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SMILE Trial protocol: Comparing Specialist Medical Care (SMC) with SMC plus Lightning Process (LP)

Dolphin

Senior Member
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Fulltext available free at: http://www.trialsjournal.com/content/14/1/444/abstract

Trials. 2013 Dec 26;14(1):444. [Epub ahead of print]

Comparing specialist medical care with specialist medical care plus the Lightning Process(R) for chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME): study protocol for a randomised controlled trial (SMILE Trial).

Crawley E, Mills N, Hollingworth W, Deans Z, Sterne JA, Donovan JL, Beasant L, Montgomery A.

Abstract*

BACKGROUND:

Chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is a relatively common and potentially serious condition with a limited evidence base for treatment.

Specialist treatment for paediatric CFS/ME uses interventions recommended by National Institute for Health and Clinical Excellence (NICE) including cognitive behavioural therapy, graded exercise therapy and activity management.

The Lightning Process(R) (LP) is a trademarked intervention derived from osteopathy, life-coaching and neuro-linguistic programming, delivered over three consecutive days as group sessions.

Although over 250 children with CFS/ME attend LP courses each year, there are no reported studies on the effectiveness or cost-effectiveness.

METHODS:

This pragmatic randomised controlled trial is set within a specialist paediatric CFS/ME service in the south west of England.

Children and young people with CFS/ME (n = 80 to 112), aged 12 to 18 years old will be randomised to specialist medical care (SMC) or SMC plus the LP.

The primary outcome will be physical function (SF-36 physical function short form) and fatigue (Chalder Fatigue Scale).

DISCUSSION:

This study will tell us whether adding the LP to SMC is effective and cost-effective compared to SMC alone.

This study will also provide detailed information on the implementation of the LP and SMC.Trial registration: Current Controlled Trials ISRCTN81456207 (31 July 2012).

*I gave each sentence its own paragraph
 

Dolphin

Senior Member
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A lot of the points I'd make have been made in previous threads on this trial e.g.

Here are two comments from reading the protocol:

The abstract says:

The primary outcome will be physical function (SF-36 physical function short form) and fatigue (Chalder Fatigue Scale).

The full text says:

Primary outcome

The primary outcome will be the SF-36 physical function subscale analysed as a continuous variable collected at six months post-randomisation.

The SF-36 will be scored as the sum of responses to the ten items, each of which is coded 0 for ‘Yes, limited a lot’, 5 for ‘Yes, limited a little’ and 10 for ‘No, not limited at all’.

This yields a score varying from 0 (for the highest level of disability) to 100 for no disability.

The SF-36 physical function subscale will be used as we are primarily interested in change in physical function.

It has been used in studies of adolescent CFS/ME [21] and in CFS trials in adults [15].

We chose six months as this was the first time that all those randomised to LP and SMC will have received LP.

Secondary outcome measures will be school attendance, calculated as a percentage of expected sessions, at 3, 6 and 12 months; the SF-36 (physical function) at 3 and 12 months; the Chalder Fatigue Scale score at 3, 6 and 12 months; pain visual analogue scale at 6 months and quality adjusted life years (QALYs, derived from the EQ-5D) over the 12 month followup period.

ISRCTN Register says:
Primary outcome measure(s)

1. Chalder Fatigue Scale at 6 months
2. SF 36 physical function short form at 6 months

So conflicting information there on the most important reason for releasing/publishing a trial protocol!
 
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Dolphin

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Even though over 250 children and young people a year use the LP as an intervention for their CFS/ME, there are currently no reported studies investigating the effectiveness or possible side effects (for example serious adverse events) of the LP.

This is the only reference I saw talking about "possible side effects":

The data monitoring group will receive notice of serious adverse events (SAEs) for the sample as whole. If the incidence of SAEs of a similar type is greater than would be expected in this population, it will be possible for the data monitoring group to receive data according to trial arm to determine any evidence of excess in either arm.

Primary outcome data at six months will be examined once data are available from 50 patients, to ensure that neither arm is having a detrimental effect on the majority of patients. An independent statistician with no other involvement in the study will investigate whether more than 20 participants in the study sample as a whole have experienced a reduction of ≥ 30 points on the SF-36 at six months. In this case, the data will then be summarised separately by trial arm, and sent to the data monitoring group for review. This process will ensure that the trial team will not have access to the outcome data separated by treatment arm.

http://www.trialsjournal.com/content/pdf/1745-6215-14-444.pdf

A 30+ point deterioration is a huge deterioration.
Requiring 20 participants have it is a high threshold. For example, with 50 patients, there will on average only have been 25 patients who had done LP.

