MAGENTA (Managed Activity Graded Exercise iN Teenagers and pre-Adolescents) - Esther Crawley

Is the idea generally that you try and disprove your hypothesis, not go out if your way to reinforce it ?
One of the biggest problems with Esther Crawleys work is that she never really says what her 'hypothesis' is. She just appears to think that her treatment works (most of the time), the kids are all happy and that's it.

eta:
From Reviewer 1's comments on the first draft, she warns about high rates of increase of exercise, given that subjects have ME/CFS!
://bhttpsmjopen.bmj.com/content/bmjopen/6/7/e011255.reviewer-comments.pdf Page 2

"P 8, Lines 4 and 29-30: A progression of 10-20% per week in physical activity is regarded as standard for healthy adults. Other CFS research suggests that progression for CFS patients should be a lot less or at least self-paced with periods of no progression if symptomatic. Can the authors explain why the 10-20% progression was chosen and support this with references from CFS literature?"

Crawley et al's response is:
"2) A progression of up to 20% is the guidance provided by the National Institute of Clinical Excellence1 and is standard practice in the UK. This is also consistent with the PACE trial, the largest trial done to date. We have now included a reference to NICE guidelines and the PACE trial, the protocol now reads: “The intervention will encourage children and adolescents to find a baseline level of exercise which will be increased slowly (by 10-20% a week, as per NICE guidance1 and the PACE trial2)”.
with reference to my last comment:
the real reason is it's what they do at her clinic
"
When can I increase my activity levels?
When you have managed 2 weeks of the same activity daily, you can start to increase by 10% a week."
http://www.ruh.nhs.uk/patients/serv...tric_cfs_me/documents/CFSEnergyManagement.pdf

eta2: also don't forget Crawley was a key advisor for the 2007 NICE guidelines; I don't what the 'rules' re increasing activity %s for GET before that were(?).
 
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We will calculate the proportion of children who wear the accelerometer and provide usable data. We will assume periods of sixty minutes or more with zero readings as “non:wear” time. Participant’s data will be included if they provide two or more weekdays of data with at least 500 minutes of data between 6am and 11pm.

The authors are introducing a rule on how to interpret accelerometer data that can only increase, never decrease, apparent activity levels.

It's possible that their assumption is valid. One would have to check how they justify this.

It's also possible that "periods of sixty minutes or more with zero readings" might just be periods where the patient is sleeping during the day due to exhaustion. In my experience, periods where I attempted to be more active and walk every day or most days, resulted in much more daytime sleep. If the device is not highly sensitive or the patient simply doesn't move, then these daytime naps could be erroneously counted as no wear time. The kind of exhaustion that makes me sleep or nap during the day tends to be so profound that I don't even moving a limb or turn around in bed.

In addition to questionnaire measures, participants in both trial arms will be asked to wear an accelerometer (GT3X+) to measure physical activity for seven days within one month of randomisation and at 3 and 6 months follow:up.

Does this indicate that a patient could have received treatment for up to 3 weeks before the first measurement of activity levels are made? Both treatment arms are described as having an initial activity reduction component. If the patient reduces their activity as told, and only then the first measurement of activity levels is performed, it could lead to the illusion of improvement.

This could easily happen if the patient, during the first contact with the service, receives both the accelerometer and the advice to reduce activity levels.

The accelerometer data will be processed to identify mean minutes of sedentary, light and moderate to vigorous intensity physical activity per day using established accelerometer cut off points and protocols.

Such subgrouping could also give an unscrupulous reeseacher more opportunities for spin and p-hacking. For example it's possible that light activity increases at 3 and 6 months, but that moderate and vigorous activity decrease. If the researcher only reported that light activity levels increased it would be misleading. What is wrong with just reporting accelerometer counts?

Accelerometers are small, match box sized devices that measure physical activity. They have been shown to provide reliable indicators of physical activity among children and adults.

I recall reading that people tend to temporarily modify their activity levels when they know that it's being recorded with accelerometers. So any measurements need to take this effect into account and be performed for long enough periods for this to not be a significant factor. Whether one week is enough needs to be checked.

Edited for clarity.
 
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I might have missed this in the exchanges. The trial registration lists the outcomes for both the feasibility study and the full trial. Is there a feasibility study protocol? Did they specify before doing the feasibility study what the full trial outcomes would be if it got extended, or did they just select them after gathering the data from the feasibility trial?
 
