Intravenous Cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An Open-Label Phase II Study - 2020 - Rekeland, Mella, Fluge et al

Jaybee00 said:
Multicenter phase 3 if you want to wait about 6+ years. The current study began in 2015 and was published in 2020. A phase 3 study is more complex, plus they have to secure funding. So maybe published in 2027 or 2028. This is not a great option if you have progressive MECFS.
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There are no other great options if you have bad or progressive MECFS though are there ? Atleast it is a treatment study and perhaps with the potential of increased European funding, it’s something they can tap into, or else get a 50/50 split patient/ state funding as they did for rituximab.

just linking here to another treatment exploration study given there arent many I’m aware of
http://simmaronresearch.com/2019/04/help-simmaron-amplify-therapies-for-m-e/
 
strategist said:
They improvements could disappear in a phase 3 trial, but how does one explain the association between greater improvement and HLA alleles?

Is it possible that the treatment is no better than placebo, but the HLA alleles are protective and improve outcomes?
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They are comparing a group of 12 with the alleles with a group of 28 without. The numbers are just much too small to be reliable and meaningful. My bet is it is just random, it means nothing.
 
Sid said:
We've been down this road before with open label rituximab studies before the blinded RCT showed it was trending toward being worse than useless.

The results here are strongly suggestive of a spontaneous improvement / regression toward the mean / placebo response in patients who were probably on the trajectory of improving slightly anyway and now this improvement has been attributed to the drug because they happened to be on the drug while the improvement was happening. Humans have a natural tendency to attribute random events to specific causal factors which is why blinded studies are essential.

Their patients were mild to begin with (3,200 steps per day prior to treatment). The responders were doing better to begin with (3,622 steps prior to treatment) and the improvement in responders only increased their step count by ~2,000 steps which is well within the range of mild spontaneous improvement and wishful thinking encouraging people to push the boundaries of their existing energy envelope. I know many normal sedentary people who do only 3000-4000 steps per day. And when I had mild ME/CFS, I could do more steps than this yet was still feeling like death most of the time.

The SF-36 score in improved patients suggests that they were still maimed and functioning at the level of people with kidney or heart failure.

I hope that the unscrupulous doctors who prescribed rituximab off-label to (understandably desperate) patients despite constant warnings not to do so by the Norwegian researchers won't use this paper as justification for doing the same with cyclophosphamide considering its side effect profile.
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It seems that mild ME was reason for exclusion
Inclusion criteria were: a diagnosis of ME/CFS according to the Canadian criteria (4); age 18–66 years; disease duration more than 2 years; and disease severity mild-to-moderate, moderate, moderate-to-severe, or severe. Patients with either mild or very severe disease (completely bedbound and in need of help for all basic activities of daily living) were not included.

As far as I understand 3.200 steps pr. day was mean, not for everyone? So there might have been a few patients able to go for walks and thus pulling that number upwards for the rest. It's also interesting that they write:
“Steps per 24 hours” is an objective measure, but not a perfect way to validate symptom improvement because individual patients will use their improved energy for different purposes. Some will walk, while some will prefer to read or increase the time for social activity.
 
Kalliope said:
It seems that mild ME was reason for exclusion
Inclusion criteria were: a diagnosis of ME/CFS according to the Canadian criteria (4); age 18–66 years; disease duration more than 2 years; and disease severity mild-to-moderate, moderate, moderate-to-severe, or severe. Patients with either mild or very severe disease (completely bedbound and in need of help for all basic activities of daily living) were not included.

As far as I understand 3.200 steps pr. day was mean, not for everyone? So there might have been a few patients able to go for walks and thus pulling that number upwards for the rest. It's also interesting that they write:
“Steps per 24 hours” is an objective measure, but not a perfect way to validate symptom improvement because individual patients will use their improved energy for different purposes. Some will walk, while some will prefer to read or increase the time for social activity.
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Ok so they were "mild-to-moderate" not mild. The subgroup of responders was doing 3,600 steps per day on average before the treatment. That's quite a lot considering that half of the general population walks less than that:

Poll commissioned by Cancer Research UK finds 52% of adults walk only 2,000 steps a day, figures described as ‘worrying’ and likely to increase cancer risk.
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https://www.theguardian.com/society...-of-adults-walk-less-than-a-mile-a-day-survey
 
Sid said:
We've been down this road before with open label rituximab studies before the blinded RCT showed it was trending toward being worse than useless.