And in total they
"aim to recruit 80 to 112 participants to the study."
i.e. 40 to 56 participants, on average, for LP.

By contrast, this is what they are using for improvements:
We used a definition of a clinically important difference for the SF-36 physical function subscale from three expert consensus panels for chronic diseases in adults. The panels conducted a literature search and used the Delphi technique to reach consensus on the thresholds for change over time for small, moderate and large clinically important SF-36 change scores [23]. Consensus was agreed by each panel that a small clinically important difference would be 10 as this is the equivalent to two state changes (a state change is one improvement in one item - the minimum difference between inventories). A moderate improvement was defined as 20 and a large improvement as 30.

23. Wyrwich KW, Tierney WM, Babu AN, Kroenke K, Wolinsky FD: A comparison of clinically important differences in health-related quality of life for patients with chronic lung disease, asthma, or heart disease. Health Serv Res 2005, 40(2):577–591.
 
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Thanks D.

Consensus was agreed by each panel that a small clinically important difference would be 10 as this is the equivalent to two state changes

Anyone know who 'each panel' are?
 

Dolphin

Senior Member
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17,567
Thanks D.

Consensus was agreed by each panel that a small clinically important difference would be 10 as this is the equivalent to two state changes

Anyone know who 'each panel' are?
I'm guessing it was panels for chronic lung disease, asthma, and heart disease
23. Wyrwich KW, Tierney WM, Babu AN, Kroenke K, Wolinsky FD: A comparison of clinically important differences in health-related quality of life for patients with chronic lung disease, asthma, or heart disease. Health Serv Res 2005, 40(2):577–591.
I've now added in reference 23 to the extract above.
 

Dolphin

Senior Member
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17,567
(Minority interest)

One of the reviewers, Per Fink, makes this suggestion:

The authors plan to use the SF36 physical function subscale as primary outcome measurement. I am not quite confident that this is a good idea. To my knowledge, the SF36 has only been used in very few studies on children and has not been validated among children and adolescents. Why not use the FDI (Functional Disability Inventory), which is validated and commonly used for children and adolescents?

The authors replied:
Thank you. We have used the SF 36 in all our studies to date in children with CFS/ME. It is a popular measure for the teenagers and is important predictor of school attendance[6]. It was also the primary outcome in the largest trial in adults with CFS/ME. We have made this clearer by adding “. It has been used in studies of adolescent CFS/ME[6]” in the section on primary outcome, page 8, and deleting it has been used previously. This now reads: “. It has been used in studies of adolescent CFS/ME and in CFS trials in adults[7].
 

Dolphin

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17,567
Possibly of interest the authors don't think patients should have a diagnostic interview

One of the reviewers, Per Fink (psychiatrist), makes this suggestion:

5) The clinical and diagnostic assessment at inclusion in the study is only superficially described. It has to be better described, i.e. how will the establish the diagnosis, which criteria will be used and how will they ensure a proper diagnostic procedure, both as to psychiatric and non-psychiatric differential diagnoses etc. The best would be if they used a standardised procedure such as a diagnostic interview, which is available in child psychiatry.

The authors replied:

We have added the following sentence to the paragraph on “population” page 5: “Children are given a diagnoses of CFS/ME after a thorough assessment and screening blood tests according to guidelines produced by the National Institute for Health and Care Excellence (NICE)[8].” Whilst it is possible that CFS/ME services may miss some psychiatric diagnoses, we disagree that a diagnostic interview would be appropriate in a clinical setting, and indeed this is not recommended by NICE. We therefore feel that adding a diagnostic interview for this trial would not reflect what happens in specialist medical care and would not be appropriate. However, we do feel it is important for other questions around co-morbid mood disorders and intend to use this in future research. We have discussed these issues previously [9,10] and plan to discuss them again when we report the full trial.
 

Bob

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England (south coast)
Consensus was agreed by each panel that a small clinically important difference would be 10 as this is the equivalent to two state changes...
That's slightly more stringent than the PACE trial which required an SF-36 PF improvement of 8 points for a clinically useful improvement to be recorded.

Edit: I've changed this post. I had misinterpreted their text earlier.
 
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I'm guessing it was panels for chronic lung disease, asthma, and heart disease

I've now added in reference 23 to the extract above.

Thanks D.

