This study explores physicians’ views on recovery from ME and CFS. We conducted semi-structured interviews with 10 physician participants who are experts in the ME and CFS field. Our deductive thematic analysis, using a realist perspective, provided a framework for differentiating recovery and significant improvement. Results: Physicians conceptualised recovery as complete symptom remission and a return to premorbid functioning (adjusted for with age), whereas they viewed significant improvement as a substantial reduction in symptoms with considerable functional gains, where patients may operate in daily life but still must cope or be treated. Conclusions: Our findings provide recommendations and approaches for measuring: daily functioning, symptomatology, quality of life, and physical functioning. • Implications for rehabilitation • Physicians viewed recovery as complete symptom remission and a return to premorbid functioning (adjusted for with age). • Recovery from myalgic encephalomyelitis and chronic fatigue syndrome should be viewed as multidimensional, considering patients’ daily life, psychosocial functioning, and overall physical functioning. • These findings can improve practitioner-client interactions, as they provide recommendations for measuring recovery in research and practice.
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Editor's Summary In a recent Round the Corner, Mitchell commented on a Cochrane Review of exercise therapy for chronic fatigue syndrome (CFS). One of the trials included in that review, and discussed by Mitchell, was the PACE trial. In this month's Round the Corner we are publishing a response we received from authors of the PACE trial (Chalder, White & Sharpe), together with Mitchell's reply. Ed.
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Cognitive behavioural therapy and graded exercise therapy are promoted as evidence-based treatments for myalgic encephalomyelitis/chronic fatigue syndrome. This article explores patients' symptom responses following these treatments versus pacing therapy, an approach favoured by many sufferers. We analyse data from a large cross-sectional patient survey ( n = 1428) and compare our findings with those from comparable patient surveys ( n = 16,665), using a mix of descriptive statistics and regression analysis modelling. Findings from analysis of primary and secondary surveys suggest that cognitive behavioural therapy is of benefit to a small percentage of patients (8%-35%), graded exercise therapy brings about large negative responses in patients (54%-74%), while pacing is the most favoured treatment with the lowest negative response rate and the highest reported benefit (44%-82%).
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BACKGROUND: Recently, we critically evaluated the claim from the PACE trial that cognitive behavioural therapy (CBT) and graded exercise therapy (GET) can lead to recovery from chronic fatigue syndrome. We showed that the trial’s definition of recovery was so loose it failed to capture the term’s core meaning. Also, this definition was substantially loosened very late in the trial, in ways that favoured the study hypotheses. The investigators do not acknowledge any of these criticisms and stand by their original analyses. PURPOSE: To examine the arguments advanced in defence of PACE’s recovery claims. METHODS: Drawing on various sources of evidence, we consider three major arguments raised in defence of PACE’s recovery claims: 1) that since there is no agreed definition of recovery, it comes down to a matter of opinion; 2) that the original definition was “too stringent”; and 3) the revised definition generates results that align with previous studies. RESULTS: We find that: 1) “recovery” is a strong claim, which implies evidence a return to health, and that the trial’s final definition did not preserve this core meaning; 2) there is no evidence to suggest that the original protocol-specified definition was “too stringent”; 3) absolute recovery rates from other studies are not a legitimate source of support for the recovery definition used. CONCLUSIONS: The PACE trial provides no evidence that CBT and GET can lead to recovery from CFS. The recovery claims made in the PACE trial are therefore misleading for patients and clinicians.
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BACKGROUND: Publications from the PACE trial reported that 22% of chronic fatigue syndrome patients recovered following graded exercise therapy (GET), and 22% following a specialised form of CBT. Only 7% recovered in a control, no-therapy group. These figures were based on a definition of recovery that differed markedly from that specified in the trial protocol. PURPOSE: To evaluate whether these recovery claims are justified by the evidence. METHODS: Drawing on relevant normative data and other research, we critically examine the researchers’ definition of recovery, and whether the late changes they made to this definition were justified. Finally, we calculate recovery rates based on the original protocol-specified definition. RESULTS: None of the changes made to PACE recovery criteria were adequately justified. Further, the final definition was so lax that on some criteria, it was possible to score below the level required for trial entry, yet still be counted as ‘recovered’. When recovery was defined according to the original protocol, recovery rates in the GET and CBT groups were low and not significantly higher than in the control group (4%, 7% and 3%, respectively). CONCLUSIONS: The claim that patients can recover as a result of CBT and GET is not justified by the data, and is highly misleading to clinicians and patients considering these treatments.
