I don't think it's right to attribute non-drug improvements to 'placebo effects'. They're 'non-treatment' effects and as well as placebo (an effect of belief on the physical body), they can reflect spontaneous, genuine improvement; self-deception; and misreporting (to please others).
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KPAX Synergy (methyphenidate/Ritalin) trial results are out
- Thread starter Sasha
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I don't think it's right to attribute non-drug improvements to 'placebo effects'. They're 'non-treatment' effects and as well as placebo (an effect of belief on the physical body), they can reflect spontaneous, genuine improvement; self-deception; and misreporting (to please others).
Cort
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That's because you're getting caught up in the significance figures which are highly relative vis a vis the placebo response. . Suppose the placebo response had been less. Suppose it had been what it was in the methylphenidate trial. This product would have a highly significant positive response. The degree of the placebo response clearly makes a difference in how a product assessed. I don't know how far that is when placebo response rates boomerang around so much.
The fact that this trial was highly promoted very well may have lent itself to a strong placebo response.
You also missed the fact that the response was going up at the end of the trial and the placebo response was going to down. That suggested a longer trial would have been more statistically significant.
You also ignored the fact that Kaiser held off using stimulants for quite because of just your concerns -what "everyone knows". It turned out that was dogma. In fact the very low rate of side effects for the KPAX formulations - relative to the original methylphenidate trial which did not employ them - indicated that the supplements did in fact protect against side effects.
The CIS score has been well adjusted to functionality - so it's not just a symptom score.
Sorry Valentijn - not a very objective critique in my opinion...
It was not a great result for the trial for sure but it did present possibilities that you ignored IMO.
Cort
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Actually it's just the opposite. One purpose of the phase II trial was to figure out the how big a phase III trial would have to be. The stats from the trial indicate the results would have been statistically significant if the trial had been enlarged substantially....
The idea that the people pushing a mitochondrial/immune supplement packaged with methylphenidate think people with ME/CFS just need to perk up a little bit is ludicrous. Kaiser spent years developing his formula. He originally based it on a nutrient formula that protected HIV/AIDS patients from the harsh effects of antiretroviral drugs (talk about toxic). He found it was much harder to develop for ME/CFS patients.
Why demean work like that? Why treat it like its some behavioral intervention?
The CIS was used at least in part because it was the measurement used during the methylphenidate only trial. By using it they were able to assess the effects of the nutrients better. In fact the KPAX did much better on all scores than the methylphenidate trial but the higher placebo rate - with its very high variability - with some patients having extraordinary placebo responses- reduced the statistical significance of the effect.
The idea that the people pushing a mitochondrial/immune supplement packaged with methylphenidate think people with ME/CFS just need to perk up a little bit is ludicrous. Kaiser spent years developing his formula. He originally based it on a nutrient formula that protected HIV/AIDS patients from the harsh effects of antiretroviral drugs (talk about toxic). He found it was much harder to develop for ME/CFS patients.
Why demean work like that? Why treat it like its some behavioral intervention?
The CIS was used at least in part because it was the measurement used during the methylphenidate only trial. By using it they were able to assess the effects of the nutrients better. In fact the KPAX did much better on all scores than the methylphenidate trial but the higher placebo rate - with its very high variability - with some patients having extraordinary placebo responses- reduced the statistical significance of the effect.
Exactly. The very best we can say is that maybe future research can determine if there's a subgroup who responds, or similar. To think that an insignificant result somehow suggests it's still worth trying is completely incorrect at this point.
And I'd still be far happier to see some more physical and objective outcome measurements, even in a blinded trial. I'm a helluva lot more concerned with my ability to function than how I "feel" about things. It also sounds like the primary outcome measurement was Checklist Individual Strength, which was developed by a CFS psychobabble group from the Netherlands. Pretty damned useless. Maybe they'd get more useful results with a more relevant questionnaire.
I'm getting the impression that the researchers have little understanding of ME/SEID, and think that everything will be better if we're just forced to perk up a bit
The placebo response would be present in both arms of the trial - both the treatment and the non-treatment groups. Which is why the placebo response is subtracted to determine the treatment response.
This isn't sufficient to draw any conclusion other than "maybe they should try a longer trial." It does not change that the results of the current trial were insignificant, and that there's no indication that the treatment helps more than the hype.
No, it just means that two separate trials were performed. Unless the methodologies were literally identical, other than the use of the supplement, results from one trial cannot be extracted to apply to the other. And I'm not sure what the use is of making stimulants theoretically better tolerated when they still produce no significant improvement.