The results here are strongly suggestive of a spontaneous improvement / regression toward the mean / placebo response in patients who were probably on the trajectory of improving slightly anyway and now this improvement has been attributed to the drug because they happened to be on the drug while the improvement was happening. Humans have a natural tendency to attribute random events to specific causal factors which is why blinded studies are essential.
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I dont disagree that we have to look at the results with great caution, but I dont think it is very likely that the study had so many patients that were undergoing a slow gradual spontaneous improvement. All research (not with canadia criteria mind u) suggests that around 5 percent undergoes spontaneous recovery, however, its possible they all are experiencing a placebo response (as seen in rtx-trials). Thats why we need a phase 3 to draw any conclusions
 
Trish said:
In the larger Rituximab double blind trial there were 35% 'responders' at 12 months in the placebo group.
https://www.s4me.info/threads/intra...nd-mella-fluge-et-al.14925/page-3#post-257355
In this small open label cyclophosphaminde trial there were 22 responders out of 40 at 18 months, dropping to 15 out of 40 at 4 years (37%).
So in the end, cyclo was no better than placebo.
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We dont know what the placebo rate will be next time though, it seemed unusually high for me
 
Sid said:
Ok so they were "mild-to-moderate" not mild. The subgroup of responders was doing 3,600 steps per day on average before the treatment. That's quite a lot considering that half of the general population walks less than that:

https://www.theguardian.com/society...-of-adults-walk-less-than-a-mile-a-day-survey
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As @Kalliope says this will vary between countries. Norway is not exactly an active nation, but 2/3 of our population reach the daily minimum criteria of 30 minutes of "moderate activity" set by the health department.

I'm mild and my average step count in a month can vary between around 1000 to above 17000 (I've had a few periods of remission in my years of illness), I don't think I'm the only one like this.

Marky said:
I dont disagree that we have to look at the results with great caution, but I dont think it is very likely that the study had so many patients that were undergoing a slow gradual spontaneous improvement. All research (not with canadia criteria mind u) suggests that around 5 percent undergoes spontaneous recovery, however, its possible they all are experiencing a placebo response (as seen in rtx-trials). Thats why we need a phase 3 to draw any conclusions
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What research is included in "all research"? The five percent figure comes from Ramsay, does it not? Or are you referring to the systematic review on prognosis for chronic fatigue from 2005? I can't think of others that mention five percent. What about the australian study from last year(?)?. I really dislike that we keep using this five percent when both the type of disease (ME vs other fatiguing condition) and what constitues "recovery" can be so different between studies. #rant
 
There are some of you that points out that cyclo should not be allowed by experimental doctors until a phase 3 study is performed with positive results, and the researches do too. I understand the possible risks.

Yet I disagree. I tried rituximab by the experimental doctor in Sandnes, and was glad that I wasn’t in the study. Then I had felt more obliged to adhere to the protocol and do all doses. I did four doses, and on the fourth I deviated from the protocol, having it 1,5 month late.
That was because I found myself an early responder, but the response vanished with the third dose. Then I decided I wouldn’t have more doses until the improvement came back, that was ok by the doc, I had to wait four months for that. Then I went for my fourth dose, got sick again, and never saw that improvement again. Of course I didn’t want more doses. But if I was in the study I would not feel free to just drop out. And possibly get worse by the remaining doses. That is what I think would have happened.

So, if cyclo was available for “buying” I would have bought one dose and see how that goes, and decide further after that.
But I also see the problems, yes.
 
Marky said:
I dont disagree that we have to look at the results with great caution, but I dont think it is very likely that the study had so many patients that were undergoing a slow gradual spontaneous improvement. All research (not with canadia criteria mind u) suggests that around 5 percent undergoes spontaneous recovery, however, its possible they all are experiencing a placebo response (as seen in rtx-trials). Thats why we need a phase 3 to draw any conclusions
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But these patients were not experiencing spontaneous recovery. They were mildly improved at best and as Trish pointed out the results were comparable to the placebo arm of the RTX trial. Their SF-36 score was still terrible compared to the median score in the general population.

I strongly disagree that we need a phase 3 trial of this toxic drug that showed essentially null result in an unblinded study. I would hope that no one would fund such a study and that any ethics committee looking at such a proposal would put a stop to it before more people were harmed. Enough people have been harmed by RTX already, financially and otherwise.
 
There is probably a big auto-immune component in subgroups of ME patients. Since ME still is not a disease. After 5 years of having an ME diagnosis I got diagnosed with Primary Sjogren (no sicca symptoms). Cyclofosfamide is on the list of treatments for primary sjogren... Makes sense certain patients got better in this "ME" study.
 
@Sid

I respectfully disagree with your assessment. There was not a null result in this study. "Fatigue score and other outcome variables showed significant improvements compared to baseline." "At baseline, only two of the responders had part-time work participation. During follow-up, at least nine out of 22 responders returned to either part-time of full-time work or studies." This seems to be a good thing, no? There were side effects/adverse events, but this is expected in all drug trials.

Who was physically harmed by rituximab? I don't know of people who were.

Again a lot of this boils down to an unhelpful belief on these fora that the treatment/cure for ME/CFS will be very benign, like taking a vitamin pill. Almost all of the medications for chronic diseases have serious/dreadful side effects. So I vigorously support a Phase III trial.
 