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The PACE trial was a four-arm trial of specialist medical care, compared with specialist medical care with a supplementary therapy: adaptive pacing therapy, cognitive-behavioural therapy or graded exercise therapy, for patients with chronic fatigue syndrome. The trial found that both cognitive-behavioural and graded exercise therapies were more effective than either of the other two treatments in reducing fatigue and improving physical disability. This paper describes the design, conduct and main results of the trial, along with a description of the challenges that had to be overcome in order to produce clear answers to the clinically important questions the trial posed.
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Background: Wilshire et al. suggest that we have overestimated the number of patients that recover from chronic fatigue syndrome (CFS) after receiving a course of either cognitive behaviour therapy (CBT) or graded exercise therapy (GET), as reported in a secondary analysis of outcome data from the Pacing, graded Activity and Cognitive behavior therapy; a randomized Evaluation (PACE) trial. We provide counter-arguments to this view. Purpose: To provide an alternative view to that offered by Wilshire et al. Methods: We review the two different analyses of PACE trial outcome data to estimate recovery, and compare these to other published trials and cohort studies. Results: While there is no gold standard for recovery from CFS, previous trials and cohort studies provide support for our analysis of recovery in the PACE trial. Our finding that 22% of participants recover from the current episode of CFS after either CBT or GET, compared to 8% after adaptive pacing therapy and 7% after specialist medical care alone, is consistent with the literature. Conclusions: Our original conclusions that ‘ … recovery from CFS is possible, and that CBT and GET are the therapies most likely to lead to recovery’ is an important, reasonable, and hopeful message for both clinicians and patients.
Article
Background: Cognitive behaviour therapy (CBT) added to specialist medical care (SMC), or graded exercise therapy (GET) added to SMC, are more effective in reducing fatigue and improving physical function than both adaptive pacing therapy (APT) plus SMC and SMC alone for chronic fatigue syndrome. We investigate putative treatment mechanisms. Methods: We did a planned secondary mediation analysis of the PACE trial comparing SMC alone or SMC plus APT with SMC plus CBT and SMC plus GET for patients with chronic fatigue syndrome. 641 participants were recruited from six specialist chronic fatigue syndrome clinics in the UK National Health Service between March 18, 2005, and Nov 28, 2008. We assessed mediation using the product of coefficients method with the 12 week measure of the mediators and the 52 week measure of the outcomes. The primary outcomes were fatigue measured by the Chalder fatigue scale and physical function measured by the physical function subscale of the SF-36. We included confounder covariates and used treatment by mediator interaction terms to examine differences in mediator-outcome relations by treatment group. Findings: The largest mediated effect for both CBT and GET and both primary outcomes was through fear avoidance beliefs with an effect of larger magnitude for GET (standardised effects ×10, CBT vs APT, fatigue -1.22, 95% CI -0.52 to -1.97, physical function 1.54, 0.86 to 2.31; GET vs APT, fatigue -1.86, -0.80 to -2.89, physical function 2.35, 1.35 to 3.39). Increase in exercise tolerance (6 min walk distance) was a potent mediator of the effect of GET (vs APT, fatigue -1.37, 95% CI -0.76 to -2.21, physical function 1.90, 1.10 to 2.91), but not CBT. Interpretation: Our main finding was that fear avoidance beliefs were the strongest mediator for both CBT and GET. Changes in both beliefs and behaviour mediated the effects of both CBT and GET, but more so for GET. The results support a treatment model in which both beliefs and behaviour play a part in perpetuating fatigue and disability in chronic fatigue syndrome. Funding: UK Medical Research Council, Department of Health for England, Scottish Chief Scientist Office, Department for Work and Pensions, National Institute for Health Research (NIHR), NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust, and Institute of Psychiatry, Psychology, and Neuroscience, King's College London.