The questions are too vague to be of any use in monitoring ME patients. Which is not surprising, considering the questionnaire which created by a psychobabble group which makes its living by equating ME with fatigue and various psychological disorders. I really can't see a reliable and objective application of "I feel tired", "I feel very active", "Thinking requires effort", and "I feel like doing lots of nice things" each being repeated with slightly different phrasing 4-5 times in the same questionnaire.
Any ME/SEID trial which wants to be taken seriously should be using actometers. And if it's aiming for symptomatic but not disability improvement, it should be carefully asking questions about specific symptoms, in a manner which is minimally subjective. But when a trial relies heavily on a vague and grossly subjective fatigue questionnaire created by psychosomatic proponents, that should raise some very large red flags.
The trial presented evidence that the treatment does not work. Maybe a longer trial or a trial with slightly different procedures will work better in the future, but for all practical purposes, the treatment currently is a failure.
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Bob
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Cort, we can't base our interpretation of a trial on what we'd like the outcomes to be. The whole purpose of a trial is to remove our personal biases, as far as possible, from the process of assessing an intervention. As Val says, the placebo response would be experienced in both groups (intervention and control) so a lower placebo response may make no difference to the overall outcome. A longer trial may have demonstrated efficacy, but that's guesswork, and we can only interpret the data presented. The results of a longer trial may have been better or worse. A lower placebo response may have made no difference, or may have had an unpredictable difference either way (i.e. better or worse outcomes for the intervention).
I'm sorry this trial hasn't worked out for those who wanted it to. It's always a disappointment when medical trials don't work out. I haven't scrutinised the data, but perhaps a few patients responded well to the treatment and most others didn't respond or responded negatively? This is one of the problems with ME/CFS: It's so heterogeneous that, until we have some biomarkers, many medical trials are doomed to failure because only a small subset respond to the treatment. This might be why antiviral trials are always so disappointing. The failure of this study doesn't mean that future similar trials would fail. But the results suggest that it's not going to be helpful to a majority of patients.
I think many (but not all) of us are somewhat sceptical of stimulants as potential treatments for ME/CFS because of our personal experiences with the illness. Some patients may find stimulants useful but some may find them very detrimental. Personally I wouldn't touch stimulants with a barge pole as my illness is incredibly reactive to any stimulation. I think many of us have the same concerns.
I find low dose clonazepam very helpful for stabilising my symptoms and illness, which is the opposite of a stimulant. I've often wondered if epileptic (anti-seizure) drugs might help me, because of the similar actions to clonazepam and their neurological stabilising effects. But I've never tried them. I believe that fibro patients can get pregablin and gabapentin prescribed in the UK, so perhaps I should try to get hold of them.
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Cort
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Bob the difference between what I did and what you did is that I "interpreted" the trial - I didn't take it on its face value. I think we should dig deeper in these trials. Yes, the placebo should be the same on both sides. Large swings in variability in the placebo response would make a getting significant result more difficult, however. Note that the gap between the placebo response in the KPAX and the methylphendiate trials was actually larger in the KPAX trial. Why was it not significant while the methylphenidate trail ? My guess that was due to high variability in the placebo response in the KPAX trial - probably driven by the high expectations the participants had.
I understand your skepticism. As I noted earlier, though, while the stimulants alone did have high rates of side effects but it did not in the KPAX trial. In fact the rate of negative side effects was so low that the authors suggested that higher rates of methylphenidate might be successful. I know stimulants seem like a odd idea for ME/CFS (although they work in ADHD). You mentioned following the study results - well, those are the study results. I guess you can either ignore them or consider the possibility that stimulants with right mix of supporting nutrients might not be harmful.
If you consider the idea, though, that the mitochondria are getting whacked in ME/CFS then the idea that stimulants which activate them- provided the support is there for me - can be helpful - might make sense.
There aren't many clinical trials in ME/CFS and I think some interpretation - some guesswork - given how little we have to go on is entirely appropriate. The trial suggested that the if the trial was bigger the results would have been positive. That was not guesswork by the way. It was based on statistical analysis.
The same thing applies to Montoya's findings with antivirals. They suggested that a longer treatment trial would have been more successful This was based on the fact that patients were continuing to improve at the end of the trial. It also made sense given Lerner's experience. You can reject that because it's not proven but I suggest that with the dearth of trials done that it's probably best to consider that as a real possibility. The same is true with the KPAX trial.
Clinical trials are not as black and white and don't lead to as incontrovertible findings as you might think. The amount of funding dictates how long the trial is, how many people will be in it and what you will measure. Florinef works great for some people but it failed as a trial. I remember Nancy Klimas saying if we'd chosen a different endpoint it would have been successful.
