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Data for predefined primary outcome measure "overall improvers" has thus far not been published
Posted by 03 Aug 2012 at 16:00 GMTon
The protocol for the PACE Trial was published in 2007 (1). It gave the following primary outcome measures:
“Primary outcome measures – Primary efficacy measures
Since we are interested in changes in both symptoms and disability we have chosen to designate both the symptoms of fatigue and physical function as primary outcomes. This is because it is possible that a specific treatment may relieve symptoms without reducing disability, or vice versa. Both these measures will be self-rated.
The 11 item Chalder Fatigue Questionnaire measures the severity of symptomatic fatigue , and has been the most frequently used measure of fatigue in most previous trials of these interventions. We will use the 0,0,1,1 item scores to allow a possible score of between 0 and 11. A positive outcome will be a 50% reduction in fatigue score, or a score of 3 or less, this threshold having been previously shown to indicate normal fatigue .
The SF-36 physical function sub-scale  measures physical function, and has often been used as a primary outcome measure in trials of CBT and GET. We will count a score of 75 (out of a maximum of 100) or more, or a 50% increase from baseline in SF-36 sub-scale score as a positive outcome. A score of 70 is about one standard deviation below the mean score (about 85, depending on the study) for the UK adult population [51,52].
Those participants who improve in both primary outcome measures will be regarded as overall improvers.”
The details for none of these have been published so far.
In the Lancet paper (2), the authors made reference to changing the primary outcome measures for the Chalder fatigue questionnaire and the SF-36 to continuous measures: "We used continuous scores for primary outcomes to allow a more straightforward interpretation of the individual outcomes, instead of the originally planned composite measures (50% change or meeting a threshold score)." It should be pointed out that the protocol had already predefined secondary outcome measure using continuous values for the Chalder fatigue questionnaire ["1. The Chalder Fatigue Questionnaire Likert scoring (0,1,2,3) will be used to compare responses to treatment."] so that data could have been published anyway without making changes to the protocol, just not as the primary outcome measure.
No mention was made of the third primary outcome measure, "overall improvers". In the Lancet paper, post-hoc definitions for the percentages of participants improved for the Chalder fatigue questionnaire, the SF-36 Physical Functioning questionnaire, as well as both of them, were introduced. It is unclear why such criteria were necessary as these are dichotomous like the original primary outcome measure criteria so the argument for using continuous criteria doesn't apply. Also, the primary outcome measures used a validated definition for fatigue caseness.
The threshold to qualify as improved was much lower with these new post-hoc criteria. This can be seen in when one looks at the percentage that improved with specialist medical care (SMC) under the new definitions of improvement: 65% for fatigue, 58% for physical function and 45% for both (2).
The calculations the authors had made in designing the paper were for a much lower improvement rate (1):
"The existing evidence does not allow precise estimates of improvement with the trial treatments. However the available data suggests that at one year follow up, 50 to 63% of participants with CFS/ME had a positive outcome, by intention to treat, in the three RCTs of rehabilitative CBT [18,25,26], with 69% improved after an educational rehabilitation that closely resembled CBT . This compares to 18 and 63% improved in the two RCTs of GET [23,24], and 47% improvement in a clinical audit of GET . Having usual rather than specialist medical care allowed 6% to 17% to improve by one year in two RCTs [18,25]. There are no previous RCTs of APT to guide us [11,12], but we estimate that APT will be at least as effective as the control treatments of relaxation and flexibility used in previous RCTs, with 26% to 27% improved on primary outcomes [23,26]. We propose that a clinically important difference would be between 2 and 3 times the improvement rate of SSMC."
For a therapy to be three times the improvement rate of SSMC would mean 90% to 135% of patients doing that therapy would be improved (numbers over 100% impossible).
A letter has previously been published explaining the problem of using 0.5SD of the baseline values as cut-offs for a clinically useful difference (3). Basically because the baseline values were artificially restricted, the standard deviation is artificially restricted. In this circumstance other values should be used for a clinical useful difference.
The current paper (4) again uses these post-hoc criteria for improvement rather than the prespecified primary outcome measure.
It would be good if the data for the prespecified primary outcome measure for overall improvers could be released.
1. White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; on behalf of the PACE trial group. Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or
encephalopathy. BioMed Cent Neurol 2007; 7: 6. http://www.biomedcentral....
2. White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, et al. (2011) Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 377: 823–836.
3. Giakoumakis J. The PACE trial in chronic fatigue syndrome. Lancet. 2011 May 28;377(9780):1831; author reply 1834-5. Epub 2011 May 16.
4. McCrone P, Sharpe M, Chalder T, Knapp M, Johnson AL, et al. (2012) Adaptive Pacing, Cognitive Behaviour Therapy, Graded Exercise, and Specialist Medical Care for Chronic Fatigue Syndrome: A Cost-Effectiveness Analysis.PLoS ONE 7(8):e40808. doi:10.1371/journal.pone.0040808
Another published letter also criticised the post-hoc criteria for improvement
03 Aug 2012 at 16:36 GMTreplied to on
I forgot to mention another letter (1) that criticised the (post hoc) definition of improvement used in this paper and the original Lancet paper (2,3).
1. Stouten B, Goudsmit EM, Riley N. The PACE trial in chronic fatigue syndrome. Lancet. 2011 May 28;377(9780):1832-3; Epub 2011 May 16.
2. McCrone P, Sharpe M, Chalder T, Knapp M, Johnson AL, et al. (2012) Adaptive Pacing, Cognitive Behaviour Therapy, Graded Exercise, and Specialist Medical Care for Chronic Fatigue Syndrome: A Cost-Effectiveness Analysis.PLoS ONE 7(8):e40808. doi:10.1371/journal.pone.0040808
3. White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, et al. (2011) Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 377: 823–836.