cassava7
Senior Member (Voting Rights)
Merged thread
A cursory look at this study.
Participants
The participants had the following conditions and were all stable (low inflammation markers):
The inclusion criterion regarding fatigue was that it had to be persistent (>3 months) and clinically significant, defined as “≥6 on numerical rating 0–10 scale measuring average level of fatigue during the past 7 day”.
Interventions
The active interventions (personalised exercise a.k.a. PEP and CBT) were delivered by therapists over the phone, with at most 7 one-to-one sessions of up to 45 mins per participant, over 14 weeks. The number of sessions received by each participant was decided individually between them and their therapist, but a booster session was added at 22 weeks for all participants. PEP participants received a median of 5 sessions (IQR 1-8) and CBT participants a median of 8 sessions (IQR 2-8).
Both interventions were based on the usual exertion fear-avoidance model of the PACE trial, which is directly cited (ref. 12, as @Andy pointed out):
The usual care consisted of “a Versus Arthritis education booklet for fatigue” (no therapist involved), which seems to be this one from a quick Google search. It essentially explains adaptative pacing as in the PACE trial, i.e. trying to gradually increase exercise while recommending “the four P’s”: problem solving, planning, prioritising and pacing.
Outcomes
The primary outcome was the Chalder fatigue scale (0-33 rating) and, because there was an improvement, the FSS was also included. They were both evaluated at 10, 28 and 56 weeks. The following mean changes at 6 months post-treatment (56 weeks) are reported:
- PEP compared to usual care:
CFS: -3.03, 97.5% CI [-5.05, -1.02] (p = 0.0007)
FSS: -0.64 [-0.95, -0.33] (p = 0.0058)
- CBT compared to usual care:
CFS: -2.36 [-4.28, -0.44] (p < 0.0001)
FSS: -0.58 [-0.87, -0.28] (p < 0.0001)
The authors chose half a standard deviation as the minimally important difference (MID, i.e. the minimal change that can be considered clinically significant) on the Chalder fatigue scale:
However, this seems inappropriate. First, their choice of half a SD is based on a small review of 32 studies that reported quality-of-life outcomes; this rule of thumb has been contested. [1] Second, they chose a smaller MID than those reported previously for lupus & rheumatoid arthritis on the CFS and the FSS, which respectively ranged from 2.3 to 3.3 and 0.5 to 1.2. [2] Third, the interventions are directly based on the PACE trial, as was the GETSET trial; in contrast, a MID of 3 points for the CFS was chosen in the latter. Importantly, all reported confidence intervals for the CFS and the FSS include values under their respective MIDs.
It is unfortunate that the authors reported a “clinically significant” change of “medium size” despite their results 1) showing uncertainty that they even reached MIDs, 2) likely owing to response bias on the questionnaires rather than a true effect from the intervention, considering the small differences compared to usual care.
In particular, for participants who received 3 or more sessions of PEP, either exercise was indeed slightly more effective than usual care and CBT or response bias might have been particularly pronounced, as there was a greater improvement on the CFS and the confidence interval did not include the MID:
Further, while there was a reported improvement with PEP on the Work Productivity and Activity Impairment questionnaire (which concerns the prior 7 days) on “overall work impairment” (p = 0.010), none was observed on the “valued life activities” subscale of this questionnaire. Generally, despite “statistically significant” changes being reported on some secondary outcomes, they were not corrected for multiple comparisons, and other important secondary outcomes were null:
Conclusion
Overall, it seems fairly clear from the results that the interventions were not effective. I do not understand why the Lancet’s peer reviewers did not point this out and agreed to publish the article as such, that is, with the claims of improvement that it makes.
While the authors mention that they will report on cost-effectiveness in a later article, I cannot see how they can make the case that their interventions are cost-effective (3+ months of treatment for barely reaching MIDs).
Perhaps the most unfortunate part of this trial is that it was funded by the charity Versus Arthritis. Prof Gary MacFarlane, one of the co-authors, is VA’s vice-director; surely this must have helped securing funding.
[1] Norman, G. R., Sloan, J. A., & Wyrwich, K. W. (2003). Interpretation of changes in health-related quality of life: the remarkable universality of half a standard deviation. Medical care, 41(5), 582–592. https://doi.org/10.1097/01.MLR.0000062554.74615.4C
[2] Nordin, Å., Taft, C., Lundgren-Nilsson, Å., & Dencker, A. (2016). Minimal important differences for fatigue patient reported outcome measures-a systematic review. BMC medical research methodology, 16, 62. https://doi.org/10.1186/s12874-016-0167-6
A cursory look at this study.
Participants
The participants had the following conditions and were all stable (low inflammation markers):
Of those treated, 202 (55%) were diagnosed with rheumatoid arthritis, 78 (21%) with connective tissue disease, 72 (20%) with axial spondyloarthritis, 14 (4%) with other inflammatory rheumatic diseases, and 1 requested their data to be withdrawn.
The inclusion criterion regarding fatigue was that it had to be persistent (>3 months) and clinically significant, defined as “≥6 on numerical rating 0–10 scale measuring average level of fatigue during the past 7 day”.
