Do the change in endpoints in the paper refer to changing the outcomes measured, or the way that outcome is reported? PACE continued to use SF36 and CFQ as primary outcomes but changed from categorical to continous reporting.
No, as I recall, it doesn't make any point on such an issue. To me, that's still a change and I don't recall reading anything that said otherwise.
The piece is only 3 pages and there are no numbers so other people could read the full piece if they preferred.
Two specific points: they also went from bimodal scoring to Likert scoring with one of the primary measures so not quite simply a change from categorical to continuous scoring.
Also, one of the secondary outcome measures was:
The Chalder Fatigue Questionnaire Likert scoring (0,1,2,3) will be used to compare responses to treatment [27].
so it could be called substituting a primary outcome measure with a secondary outcome measure. Put another way, the data that was presented as a primary outcome measure for fatigue could still have been presented if they stuck to published protocol.[/QUOTE]
The changes were approved by the Trial Steering committee who would not have had seen any interim data and are independent of the trial investigators (that's the point of it) so would meet the criteria for appropriate people to approve the change, which they did.
If you mean by "independent of the trial investigators" that it did not include the trial investigators, that is not correct, although it is easy to miss it on the PACE Protocol website:
Trial Steering Committee (TSC)
The Trial Steering Committee (TSC) is responsible for the independent oversight of the progress of the trial, investigation of serious adverse events, and determining the future progress of the trial in the light of regular reports from the DMEC. The TSC is composed of:
Professor Janet Darbyshire (Chair),
Professor Jenny Butler (occupational therapist),
Professor Patrick Doherty (physiotherapist),
Dr Stella Harris (patient representative),
Dr Meirion Llewelyn (consultant physician in infectious diseases), and
Professor Tom Sensky (liaison psychiatrist and CBT therapist).
-----
Observers include:
Professor Mansel Aylward (previously of DWP),
Mr Chris Clark (Action for M.E.),
Peter Craig (Scottish Executive),
Dr. Moira Henderson (DWP)
Susan Lonsdale (DH) and
Dr Sarah Perkins (MRC),
Professor Stephen Stansfeld (Queen Mary University of London, on behalf of the sponsor).
Dr Alison Wearden (Principal Investigator of the FINE trial, an MRC funded, sister study to PACE also researching CFS/ME).
-----
Other members include the three investigators, the trial statisticians, and the trial manager (secretary to the committee).
Membership has been approved by the MRC.
Previous members/observers include:
Dr Robin Buckle (MRC)
Professor Clair Chilvers (R&D, DH)
I also have minutes from meetings where the three investigators were at them (and not listed as observers).
Indeed at the end, the one I'm looking at has at the end
MS, PW and TC 24/4/04 Minutes
revised 16/5/2004
so the PIs look like they were writing up the minutes.
oceanblue said:
Changes in endpoints should also be declared when submitting a manuscript to a journal, so that the results can be properly evaluated. Reporting of a clinical trial with any modified endpoint should include: (1) a clear statement describing the fact that information obtained after trial initiation led to the change in endpoint; (2) a description of the reasons (e.g., whether the endpoint was suggested by the data) and decision procedure (e.g., who made the decision and whether data were unblinded); (3) a discussion of the potential biases induced by the change of the endpoints; (4) if warranted, (i.e., if the decision to add endpoints was not independent of the data), a disclaimer that the results should be interpreted with caution and should be confirmed in future trials; and (5) a report of the reasons for excluding endpoints from the analyses and whether this was independent of trial data.
The authors seemed to have done all of this apart from point 3. Point 1 is flaky - they cited a paper on assesssing trial stats that was published after their protocol, but I'm not sure this paper actually said anything that hadn't been in the literature available when they wrote the protocol. They didn't address the issues very well but they did address them in the paper. I think they have, as usual, been very slippery here - they haven't done everything right but they've done enough right to get away with it (while completely breaching the spirit of such guidelines).
No, the authors didn't do all of them apart from (3).
One of the aims of the trial was to assess safety. They didn't report the outcome measures they said they would there or mention they had changed them.
Adverse outcomes
Adverse outcomes (score of 57 of the self-rated CGI) will be monitored by examining the CGI at all follow-up assessment interviews [49] (they didn't give us CGI scores of 5 - they were combined in with 3 and 4 which I don't believe counts as it is no listed as "no change" and we don't get the percentage for it). An adverse outcome will be considered to have occurred if the physical function score of the SF-36 [28] has dropped by 20 points from the previous measurement (they didn't give us this information: they changed this to: "decrease of 20 or more between baseline and any two consecutive assessment interviews). This deterioration score has been chosen since it represents approximately one standard deviation from the mean baseline scores (between 18 and 27) from previous trials using this measure [23,25]. Furthermore, the RN will enquire regarding specific adverse events at all follow-up assessment interviews.
There was at least one other change I can recall (apart from outcome measures they didn't give):
An operationalised Likert scale of the nine CDC symptoms of CFS
They didn't give us Likert scores for the total symptoms or the two symptoms they listed; they just gave presence/absence.
Also, with regard to the primary outcome measures, as well as giving continuous scoring, they could still have given the score for improvement (see third section):
The 11 item Chalder Fatigue Questionnaire measures the severity of symptomatic fatigue [27], 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 [27].
The SF-36 physical function sub-scale [29] 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.
We are instead given figures for improvement which is defined in a different way
A clinically useful diff erence between the means of
the primary outcomes was defi ned as 05 of the SD of
these measures at baseline,31 equating to 2 points for
Chalder fatigue questionnaire and 8 points for short
form-36. A secondary post-hoc analysis compared the
proportions of participants who had improved between
baseline and 52 weeks by 2 or more points of the Chalder
fatigue questionnaire, 8 or more points of the short
form-36, and improved on both.
which when reported in the results sounds like improvement scores (I'm not saying people would think it was the same as the protocol, but the wording is similar)
64 (42%) of 153 participants in the APT group improved
by at least 2 points for fatigue and at least 8 points for
physical function at 52 weeks, compared with 87 (59%) of
148 participants for CBT, 94 (61%) of 154 participants for
GET, and 68 (45%) of 152 participants for SMC. More
participants improved after CBT compared with APT(p=00033) or SMC (p=00149), and more improved with
GET compared with APT (p=00008) or SMC (p=00043);
APT did not diff er from SMC (p=061; webappendix p 2).