GETSET (white) in Lancet 22/06/17

[lilpink]

so much more, but these are the main ones

Has anyone looked at the protocol to see if the same issues with informed consent we saw in PACE (ie: the PI's did not inform patients of their vested interests as they should do in accordance with the Helsinki Agreement) also apply?

 

[RogerBlack]

Also the primary end points were changed twice:

Added 21/07/2015:
2. Chalder fatigue scale measured at 12 weeks and 1 year

Updated 28/02/2017:
2. Chalder Fatigue Scale measured at 12 weeks

So, after they had the data, but before the data was 'formally analysed' - they made the decision to drop the 1 year outcome.

I guess there can be no rational reason for this other than to weaken the paper, as it was too strong, and the great results from the 1 year outcome can be split into another paper!

Sigh.
Or, perhaps not and they're a bunch of crooks, and the tiny placebo response they got has completely washed out.

 

[Hutan]

Re AfME's statement:

“This situation will only change if we see significant mainstream investment into collaborative research that helps us stratify the illness, identify biomarkers, and ultimately lead to targeted treatments for everyone with M.E., not just a minority.”

I agree with others who have said that, rather than indicating a rift with Crawley, AfME's statement is more likely designed to increase support for MEGA.

Data may be available in a controlled form perhaps @Keith Geraghty could explore.

It will be important to get the dates of the questionnaire completion by each participant. This will allow analysis to recreate what the researchers were seeing when they made decisions about adding another outcome, extend the trial length in order to recruit more participants and subsequently removing a 12 month outcome.

I wonder if (any) participants actually completed the Chalder Fatigue questionnaire at 12 months (given that that outcome was added and then removed). Are there any trial participants reading this thread who can say what happened?

It was heartening to see the comments from Chris Ponting and Simon Day - thank you to them.

 

[Dolphin]

All randomised participants with outcome data at follow-up (ie, the modified intention-to-treat population) were included in analyses, regardless of any departure from the allocated intervention.

They have modified the intention-to-treat so that it is no longer an intention to treat but the set of people who gave follow up data. That is not intention to treat at all and highly misleading.

Yes, I thought that might be interesting. But they do say:

Strict intention-to-treat analysis, with imputed missing information included (n=211), confirmed the findings of the main analysis for the primary outcomes (table 4).

 

[Dolphin]

After the last guidance session, the physiotherapist will rate the participant’s CGI (health), their adherence to the GES guided support, and their acceptance of the therapy model.

Departure from Intended Treatment

To measure departure from intended treatment, participants will be asked at follow-up whether they adhered to the booklet and guidance, and how much PA they undertook in the past week.

Physiotherapist-rated data on adherence to GES were available for 104 (97%) participants offered GES; the remainder did not attend enough therapy sessions to be rated. The physiotherapists reported that 43 participants (42%) adhered to GES completely or very well, 31 (30%) moderately well, and 30 (29%) slightly or not at all.

So we are given information on physiotherapist-rated data on adherence but as far as I can see not information on how the patients rated their adherence to the protocol.

 

[Dolphin]

Second, we will test the hypothesis that GES will be acceptable to patients diagnosed as having CFS/ME in specialist secondary care clinics, as demonstrated by less than 25% of eligible patients declining participation in the trial, and more than 75% of those participating being satisfied with the approach.

This isn't a perfect test of acceptability because lots of patients know that the English services are based on the NICE guidelines which are for CBT and graded exercise therapy. It's likely that some other patients have already excluded themselves.

 

[Dolphin]

Papers to follow:

Participants were also followed up at 12 months after randomisation, and these results will be published in a separate paper.

Quality of life, (measured by EQ-5D) and economic measures will be reported separately in another paper.

 

[Dolphin]

Baseline

The following self-rated inventories will be collected at the first assessment (baseline): 11-item Chalder fatigue questionnaire (CFQ), using Likert scoring [30]; SF-36 physical function short form subscale (SF-36 PF) [31]; Hospital Anxiety and Depression Scale (HADS) [32]; Euroqol Questionnaire (EQ-5D) [33]; Work and Social Adjustment Scale (WSAS) [34]; International Physical Activity Questionnaire (IPAQ) [35]; Tampa Scale of Kinesiophobia-Fatigue (TSK-F) [36]; Client Service Receipt Inventory (CSRI) [37]; and Patient Health Questionnaire (PHQ-15) [38]. Participants will be asked when their CFS/ME started; whether they have ever received GET, CBT, or pacing from a therapist; whether they have ever used any listed self-help resources; and whether they are members of a CFS/ME self-help group. Participants will also be asked about their ethnicity, highest education level, current employment status, whether they have had to reduce/stop work due to their CFS/ME, other health problems, and whether they are taking antidepressant medication for any reason.

I don't believe any of the underlined bits were reported, not that they are necessarily very important.

 

[Dolphin]

I wonder if (any) participants actually completed the Chalder Fatigue questionnaire at 12 months (given that that outcome was added and then removed). Are there any trial participants reading this thread who can say what happened?

It was only removed as a primary outcome measure. I think it still would have been recorded for everyone.

12-Months Post-randomization
The primary purpose of the 12-month follow-up will be to obtain the health-economic assessment (see section below); however, we will also collect data on the primary outcome measures and the CGI so that we can assess longer-term physical functioning, fatigue, and change in overall health and CFS. The following information will be collected via questionnaires sent in the mail with a stamped addressed envelope for return: CFQ, SF-36 PF, CGI, EQ-5D, and CSRI.

