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What is the ME Association doing about Rituximab? Statement 8 July 2013

Dolphin

Senior Member
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Thanks Dolphin. Do you mean SF-36 v2, or something else?
Yes, SF36v2. I think the questions are the same (or perhaps very small changes) but scoring method different. Population mean of 50, standard deviation (IIRC) of 10.
 

Jonathan Edwards

"Gibberish"
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5,256
Isn't that 3 out of 15 treated? The other 15 were on placebo? 20% full remission is considered the best sort of outcome for drugs for rheumatoid arthritis. In practice that tends to pan out to about two thirds of patients being very satisfied with their response. To get this level of response without subgrouping is surprisingly good to my mind. We just need to be sure it is reproducible in other populations.
 

Bob

Senior Member
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I don't have time to re-read the paper just now, Bob - someone else will have to pick this one up - but just wanted to say that I think you're setting the bar extremely high if you're saying that patients who don't get a full remission - full remission! - will be disappointed. Frankly, at this point, I'd be thrilled with an increase in function of ten percentage points. It would transform my life.

Yes, that's a good point. I'm just trying to determine what our expectations should be. And I think it's OK to point out that most of us shouldn't expect full remission after treatment with Rituximab. But what can we expect, based on the information available so far? I can't yet work it out, and that's what I'm trying to do.

Thanks for raising these issues, though. If you've got these questions, others will and it will be useful to discuss it. I just think it's important not to get sucked into the mindset of 'it's not perfect so it's not good enough'. I understand, of course, the years of frustration that people have and our wish for a return to health. But getting there is going to be a series of research steps and this is a very important one to take.

It's confusing that there are so many threads about Rituximab now, and perhaps I should have posted my concerns and analysis on a thread that isn't related to fundraising? I'll have a look for the original thread re the Fluge and Mella study.

I don't have fixed views on Rituximab, except that I think the research is very important and has the potential to transform our lives. I think it's a reason for cautious optimism, and I absolutely want to see this trial go ahead.

But I think we both agree that we should all donate! :)
Donations always welcome! :)
 

Dolphin

Senior Member
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17,567
OK, thanks Dolphin. I can't see that information in the paper but I'll have another look.

It was clarified in this comment:

http://www.plosone.org/annotation/listThread.action?root=21433


Could the authors give the raw (non-normalized) SF-36 subscale scores

Posted by tkindlon on 05 Nov 2011 at 14:49 GMT
The eight SF-36 subscale scores in the Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) field have generally been given in the past as raw scores (the PCS and MCS are given as normalised scores). The figures in Table 4 look to me like the eight subscales have been normalised. This makes comparisons with most of the studies in the ME/CFS field difficult especially when different population norms exist for different countries. Also, it means many may interpret them as raw scores when as I say they appear to me to be normalised scores.

Assuming I am correct and these are normalised scores, could the authors give the eight subscale scores as raw (i.e. unadjusted scores). Alternatively, could the authors give the data on which population norms were used e.g. was it a Norwegian sample or a US sample (for example).

The figures look much more impressive if the figures in Table 4 are normalised scores e.g. if one looks at the physical function subscale, with a baseline mean of 34 and a mean max change of 39%. A mean max change of 39% is 47.26 (although this may not be exactly correct as there is rounding). This is very close to 50 i.e. the population norm so looks much more impressive than if it was 47 as a raw score.

Thank you.
Competing interests declared: I am the information officer of the Irish ME/CFS Association. All my work for the Association is voluntary (i.e. unpaid).
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RE: Could the authors give the raw (non-normalized) SF-36 subscale scores

