PACE trial authors’ reply to letter by Kindlon

People reading the response by White and colleagues could be forgiven for thinking there were inaccuracies in my letter.1 I said none of the primary outcome measures have been published as in the protocol.2 This is true. The new primary outcome measures do use data from the same questionnaires; however, altering how an outcome is reported by using a different threshold or method of analysis can be considered a significant change.3

It is true that the investigators did alert readers to some changes to outcome measures; however other outcomes e.g. on safety, were also changed without this being highlighted or explained.2,4

Only 0.26% (10/3774) of the adverse events have been reported with both the intervention and details of the event.4 Moreover, patient compliance was considered to be adequate if a participant simply attended (which could be by phone) 10 out of the 15 sessions. For the six-minute walk test, the chief objective measure, there were minimal improvements recorded for graded exercise therapy, and no improvement recorded for cognitive behavioural therapy, so I question we have good data on the safety of dutifully adhering to these graded activity-oriented interventions, given the abnormal response to exertion in the condition.4

Three of the four elements of the recovery definition in the protocol were
changed.2,5 Two of the new thresholds for recovery could be satisfied by participants scoring worse than at baseline.2,5

Minutes from the trial's steering committee, released via an earlier FOI, show that the criteria for a 'positive outcome' (one of the original primary outcome measures) had been made more demanding, involving a SF36 physical functioning score of 75, in order to ensure improvements were "more than trivial" from a baseline score of 65. The post-hoc recovery criteria required a score of just 60, down from 85.5

References:

1. White PD, Chalder T, Sharpe M, Johnson T, Goldsmith K. PACE trial authors’ reply to letter by Kindlon. BMJ 2013;347:f5963.

2. White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; 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. BMC Neurol 2007;7:6.

3. Evans S. When and how can endpoints be changed after initiation of a randomized clinical trial? PLoS Clin Trials 2007;2, e18.

4. Kindlon T. Reporting of harms associated with graded exercise therapy and cognitive behavioural therapy in myalgic encephalomyelitis/chronic fatigue syndrome. Bulletin of the IACFS/ME 2011;19:59-111.

5. White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M; PACE Trial Management Group. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med 2013; published online 31 Jan.