I think the step count should be taken with a grain of salt, and referred to as an activity measure. That's okay if you are comparing like with like. The paper describes using SenseWear activity armband. So if you have sufficient arm movement it may count as steps.

I've no idea which version of armband they used but this papers conclusions should be taken into account.
Validity of the SenseWear armband step count measure during controlled and free-living conditions
Conclusion
The SWA underestimates steps during treadmill walking and appears to overestimate steps during free-living compared to the DIGI pedometer. Caution is warranted when using the SWA to count steps. Modifications are needed to enhance step counting accuracy.
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Jaybee00 said:
Who was physically harmed by rituximab? I don't know of people who were.
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Anecdotally I'm aware of a number of people who were. Given that they haven't gone public with their stories I won't reveal names, which I appreciate then means that I can't provide you with any proof, other than the fact that I believe there were. Additionally, 26% of patients (20 in total) in the stage 3 Ritux trial had adverse effects - can't access the full paper at the moment to look at what they where but that is the figure reported in the abstract.

Jaybee00 said:
Again a lot of this boils down to an unhelpful belief on these fora that the treatment/cure for ME/CFS will be very benign, like taking a vitamin pill.
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I have seen no evidence of such a belief here. With almost every treatment there will always be a cost to go along with the benefit, and currently there is insufficient evidence of potential benefit that outweighs the potential cost to convince me to take cyclo, or to be comfortable in supporting people to try this outside of a trial.

I'm in two minds about a stage 3 trial of cyclo - the results from this trial seem to mirror the results of the stage 2 ritux trial too closely for my liking, which puts me off, but we might need a stage 3 trial to provide us with a, hopefully, definitive answer.
 
OMF in their new may fundraiser info say they plan to do two pilot treatment trials of kynurenine & mestonin. I think that the Later i am not impressed particular will certainly please a lot of people. Jen brea had help from it and a science graduate on Twitter has gone on it following a CPET test with abnormal results, and found it helpful I believe. So I’m delighted there are a few therapies being explored.

if this is considered too off topic please move but I thought that it Tied in with theme of current and proposed treatment trials.
 
Andy said:
I'm in two minds about a stage 3 trial of cyclo - the results from this trial seem to mirror the results of the stage 2 ritux trial too closely for my liking, which puts me off, but we might need a stage 3 trial to provide us with a, hopefully, definitive answer.
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I feel the same way. I'm hoping there might be a few more papers to come, perhaps trying to detect certain antibodies such as the peptide array method of this paper. Maybe they can identify something common among responders.
Humoral Immunity Profiling of Subjects with Myalgic Encephalomyelitis Using a Random Peptide Microarray Differentiates Cases from Controls with High Specificity and Sensitivity.

I think Bateman Horne had promising findings on a similar peptide array study from a first cohort that they were running a second cohort through. But not heard anything on that for 18 months or more.......
 
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alalush said:
There is probably a big auto-immune component in subgroups of ME patients. Since ME still is not a disease. After 5 years of having an ME diagnosis I got diagnosed with Primary Sjogren (no sicca symptoms). Cyclofosfamide is on the list of treatments for primary sjogren... Makes sense certain patients got better in this "ME" study.
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That's interesting, I've read that people with Sjogren's have an increased risk of developing non-hodgkin's lymphoma. I believe that they first noticed that cyclophosphamide was having an effect when they treated patients for non-hodgkin's who also had ME and found that the ME improved after the treatment (this was certainly the case with rituximab but I think also the case with cyclophosphamide?) Might it be that those patients actually had undiagnosed Sjogren's prior to developing non-hodgkin's? Maybe in the trial it is helping the subgroup who actually have Sjorgren's?

nb/ - I might also be completely wrong about this, it's all a bit over my head, do correct me if this is irrelevant/wrong!
 
Midnattsol said:
As @Kalliope says this will vary between countries. Norway is not exactly an active nation, but 2/3 of our population reach the daily minimum criteria of 30 minutes of "moderate activity" set by the health department.

I'm mild and my average step count in a month can vary between around 1000 to above 17000 (I've had a few periods of remission in my years of illness), I don't think I'm the only one like this.


What research is included in "all research"? The five percent figure comes from Ramsay, does it not? Or are you referring to the systematic review on prognosis for chronic fatigue from 2005? I can't think of others that mention five percent. What about the australian study from last year(?)?. I really dislike that we keep using this five percent when both the type of disease (ME vs other fatiguing condition) and what constitues "recovery" can be so different between studies. #rant
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Yes 5 percent has been the mean in the studies looked at (not after strict criteria,), the systematic review being one of them. Im not claiming it is correct or anything but I know for a fact its not higher, hence why i used it for the sake of argument here.
 
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