I was just reading a commentary on that, which seemed relevant to a lot of discussion on PR, and perhaps particularly to @Simon

eg:

If one accepts that HRQL measurement must be fundamentally patient-centered, the first choice for establishing the MID should be a patient-based approach. Relative to patients, clinicians may overemphasize treatment effects (Puhan et al. 2004) and agreement between patients and proxies in rating of HRQL is not perfect (Sneeuw, Sprangers, and Aaronson 2002; Ubel, Loewenstein, and Jepson 2003; von Essen 2004). Again, if one accepts that patients are at the center in HRQL measurement, then investigators, when they do use proxies, should instruct those proxies to focus on what they believe patients consider important.
Wrywich and colleagues took a different approach. “Panelists were not provided with any specific definition of a CID (clinically important difference), but left to determine their own meaning for this term” (p. 580). Thus, the investigators did not specify to the participants that they were to estimate the difference that patients consider important. Further, they used the term “CID,” further permitting ambiguity about the group to whom the difference is important.

In summary, the MID provides an important strategy to make interpretable the results of HRQL studies. To be maximally informative, representative samples of informed patients or their proxies should provide estimates of the MID.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1361157/

The full paper for the study cited and being commented upon is here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1361158/

I've not read that yet though.
 
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I just had a quick look at that paper, and thought: isn't this MID based on the assumption that response bias, etc has all been properly accounted for? In that case, it would mean it was inappropriate to use those panels as a justification for setting the MID in a non-blinded trial for a treatment intended to lead to patient thinking differently about their symptoms.
 

Simon

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This is the only reference I saw talking about "possible side effects":
Primary outcome data at six months will be examined once data are available from 50 patients, to ensure that neither arm is having a detrimental effect on the majority of patients. An independent statistician with no other involvement in the study will investigate whether more than 20 participants in the study sample as a whole have experienced a reduction of ≥ 30 points on the SF-36 at six months.

http://www.trialsjournal.com/content/pdf/1745-6215-14-444.pdf

A 30+ point deterioration is a huge deterioration.
Requiring 20 participants have it is a high threshold. For example, with 50 patients, there will on average only have been 25 patients who had done LP.

And in total they
"aim to recruit 80 to 112 participants to the study."
i.e. 40 to 56 participants, on average, for LP.

By contrast, this is what they are using for improvements:
Consensus was agreed by each panel that a small clinically important difference would be 10... A moderate improvement was defined as 20 and a large improvement as 30.
Yes, 30+ points is a huge deterioration, 3.5x what PACE called a clinically useful difference. We are talking relapses here, so effectively the authors are saying that:
"Primary outcome data at six months will be examined once data are available from 50 patients, to ensure that neither arm is having a detrimental effect on the majority of patients" means that if less than half of patients relapse then there is nothing major to worry about. I wonder if that would be acceptable in a drug trials?

Thanks D.

I was just reading a commentary on that, which seemed relevant to a lot of discussion on PR, and perhaps particularly to @Simon

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1361157/

The full paper for the study cited and being commented upon is here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1361158
My hear always sinks when someone flags a up a paper that looks both relevant and important: lot of reading needed. But thanks.
 
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My heart always sinks when someone flags a up a paper that looks both relevant and important: lot of reading needed. But thanks.

Sorry Simon. The commentary which I thought would be of most interest to you was pretty short, and seems to just back up all the things you've been saying.

Although there is stuff like this from the cited paper:

However, the measures we are investigating are, indeed, patient-reported, and patient-informed thresholds for important change are needed, as well as a more directly informed method to incorporate a clinical perspective. Undeniably, in an ideal approach to medical decision making, clinicians and other consumers of CID standards would always use and incorporate their knowledge of the patient's preferences and values. Therefore, it is important to articulate that we have chosen not to value the panels' opinions as “greater” than patients', despite the focus of this comparison report. Instead, in addition to the expert panel data, we are also gathering two other streams of data as part of a large multicentered study.

re the LP paper and this claim:

Consensus was agreed by each panel that a small clinically important difference would be 10 as this is the equivalent to two state changes

Actually, two of the three (COPD and asthma panels) panels decided 10 was a small clinically important difference, while the heart disease panel decided that 15 was a small CID. And none of them said that a change of just 10 would be important in a trial like SMILE, where there's such potential for bias to distort results - I think that this is important, as a smaller change could be assumed to be important if there was clear evidence that the change was a result of a real improvement in health rather than bias.