Fluge replied to tkindlon on 07 Nov 2011 at 15:03 GMT


We thank dr. Kindlon for his remark to Table 4 in our article describing SF-36 scores, and for the opportunity to clarify aspects of the analyses to help the readers interpret the data.
The patients recorded the SF-36 short form scheme (Norwegian translation) at baseline (pre-treatment) and every month until 10 months follow-up.
The analyses of SF-36 short forms, with physical health summary score, mental health summary score, and scores for the eight SF-36 subdimensions, were generated from a SPSS syntax file.
Dr. Kindlon is correct that the values for the SF-36 subdimentions are norm-based, and the population norm from US 1998 was used.
The table presents data on SF-36 scores for physical health summary score, mental health summary score, and scores for the eight SF-36 subdimensions, and shows baseline levels (mean with SD) for both the Rituximab and Placebo groups. Because the time-frame for responses vary among patients, we chose also to present the mean values of maximum changes in SF-scores during follow-up, as compared to baseline.
We think the SF-36 data supports the main findings of the study, showing a significant difference in maximum changes as compared to baseline, in favour of the Rituximab group, for physical health summary score, and the subdimentions physical function and bodily pain. We should take caution in comparing these data to other CFS/ME studies, and we think the most important aspect is the comparison between the two intervention groups in our study.
Competing interests declared: Haukeland University Hospital has patents and pending patent applications on the issue of B-cell depletion therapy for chronic fatigue syndrome. Family members of WO2009083602 A1 are pending, as well as granted US 12/348024. The two authors ØF and OM are named as inventors in these applications.
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RE: RE: Could the authors give the raw (non-normalized) SF-36 subscale scores

SMcGrath replied to Fluge on 30 Nov 2011 at 10:00 GMT


Thank you for clarifying that Table 4 uses SF-36 norm-based scores. Could the authors also confirm if the maximum change percentages are per cent changes to the norm-scores or to the raw (0-100) scores?

Ideally, could the authors also provide mean "maximum" SF-36 scores (I don't think they can be calculated from the data given in Table 4) for both Rituximab and placebo groups? This aditional information would give readers the fullest picture of the size of the effect from Rituximab.
No competing interests declared.
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RE: RE: RE: Could the authors give the raw (non-normalized) SF-36 subscale scores

Fluge replied to SMcGrath on 01 Dec 2011 at 17:15 GMT


The analyses of the SF-36 short forms were generated from a SPSS syntax file, with values norm-based using the population norm from US 1998.
For all dimensions (physical health summary score, mental health summary score, and the eight subdimensions), the baseline values (before intervention) and values generated from SF-36 recorded every month until 10 months after intervention, were calculated the same way using the same syntax file.
Due to different time frames for clinical responses, we chose to calculate in each patient the maximum changes during follow-up (for each dimension), as compared to the baseline level for the actual dimension.

In addition to the baseline levels for each dimension presented as mean with standard deviation in each group, we also the present the maximum changes during follow-up as compared to baseline (in percent), and demonstrated as mean with standard deviation for each group (Rituximab and Placebo). These maximum changes during follow-up therefore are not representative for the complete follow-up period, but reflect the status at the time the patients are feeling at the best (or worst) i.e. with maximum difference from baseline.
As an answer to the question, the maximum changes presented are percent changes from the baseline scores, which were norm-based.

Two examples:
For patient ID4 in the Rituximab group, the scores for mental health summary score during the study were: baseline: 52.9, month 1: 52.9, month 2: 54.0, month 3: 56.9, month 4: 57.5, month 5: 56.9, month 6: 52.4, month 7: 53.4, month 8: 52.9, month 9: 52.9, month 10: 51.2.
Thus in this patient the maximum change in mental health summary score during follow-up was 9%. (Score 57.5 (at 8 months) – score 52.9 (baseline)/ score 52.9 (baseline)=0.09).
In Table 4, the mean values for mental health summary score at baseline were 46 in the rituximab group, and 46 in the placebo group.
When calculating the maximum difference from baseline during follow-up for all patients, for mental health summary score, the mean values were 9% (SD 54) in the rituximab group, and 5% (SD 32) in the placebo group, which was not a significant difference between the two groups.

