I wrote to Live Landmark on twitter:
...
Not sure if I am shocked about this or not. She actually says that the result of the PACE trial is as good as what the preliminary studies on Rituximab has shown. Does she really think that a study that shows no change on walking tests are equal to the results of Rituximab? Didn't we discuss this in some thread? About SF36? Can anyone point me in the right direction?
The phase ii rituximab trials [1,2] have indicated that roughly two thirds of patients are responding to treatment, with a 13% response rate in the placebo group of the double-blind trial. This means that there's more than a 50% net response rate. In the double-blind phase ii trial (n=30), there was a 67% response rate in the rituximab arm and a 13% response rate in the placebo arm. And a substantial proportion of responders in both phase ii trials experienced major improvements.
It should be noted that the first phase ii rituximab trial and the ongoing phase iii rituximab trial are gold-standard double-blind placebo-controlled trials whereas the PACE trial was an uncontrolled (there was no placebo or other control arm of the trial) open-label trial that used subjective measures for its primary outcomes. Being open-label and without a control arm of the trial, the pace trial does not meet the basic quality requirements for modern medical trials and so the data should be rejected on the grounds of the poor quality [3,4].
But even taking the pace trial data at face value, the self-report primary outcomes indicated a 13-15% net response rate to CBT/GET, over and above the SMC (similar to usual care) comparison arm of the trial. This compares to a 54% net response rate in the double-blind phase ii rituximab trial. However, as the PACE trial was open-label and not controlled for a placebo response, the PACE trial data are not comparable but are meaningless as they could potentially be the results of biases inherent to the trial design [3,4].
And, significantly, for CBT, there were no significant average improvements in any objective outcomes, including a walking test [5], a fitness test [6], employment data, welfare benefits claims, and private insurance claims [7]. So CBT was clearly not improving the underlying disease process, but was simply helping people to make adjustments to the way they reported their symptoms in a questionnaire in an open-label trial with inherent methodological flaws to the trial design.
So the results of the PACE trial and the rituximab trials are not comparable, for various reasons.
If Live Landmark is referring to the recovery data for the PACE trial, the pace trial's recovery paper has been discredited because patients could suffer from severe or substantial impairment in physical function, or deteriorate after treatment, and they could still be classed as 'recovered' [8]. The pace trial authors made statistical blunders when setting the recovery thresholds [9]. The recovery paper has not yet been corrected or withdrawn but it should have been. Using the flawed recovery criteria whereby a 'recovered' patient could deteriorate after treatment or could suffer from substantial/severe physical impairment, there was a net 15% recovery rate for CBT/GET when compared to the SMC comparison arm of the trial. Note that this is exactly the same as, or higher than, the primary self-report improvement rates of 13-15% for CBT/GET.
The open-label uncontrolled PACE trial and the fundamentally flawed recovery paper are an embarrassment to science. The recovery thresholds are flawed and so the recovery paper is misleading for patients and clinicians.
References:
1. Fluge Ø, Bruland O, Risa K, Storstein A, Kristoffersen EK, Sapkota D, Næss H, Dahl O, Nyland H, Mella O. Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study. PLoS One. 2011; 6:e26358.
http://www.ncbi.nlm.nih.gov/pubmed/22039471/
2. Fluge Ø, Risa K, Lunde S, et al. B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment. PLoS ONE. 2015; 10:e0129898.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488509/?report=classic
3. Kindlon TP. Objective measures found a lack of improvement for CBT & GET in the PACE Trial: subjective improvements may simply represent response biases or placebo effects in this non-blinded trial. BMJ Rapid Response 2015.
http://www.bmj.com/content/350/bmj.h227/rr-10
4. Wilshire CE. Re: Tackling fears about exercise is important for ME treatment, analysis indicates. BMJ Rapid Response 2015.
http://www.bmj.com/content/350/bmj.h227/rr-7
5. White PD, Goldsmith KA, Johnson AL 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; 377:823-36.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60096-2/abstract
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; 2:141–52
http://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(14)00069-8/abstract
7. 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
8. Courtney R. Letter to the Editor: ‘Recovery from chronic fatigue syndrome after treatments given in the PACE trial’: an appropriate threshold for a recovery? Psychol Med. 2013; 43:1788-9.
http://journals.cambridge.org/abstract_S003329171300127X
9. Matthees A. Assessment of recovery status in chronic fatigue syndrome using normative data. Qual Life Res. 2015; 24:905-7.
http://link.springer.com/article/10.1007/s11136-014-0819-0#page-1