Also, the cited paper could (if taken seriously) be seen as evidence that different conditions have different CIDs, and therefore that SMILE should not just use the asthma and COPD panel's consensus for CID for CFS patients.

Really though, I thought the commentary did a good job of criticising this paper, and found it hard to take it that seriously.

(I need to leave SMILE alone until I get some other things done!!)
 
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biophile

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Minor correction in red below:

Simon rephrasing the authors said:
"Primary outcome data at six months will be examined once data are available from 50 patients, to ensure that neither arm is having a major detrimental effect on the majority of patients" means that if less than half of patients relapse then there is nothing major to worry about. I wonder if that would be acceptable in a drug trials?

I would not trust these researchers with my child.
 

Simon

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Location
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the authors don't think patients should have a [psychiatric] diagnostic interview

A peer reviewer said:
5) The clinical and diagnostic assessment at inclusion in the study is only superficially described. It has to be better described, i.e. how will the establish the diagnosis, which criteria will be used and how will they ensure a proper diagnostic procedure, both as to psychiatric and non-psychiatric differential diagnoses etc. The best would be if they used a standardised procedure such as a diagnostic interview, which is available in child psychiatry.
in reply the authors said:
We have added the following sentence to the paragraph on “population” page 5: “Children are given a diagnoses of CFS/ME after a thorough assessment and screening blood tests according to guidelines produced by the National Institute for Health and Care Excellence (NICE)[8].” Whilst it is possible that CFS/ME services may miss some psychiatric diagnoses, we disagree that a diagnostic interview would be appropriate in a clinical setting, and indeed this is not recommended by NICE. We therefore feel that adding a diagnostic interview for this trial would not reflect what happens in specialist medical care and would not be appropriate.
I think this is important. I hadn't realised that NICE didn't require a psychiatric diagnostic interview (required by all research case definitions) and it's worrying that such interviews are not standard practice, particularly as the authors admit some psychiatric cases may be misdiagnosed as CFS as a result.

As far as this trial of the Lightning Process goes it is worrying that the study may well include non-CFS psychiatric cases as they may respond well to such a technique, and so lead to misleading results for the trial.
 
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Snow Leopard

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I'm not impressed with their protocol on the issues mentioned above...

Several UK studies found that misdiagnosis was common in adults:

http://www.ncbi.nlm.nih.gov/pubmed/22299071
http://www.ncbi.nlm.nih.gov/pubmed/21132135

Do you guys thing that psychological screening should be implemented into the NICE guidelines? Keeping in mind that some/many patients may dislike psychiatric screening if conducted by a psychiatrist.

Regardless, it should be a part of this trial.
 

Dolphin

Senior Member
Messages
17,567
Do you guys thing that psychological screening should be implemented into the NICE guidelines? Keeping in mind that some/many patients may dislike psychiatric screening if conducted by a psychiatrist.

Regardless, it should be a part of this trial.
Yes, there are two questions: the research scenario and general clinical practice.

It could be quite easy for plenty of people to be misdiagnosed and given one or more psychiatric diagnoses they don't have if it was the norm so I have some doubts although am undecided. In the Belgian clinics, which used Fukuda, there were huge variations in the rates of somatisation disorder diagnosed, with some clinics having rates in the low single figures while at least one had a rate around 90%! It is difficult to believe the patients were that different which suggests bias in terms of diagnosis.

James C. Coyne has written about the problems of screening for distress with Cancer patients.

Another problem with having default psychiatric diagnostic screening in ME/CFS clinics is that it means a psychiatrist will be involved in every clinic who might then have influence about the overall philosophy.

So as I say, I'm undecided for general clinical practice. However, in the research scenario, precision is more important.
 

Tom Kindlon

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Dolphin

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Includes 3 people with "CFS/ME" who got worse after LP

Glob Adv Health Med. 2012 Mar;1(1):30. doi: 10.7453/gahmj.2012.1.1.008.
Worst Cases Reported to the NAFKAM International Registry of Exceptional Courses of Disease.
Fønnebø V, Drageset BJ, Salamonsen A.
Author information

KEYWORDS:
CFS, Exceptional Courses of Disease, Lightning Process, ME, NAFKAM, Registry, case reports, chronic fatigue syndrome, hematologic cancer, homeopathy, myalgic encephalomyelitis, necrotizing vasculitis, prostatitis, sinusitis, worst cases

PMID:

24278799

[PubMed]
PMCID:

PMC3833488

Free PMC Article http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3833488/