For patient ID19 in the rituximab group, the scores for the subdimension bodily pain during follow-up were: baseline: 28.7, month 1: 28.7, month 2: 36.6, month 3:36.6, month 4: 50.3, month 5: 50.3, month 6: 36.6, month 7: 36.6, month 8: 40.7, month 9: 32.8, month 10: 28.7.
Thus in this patient the maximum change in bodily pain score during follow-up was 75%. (Score 50.3 (at 8 months) – score 28.7 (baseline)/ score 28.7 (baseline)=0.75)
In Table 4, the mean values for bodily pain score at baseline were 32 in the rituximab group, and 34 in the placebo group.
When calculating the maximum difference from baseline during follow-up for all patients, for bodily pain, the mean values (for maximum difference) were 40% (SD 31) in the rituximab group, and 8% (SD 24) in the placebo group, which was a significant difference between the two groups.
Competing interests declared: Haukeland University Hospital has patents and pending patent applications on the issue of B-cell depletion therapy for chronic fatigue syndrome. Family members of WO2009083602 A1 are pending, as well as granted US 12/348024. The two authors ØF and OM are named as inventors in these applications.
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RE: RE: RE: RE: Could the authors give the raw (non-normalized) SF-36 subscale scores

SMcGrath replied to Fluge on 16 Dec 2011 at 20:05 GMT


Thank you for the comprehensive explanation of how maximum change percentages were calculated from the norm-scores for individual patients.

For those not familiar with norm-based scoring, it's worth pointing out that the percentage increase in the underlying raw (0-100) scores will be much bigger than the increase for norm-scores.

Take the SF-36 Physical Function (PF) results as an example. The norm-score Rituximab group baseline was 34 with a mean maximum increase of 39%, giving an estimated mean maximum norm-score of 47.3. However, the equivalent raw scores for these figures are: baseline 44.9 , maximum 76.5 - an increase in the raw score of 70% or 31.6 points (i.e. much higher than the 39% increase in norm-scores).

The 31.6 points raw score gain for the Rituximab group in this example compares with a gain of 9.2 points (19%) in the Placebo group on the same basis. This represents an exceptional relative peak gain in physical function for the Rituximab group.

SF-36 Physical Function scores are of particular interest as substantial impairment is a defining feature of CFS. Although in this study SF-36 PF scores were one of a number of secondary outcomes, other studies - including the two largest clinical trials to date (1,2) - have used them as a primary outcome, albeit using endpoint rather than peak scores.

References:
1. Wearden AJ, Dowrick C, Chew-Graham C, et al on behalf of the PACE trial management group Fatigue Intervention by Nurses Evaluation (FINE) trial writing group and the FINE trial group. Nurse led, home based self help treatment for patients in primary care with chronic fatigue syndrome: randomised controlled trial. BMJ. 2010;340:c1777.

2. White PD, Goldsmith KA, Johnson AL, et al on behalf of the PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011;377(9768):823-36.
No competing interests declared.
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SF-36 PF estimate if non-responders only scored the same as the placebo group

tkindlon replied to SMcGrath on 16 Dec 2011 at 20:38 GMT


Thanks to SMcGrath for posting that information.

Note that 76.5 would be a lower bound* for the SF-36 PF scores for the responders.

We only have SF-36 PF scores for 13 of the CFS patients on Rituximab, 9 of whom were responders.
If the non-responders only increased at peak by the same amount as the placebo group i.e. 9.2, then the 9 responders would have reached, on average, a very impressive 86.5** on the SF-36 PF.

*Approximately as these calculations depend on average percentage increases - what a particular percentage increase translates to depends on the initial value. But we don't have added information to make any assumptions other than the individual differences would balance out when the mean was obtained.

**Calculation (using SMcGrath's figures): Total increase among the 13 on Rituximab: 31.6*13=410.8 points. Amount of this obtained by the four non-responders, if the response the same as the placebo group: 9.2*4=36.8.
Therefore, improvement in responders compared to baseline: (410.8-36.8)/9=41.6.
Or mean score at peak = baseline score + improvement = 44.9+41.6=86.5
Competing interests declared: Information Officer (voluntary position), Irish ME/CFS Association
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SF-36 USA 1998 population norms (raw figures)

tkindlon replied to Fluge on 16 Dec 2011 at 21:15 GMT


It took me a little while but I have now found a place giving the population norms in raw figures: http://www.sf-36.org/nbsc... (and type in a figure). There are probably other places but this does the job:

Non normalised USA 1998 population means (SDs):

PF: 83.0 (23.8)
RP: 77.9 (35.3)
BP: 70.2 (23.4)
GH: 70.1 (21.4)
VT: 57.0 (21.1)
SF: 83.6 (23.0)
RE: 83.1 (31.6)
MH: 75.2 (17.6)
Competing interests declared:Information Officer (voluntary position), Irish ME/CFS Association
 

Bob

Senior Member
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Location
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Isn't that 3 out of 15 treated? The other 15 were on placebo? 20% full remission is considered the best sort of outcome for drugs for rheumatoid arthritis. In practice that tends to pan out to about two thirds of patients being very satisfied with their response. To get this level of response without subgrouping is surprisingly good to my mind. We just need to be sure it is reproducible in other populations.