Reviewer 1 replies:
"The NICE guidelines state that a progression of up to 20% is deemed appropriate for CFS/ME clients. There is no reference in any of the published PACE articles, that I can find, that defines the actual progression. This was one of the many faults of the reporting of this trial. I suggest removing the reference to PACE and using the NICE guideline."

Then in 3) Reviewer 1 recommends using RPE (rate of perceived exertion) as it is also recommended in the NICE guidelines...

Then in 4) Rev 1 includes:
"The referencing of the PACE trial is not appropriate as nowhere in the PACE protocol paper (2007) or the main results paper (2011) can I find any description of what sort of graded exercise the participants actually did. Only the 2011 paper mentions that walking was the most popular choice. "

Have not had time to follow this through to the final ?June 2016 protocol.

Hope you all have some good stuff over the w/e

The reviewers are pointing out that the protocol does not actually define what treatment is being provided. Yet the trial seemed to have started recruiting in 2015 and these reviews are in 2016 so they are basically operating for some of the time on a protocol that the reviews were saying didn't define the treatment. Its also confusing as to whether the trial started in 2013 or 2015.
 
I recall reading that people tend to temporarily modify their activity levels when they know that it's being recorded with accelerometers. So any measurements need to take this effect into account and be performed for long enough periods for this to not be a significant factor. Whether one week is enough needs to be checked.

I think that is one of the reasons to have them for the whole period of the trial. Even if they use slightly less accurate devices. Something like a fitbit is small (much smaller than a matchbox) and some people seem to wear them all the time.
 
I might have missed this in the exchanges. The trial registration lists the outcomes for both the feasibility study and the full trial. Is there a feasibility study protocol? Did they specify before doing the feasibility study what the full trial outcomes would be if it got extended, or did they just select them after gathering the data from the feasibility trial?

They appear to have incorporated these changes in when they made it a full trial in 2017. Including the use of 100 patients from the feasibility study. So it looks like they were added in March 2017 but they are vague.

27/03/2017: The following changes have been made to the record in order to incorporate the full trial into the record:
1. The titles have been updated to encompass both parts of the trial (previous public title: The MAGENTA trial: can we investigate the effectiveness and cost effectiveness of managed activity compared to graded exercise in teenagers and pre-adolescents; previous scientific title: The feasibility and acceptability of conducting a trial investigating the effectiveness and cost effectiveness of Graded Exercise Therapy compared to Activity Management for paediatric CFS/ME: A feasibility randomised controlled trial)
2. The overall trial end date has been updated from 31/12/2018 to 31/03/2019
3. The target number of participants has been updated from 100 to 222 (this includes the 100 participants from the feasibility trial)
4. The planned publication date has been added
5. The hypothesis and outcome measures have been added for the full trial
6. The date of ethical approval for the full trial has been added

.

As far as I can tell the published trial protocol is for the feasibility study and not the full trial and it says:

Feasibility outcomes measurement
We will use quantitative and qualitative data to determine the feasibility and acceptability of a full-scale multicentre RCT. Findings will be fed back to the research team to improve the design, conduct and organisation of the main trial.

.....

At 12 months, we will assess whether the trial should continue to a full trial. The full trial is unlikely to be feasible in the format considered here if any of the following apply:

  1. Less than 70 children and adolescents have been recruited (∼70% of the target) and if the qualitative data collected suggest that recruitment cannot be improved any further.
  2. The 6-month follow-up is <80% and if the qualitative data suggest that follow-up rates cannot be improved any further.
  3. Data suggest the interventions are not acceptable to children and/or their parents.
  4. If the Data and Safety Monitoring Committee (DSMC) and the Trial Steering Committee (TSC) recommend the trial is stopped for safety reasons.

So the published trial protocol doesn't define outcomes for the full trial. But does define data collected in the feasibility study. It also says the intent is to use the feasibility data to adapt the design yet includes those from the feasibility study in the outcomes.
 
In a letter to the ethics committee who approved Magenta
http://www.bristol.ac.uk/media-library/sites/ccah/cfsme/study-docs/Ethics Letter 31.10.16.pdf

Crawley writes:
Cochrane review, attached), looked carefully at harm and side effects in 1518 patients. They concluded that: “no evidence suggests that exercise therapy may worsen outcomes.”