 

[Dolphin]

Results

Is it possible to calculate from this the mean scores at baseline of the 10 participants who dropped out ?

I'm getting odd numbers, if the final mean is 19.1 and the difference is -4.2 is the mean at baseline of the 97 that completed 23.3 ?

I don't believe one can calculate that. The 4.2 figure is an adjusted figure. Basically 22.9 - 19.1 adjusted for baseline factors.

 

[Dolphin]

12-Weeks Post-randomization

Participants will be asked to describe the following: whether they have used any of 4 listed self-help resources since randomization, including the unpublished GES guide [40-42]; how satisfied they are with the help they received; how closely they followed the GES guide; their current employment status and whether they have had to reduce/stop work due to their CFS/ME; any new health problems not already reported; and whether they are taking antidepressant medication for any reason.

I don't believe the underlined bits were reported. It looks like information relating to employment will be published in another paper.

 

[Dolphin]

However, during recruitment we noticed that a significant minority of participants scored close to the mean of the general population (ie, normal physical function) so could be considered recovered even before any intervention [43]. This is because they had substantial reductions in functioning in other domains, such as mental or social activity levels [7].

The mean is not necessarily an accurate figure as it can be reduced by very low scores; the median is more useful in such a situation. Also in the general population are a lot of elderly people as well as some with significant ongoing disabilities and illnesses who would be excluded from the study. The mean for the general population is 84. Getting close to that doesn't mean you are recovered.

 

[Dolphin]

An adverse event is defined as any clinical change, disease, or disorder recorded by the participant, whether or not it is considered to be related to the trial or its treatments. Participants will be asked to record whether they believe the adverse event was “related to following the GET guide.”

I don't believe we were given any information on the underlined bit.

 

[Dolphin]

I imagine there will be a paper on this. They seem to have gone to quite a bit of trouble though will have little information on people who deteriorated "much" or "very much" following graded exercise.

Qualitative Study
Purpose

We will undertake a nested qualitative study with a subsample of participants to ascertain patients’ views and experiences of GES, specifically looking for differences in perceptions and experiences between those who improved and worsened with GES. Both our patient representatives and the TSC suggested using the trial to better understand why patients vary in their responses to graded exercise therapy (GET), particularly by examining engagement and other barriers/facilitators to successful treatment. The best way to gather this knowledge is to undertake a small qualitative study, stratified by both good and poor outcomes. We will conduct one-on-one interviews with participants who have taken part in the active arm of the trial to investigate variations in participant attitudes to, and experiences of, GES. This study will be nested within the time-frame for the main trial.

<snipped>

Edited to add: yes it looks like they do plan to publish a qualitative study.

27 (25%) of 107 participants in the GES group received three or fewer sessions of guidance, which might reflect disengagement with the intervention; our qualitative study will address this.

 

[Dolphin]

A representative of the Association for Young People with ME will sit on the TSC

TSC: trial steering committee

A bit odd that this group was chosen given this is not a study on young people in particular. I wonder did they ask anyone else and they refused or alternatively did they immediately pick what they saw as the weakest group.

 

[user9876]

Yes, I thought that might be interesting. But they do say:

Yes they do give a figure for ITT in their sensitivity analysis but they use a method to imput data that suggests that patients are missing at random which will tend to give a more positive result than say using baseline data. (Assuming I understand their description - with no equations/code to say what they actually did!).

 

[Dolphin]

If shown to be an effective treatment, this policy of providing a guided self-help approach to initially stabilize and then increase PA in patients with CFS/ME could also be tested for patients with many other chronic disabling conditions known to respond to practitioner-delivered graded exercise approaches, including arthritis, chronic obstructive airways disease, and diabetes mellitus [58].

PA: physical activity

Except that we don't know whether people actually increased physical activity levels or instead perhaps engaged in activity substitution as suggested by data from some other studies testing graded activity-oriented CBT.

 

[Dolphin]

The most commonly chosen exercise was walking. Importantly, if a participant found that their symptoms increased after an incremental change in their activity, they were advised to maintain their activity at the same level for longer than a week, until symptoms had settled, before considering another incremental increase.

And importantly we don't know how many people stuck to this strategy of not decreasing their activity if they were experiencing increased symptoms.

 

[user9876]

Participants in the control group were no more likely to receive SMC sessions during the trial than those in the GES group. In the GES group, 28 (26%) of 107 patients attended one session, two (2%) attended two sessions, and none attended three sessions; in the control group, 28 (27%) of 104 patients attended one session, two (2%) attended two sessions, and two (2%) attended three sessions (χ2 2·126; p=0·54).

Looks like a poor control group in that most people saw a doctor once and then were sent surveys at 12 weeks and 12 months. That was the trial for them. Its more like a waiting list control group and certainly doesn't try to set similar expectations.

 

[Dolphin]

†Two patients actively withdrew from the intervention after attending one session, stating family commitments; one patient was not contactable after the first session. ‡One patient reported a family bereavement, one reported grief, and one was not contactable.

Note that these are different people. This highlights a problem with intervention such as graded exercise therapy: they require an investment in time and energy which might not be available to some people and which isn't usually required to take a tablet for example.