Ah yes, thank you, I got confused. 15 were in the treatment group. I'll amend my earlier post.

I'm not certain that three patients experienced full remission: I'm basing this on media reports. Others, including yourself, might know more about it.

I'm glad that you think it's a very good outcome. It's helpful to have your professional input about it.

I'm feeling less cautious about it than I did earlier.
 

Dolphin

Senior Member
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Thank for that, Dolphin. I don't think I'd seen those comments before now. (But with my memory, I might have read them in full. Who knows?!?) That does make it much more difficult for me to interpret the results.

Although to be clear a score of 47 normalised scoring is much, much better than 47 on the scoring used for the PACE Trial (although the 47 only represents a peak).
 

user9876

Senior Member
Messages
4,556
Although to be clear a score of 47 normalised scoring is much, much better than 47 on the scoring used for the PACE Trial (although the 47 only represents a peak).

I need to reread the paper but I think they are quoting the physical health scores which is a summary measure over four subscales which includes the physical function score that PACE uses but also the Role-Physical, Bodily Health and General health subscales.

The mental health scores are also a combination of 4 subscales.

It does worry me that they quote mean differences since I'm not sure that the questionaire structures justify the mean rather than using the median. Depending on how normalisation is done though this may help.

If you are interested in individual patient scores and what happened to the different patients graph
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0026358.g003/originalimage
Shows graphs of various responce measures over time for the 10 patients that responded.
 

Dolphin

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biophile

Places I'd rather be.
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I have not done any calculations for myself yet, but I think these are the gold nuggets:

SMcGrath said:
For those not familiar with norm-based scoring, it's worth pointing out that the percentage increase in the underlying raw (0-100) scores will be much bigger than the increase for norm-scores.

Take the SF-36 Physical Function (PF) results as an example. The norm-score Rituximab group baseline was 34 with a mean maximum increase of 39%, giving an estimated mean maximum norm-score of 47.3. However, the equivalent raw scores for these figures are: baseline 44.9 , maximum 76.5 - an increase in the raw score of 70% or 31.6 points (i.e. much higher than the 39% increase in norm-scores).

The 31.6 points raw score gain for the Rituximab group in this example compares with a gain of 9.2 points (19%) in the Placebo group on the same basis. This represents an exceptional relative peak gain in physical function for the Rituximab group.

Do keep in mind however that, as SMcGrath later points out, these are peak scores and not endpoints.

tkindlon said:
Note that 76.5 would be a lower bound* for the SF-36 PF scores for the responders.

We only have SF-36 PF scores for 13 of the CFS patients on Rituximab, 9 of whom were responders.

If the non-responders only increased at peak by the same amount as the placebo group i.e. 9.2, then the 9 responders would have reached, on average, a very impressive 86.5** on the SF-36 PF.

The more recent study (so far unpublished) is rumoured to have better results.
 

Sasha

Fine, thank you
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Do keep in mind however that, as SMcGrath later points out, these are peak scores and not endpoints..


Worth bearing in mind that patients relapsed (as I think happens with other autoimmune diseases, where they need a maintenance dose) so a peak score rather than endpoint seems appropriate. Presumably this choice was planned and based on a knowledge of how Rituximab behaves.
 

Bob

Senior Member
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Yes, the peak/maximum scores seem appropriate because long-term maintenance doses were not being administered.
I think that the next trial is investigating longer-term maintenance doses, if my memory serves me right.
 

Bob

Senior Member
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It seems that I had completely misinterpreted the Norwegian Rituximab trial, because I hadn't studied it in enough detail, and hadn't realised that the SF-36 scores had been normalised. Thanks to Dolphin and biophile for pointing out the details that I needed.