Interventions
The active interventions (personalised exercise a.k.a. PEP and CBT) were delivered by therapists over the phone, with at most 7 one-to-one sessions of up to 45 mins per participant, over 14 weeks. The number of sessions received by each participant was decided individually between them and their therapist, but a booster session was added at 22 weeks for all participants. PEP participants received a median of 5 sessions (IQR 1-8) and CBT participants a median of 8 sessions (IQR 2-8).
Both interventions were based on the usual exertion fear-avoidance model of the PACE trial, which is directly cited (ref. 12, as @Andy pointed out):
Briefly, CBA was a psychological intervention that targeted unhelpful beliefs and behaviours and aimed to replace them with more adaptive ones. PEP was an exercise programme that was individually tailored and combined with a graded exposure behavioural therapy that was aimed to normalise misperceptions of effort and enhance exercise tolerance.
The usual care consisted of “a Versus Arthritis education booklet for fatigue” (no therapist involved), which seems to be this one from a quick Google search. It essentially explains adaptative pacing as in the PACE trial, i.e. trying to gradually increase exercise while recommending “the four P’s”: problem solving, planning, prioritising and pacing.
Outcomes
The primary outcome was the Chalder fatigue scale (0-33 rating) and, because there was an improvement, the FSS was also included. They were both evaluated at 10, 28 and 56 weeks. The following mean changes at 6 months post-treatment (56 weeks) are reported:
- PEP compared to usual care:
CFS: -3.03, 97.5% CI [-5.05, -1.02] (p = 0.0007)
FSS: -0.64 [-0.95, -0.33] (p = 0.0058)
- CBT compared to usual care:
CFS: -2.36 [-4.28, -0.44] (p < 0.0001)
FSS: -0.58 [-0.87, -0.28] (p < 0.0001)

The authors chose half a standard deviation as the minimally important difference (MID, i.e. the minimal change that can be considered clinically significant) on the Chalder fatigue scale:
The clinically minimally important effect was 0.5 [22], equating to 2 points in the Chalder Fatigue Scale (assuming [a standard deviation] of 4 points), based on the trials that evaluated similar non-pharmaceutical interventions. [Note: no citation of such interventions is provided here]
However, this seems inappropriate. First, their choice of half a SD is based on a small review of 32 studies that reported quality-of-life outcomes; this rule of thumb has been contested. [1] Second, they chose a smaller MID than those reported previously for lupus & rheumatoid arthritis on the CFS and the FSS, which respectively ranged from 2.3 to 3.3 and 0.5 to 1.2. [2] Third, the interventions are directly based on the PACE trial, as was the GETSET trial; in contrast, a MID of 3 points for the CFS was chosen in the latter. Importantly, all reported confidence intervals for the CFS and the FSS include values under their respective MIDs.
It is unfortunate that the authors reported a “clinically significant” change of “medium size” despite their results 1) showing uncertainty that they even reached MIDs, 2) likely owing to response bias on the questionnaires rather than a true effect from the intervention, considering the small differences compared to usual care.
In particular, for participants who received 3 or more sessions of PEP, either exercise was indeed slightly more effective than usual care and CBT or response bias might have been particularly pronounced, as there was a greater improvement on the CFS and the confidence interval did not include the MID:
In any case, this is a disappointing result: if the reported improvement owed to the treatment itself as opposed to bias, it is likely that a dose-dependent relationship would have emerged. This is not the case.The adjustment for participants receiving at least three sessions of active treatment enhanced the effect size of PEP on fatigue severity (Chalder Fatigue Scale mean difference −4·44 [97·5% CI −5·66 to −3·21], p<0·0001), but had no impact on the treatment effect of PEP on fatigue impact or CBA effect size on either primary outcome (appendix p 16).
Further, while there was a reported improvement with PEP on the Work Productivity and Activity Impairment questionnaire (which concerns the prior 7 days) on “overall work impairment” (p = 0.010), none was observed on the “valued life activities” subscale of this questionnaire. Generally, despite “statistically significant” changes being reported on some secondary outcomes, they were not corrected for multiple comparisons, and other important secondary outcomes were null:
In particular, the effect [of PEP] on overall work impairment (Work Productivity and Activity Impairment −15·58 [95% CI −27·41 to −3·74], p=0·010) at 56 weeks was large. By contrast, neither treatment significantly improved pain, anxiety, or physical health-related quality of life (table 2).
Conclusion
Overall, it seems fairly clear from the results that the interventions were not effective. I do not understand why the Lancet’s peer reviewers did not point this out and agreed to publish the article as such, that is, with the claims of improvement that it makes.
While the authors mention that they will report on cost-effectiveness in a later article, I cannot see how they can make the case that their interventions are cost-effective (3+ months of treatment for barely reaching MIDs).
Perhaps the most unfortunate part of this trial is that it was funded by the charity Versus Arthritis. Prof Gary MacFarlane, one of the co-authors, is VA’s vice-director; surely this must have helped securing funding.
[1] Norman, G. R., Sloan, J. A., & Wyrwich, K. W. (2003). Interpretation of changes in health-related quality of life: the remarkable universality of half a standard deviation. Medical care, 41(5), 582–592. https://doi.org/10.1097/01.MLR.0000062554.74615.4C
[2] Nordin, Å., Taft, C., Lundgren-Nilsson, Å., & Dencker, A. (2016). Minimal important differences for fatigue patient reported outcome measures-a systematic review. BMC medical research methodology, 16, 62. https://doi.org/10.1186/s12874-016-0167-6
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