Yet the cochrane review says:
When exercise therapy was compared with 'passive control,' fatigue was significantly reduced at end of treatment (Analysis 1.1). Data on serious adverse reactions (SARs) were available from only one trial, and SARs were rare, but too few events were reported to allow any conclusions to be drawn (Analysis 1.3).

and

When exercise therapy was compared with pacing, fatigue (Analysis 3.1), physical functioning (Analysis 3.3), depression (Analysis 3.4), sleep (Analysis 3.6) and self‐perceived changes in overall health at end of treatment (Analysis 3.7) were significantly better. Data on SARs were available from only one trial, and SARs were rare, but events were too few to allow any conclusions to be drawn (Analysis 3.2).

So although Crawley makes claims to the ethics committee that Cochrane 'looked carefully at harm and side effects in 1518 patients' they actually looked at 160 (- drop outs) patients from the PACE trial in order to assess safety.
 
I might have missed this in the exchanges. The trial registration lists the outcomes for both the feasibility study and the full trial. Is there a feasibility study protocol? Did they specify before doing the feasibility study what the full trial outcomes would be if it got extended, or did they just select them after gathering the data from the feasibility trial?


In terms of ethics permission in the response from the ethics committee on 29 January 2016 for an unpublished amendment request from 18th Nov 2015
http://www.bristol.ac.uk/media-libr... Amendment 1. 18112015 Letter of Approval.pdf

They ethics committee state:
This amendment sought approval for the following changes :

....
.The intent to use data collected during the feasibility study for the full scale trial, point has now been added to PCF.
....

This was reviewed and approved by a subcommittee of two people:
Committee Members:
Mr Stephen Draper Retired Head teacher Yes
Mr Jeremy Ruddock Osteopath Yes
Also in attendance: Miss Lidia Gonzalez REC Assistant

So the committee had great expertise in trial design and methodology!
 
This was reviewed and approved by a subcommittee of two people:


So the committee had great expertise in trial design and methodology!

One of the committee has a page here:
https://www.alignbodyclinic.co.uk/jay-ruddock

He doesn't appear to have research experience beyond being involved in a systematic review in 2016. But he is helping train people for ethics committees which I find worrying and he is known for his 'magic' touch.
 
Right--"substantial amendments" are officially only subject to a vote by a subcommittee of at least two.
I suspect they are well aware of this and see it as a way of getting easy approval.

It is concerning that people who clearly don't know what they are doing are making such big approvals. In this case basically for a new trial but including results from people in a different trial.
 
My daughter was/is on the Activity Management arm, activities like bathroom visits, help getting dressed, eating are all high energy red activities. Once they achieved a certain amount of red per day then they were offered GET.
When completing our forms I actually wrote WC visit, putting on pj's etc, I doubt others did so not sure how results can be correct.
One of our first 'specialist' meetings involved asking to see daughter walk despite her being severe and in a wheelchair. Original protocol says no one in a wheelchair can be on the study!
I've requested results, have been assured they'll be sent via email.
 
My daughter was/is on the Activity Management arm, activities like bathroom visits, help getting dressed, eating are all high energy red activities. Once they achieved a certain amount of red per day then they were offered GET.
When completing our forms I actually wrote WC visit, putting on pj's etc, I doubt others did so not sure how results can be correct.
One of our first 'specialist' meetings involved asking to see daughter walk despite her being severe and in a wheelchair. Original protocol says no one in a wheelchair can be on the study!
I've requested results, have been assured they'll be sent via email.
Thanks a lot for posting.
We don't often get a chance to hear from people who take part in these recent 'studies'.
If there is anything you want to 'get off your chest' but not keen on posting on a public forum there is always the members only area which is a bit more (although not totally) 'private'.
 
My daughter was/is on the Activity Management arm, activities like bathroom visits, help getting dressed, eating are all high energy red activities. Once they achieved a certain amount of red per day then they were offered GET.
When completing our forms I actually wrote WC visit, putting on pj's etc, I doubt others did so not sure how results can be correct.
One of our first 'specialist' meetings involved asking to see daughter walk despite her being severe and in a wheelchair. Original protocol says no one in a wheelchair can be on the study!
I've requested results, have been assured they'll be sent via email.
I am slightly confused. I thought the oremise was to compare effectiveness between activity management and GET.
Surely if on the Activity management arm GET should not have been introduced?
 
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