It seems that S McGrath has already done the analysis that I was attempting to do earlier...

I have not done any calculations for myself yet, but I think these are the gold nuggets:
S McGrath said:
For those not familiar with norm-based scoring, it's worth pointing out that the percentage increase in the underlying raw (0-100) scores will be much bigger than the increase for norm-scores.

Take the SF-36 Physical Function (PF) results as an example. The norm-score Rituximab group baseline was 34 with a mean maximum increase of 39%, giving an estimated mean maximum norm-score of 47.3. However, the equivalent raw scores for these figures are: baseline 44.9 , maximum 76.5 - an increase in the raw score of 70% or 31.6 points (i.e. much higher than the 39% increase in norm-scores).

The 31.6 points raw score gain for the Rituximab group in this example compares with a gain of 9.2 points (19%) in the Placebo group on the same basis. This represents an exceptional relative peak gain in physical function for the Rituximab group.

To summarise S McGrath's interpretation of average peak improvements for SF-36 PF scores in the treatment group:

Equivalent raw average SF-36 PF scores & improvements in treatment group:
Baseline score 44.9
peak increase as a result of placebo effects 9.2
Maximum score after placebo effects added 54.1
further peak increase after treatment 22.4 (total peak increase for treatment, including placebo effects = 31.6)
Maximum score 76.5

Yes, these seem like respectable average peak improvements. Much better than my original interpretation! Now I better understand the enthusiasm for the research.

And, as T Kindlon points out, the benefits would be more impressive for those who responded to treatment.
 

Bob

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Sorry chaps but it's still all Greek to me :confused: o_O

I hesitate to interpret the SF-36 physical function (PF) scores further, because I haven't read the study in enough detail, and I might be inappropriately taking them out of context...

But an improvement in (non-normalised) average SF-36 PF scores from 44.9 to a peak of 76.5 seems respectable.
These are average scores, so a number of participants would have better than average peak improvements, and a number of patients would also have peak scores above 76.5.

The SF-36 PF scale is between 0-100, and a score of 100 would be perfect health. Some research papers have used a score of 80 to indicate a 'recovery', but it's not perfect health. Scores above 80 could perhaps be considered to be mild physical impairment.

But these are peak scores (the maximum score that was recorded during the trial), so long-term therapeutic effects are not indicated in these scores. I think the next study will investigate the effectiveness of maintenance doses, and will hopefully report on improvements over the longer term.
 

Sasha

Fine, thank you
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It seems that I had completely misinterpreted the Norwegian Rituximab trial, because I hadn't studied it in enough detail, and hadn't realised that the SF-36 scores had been normalised. Thanks to Dolphin and biophile for pointing out the details that I needed.

It seems that S McGrath has already done the analysis that I was attempting to do earlier...



To summarise S McGrath's interpretation of average peak improvements for SF-36 PF scores in the treatment group:

Equivalent raw average SF-36 PF scores & improvement in treatment group:
Baseline 44.9
peak increase in placebo group 9.2
Maximum after placebo effects 54.1
further peak increase after treatment 22.4 (total peak increase for placebo & treatment = 31.6)
Maximum after treatment 76.5

Yes, these seem like respectable average peak improvements! Much better than my original interpretation. Now I better understand the enthusiasm for the research.

And, as T Kindlon points out, the benefits would be more impressive for those who responded to treatment.



Thanks, Bob - looks to me like we need a good summary of this somewhere.
 

Bob

Senior Member
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Thanks, Bob - looks to me like we need a good summary of this somewhere.

Yes, that would be good, but not by me. I've got a lot of reading to do before I fully understand the paper. And my understanding of the results is based entirely on S McGrath's very helpful analysis of the SF-36 PF scores.
 

Firestormm

Senior Member
Messages
5,055
Location
Cornwall England
Morning,

Someone on Facebook was asking for information about Rituximab last night; and I remembered the following article from Discover magazine back in April. On reading it I realised that Prof. Edwards helped with some of the background and is indeed quoted. Anyway, a little refreshing of what it was all about was in order. Thought you all might like a recap too :)

Are B-Cells to Blame for Chronic Fatigue Syndrome?