I understand your skepticism. As I noted earlier, though, while the stimulants alone did have high rates of side effects but it did not in the KPAX trial. In fact the rate of negative side effects was so low that the authors suggested that higher rates of methylphenidate might be successful. I know stimulants seem like a odd idea for ME/CFS (although they work in ADHD). You mentioned following the study results - well, those are the study results. I guess you can either ignore them or consider the possibility that stimulants with right mix of supporting nutrients might not be harmful.
If you consider the idea, though, that the mitochondria are getting whacked in ME/CFS then the idea that stimulants which activate them- provided the support is there for me - can be helpful - might make sense.
There aren't many clinical trials in ME/CFS and I think some interpretation - some guesswork - given how little we have to go on is entirely appropriate. The trial suggested that the if the trial was bigger the results would have been positive. That was not guesswork by the way. It was based on statistical analysis.
The same thing applies to Montoya's findings with antivirals. They suggested that a longer treatment trial would have been more successful This was based on the fact that patients were continuing to improve at the end of the trial. It also made sense given Lerner's experience. You can reject that because it's not proven but I suggest that with the dearth of trials done that it's probably best to consider that as a real possibility. The same is true with the KPAX trial.
Clinical trials are not as black and white and don't lead to as incontrovertible findings as you might think. The amount of funding dictates how long the trial is, how many people will be in it and what you will measure. Florinef works great for some people but it failed as a trial. I remember Nancy Klimas saying if we'd chosen a different endpoint it would have been successful.
Cort
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You make a good point regarding the placebo response but please see the response to Bob for another aspect of that.
I guess you can choose what you focus on.
With regard to the CIS questionnaire - it's apparently considered good enough to be used to assess fatigue in many disorders. That suggests that its been well validated - whatever it's origins. I'm not suggesting that it's perfect but I am suggesting that it's commonly used to assess fatigue.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1739950/
http://www.ncbi.nlm.nih.gov/pubmed/24941350
http://www.ncbi.nlm.nih.gov/pubmed/25639482
http://www.ncbi.nlm.nih.gov/pubmed/25003635
Question - how many clinical trials in ME/CFS have used actometers????
Bob
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If you're saying that the data suggests that further investigation is merited, or larger trials are merited, then I don't have any argument with that.
If any drugs (stimulants or antivirals etc) would benefit even a small minority of us then it's very unfortunate that they aren't available to our community, for those who would benefit from them, esp if they have a good safety profile. I would welcome large trials for any potential treatment.
As always, we need large, well funded trials, and we need to be able to identify subsets of patients. If we don't get these, we'll never get any progress. It's the same old story - no funding.
Undisclosed
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Where has this study actually been published -- am I missing a link to the journal, it's published in.
I am very, well extremely skeptical, about this study because its a pharmaceutical company trying to sell their own supplements.
I don't see anywhere that they demonstrated efficacy.
To add to my suspicions, there were a few staff from the pharmaceutical company attempting to post on PR when the trials first started who never said they were part of the pharmaceutical company -- it seems dishonest to me.
(edited to add -- one employee said they were involved with the trials, the other 2 did not -- many posts were removed as a breach of the no advertising rule as a supplement was being advertised.)
From my experience with a daughter with extreme ADHD, ritalin loses its efficacy after awhile and stops working -- you either need to take a med holiday or up the dose. It has some really nasty side-effects and for a population that can barely tolerate any medications, one would wonder why they are using such a medication -- it helps focus people, it perks them up because it's an amphetamine-type drug. Is this an appropriate treatment for people with ME? I don't think so.
I am very, well extremely skeptical, about this study because its a pharmaceutical company trying to sell their own supplements.
I don't see anywhere that they demonstrated efficacy.
To add to my suspicions, there were a few staff from the pharmaceutical company attempting to post on PR when the trials first started who never said they were part of the pharmaceutical company -- it seems dishonest to me.
(edited to add -- one employee said they were involved with the trials, the other 2 did not -- many posts were removed as a breach of the no advertising rule as a supplement was being advertised.)
From my experience with a daughter with extreme ADHD, ritalin loses its efficacy after awhile and stops working -- you either need to take a med holiday or up the dose. It has some really nasty side-effects and for a population that can barely tolerate any medications, one would wonder why they are using such a medication -- it helps focus people, it perks them up because it's an amphetamine-type drug. Is this an appropriate treatment for people with ME? I don't think so.
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That has certainly been the experience of the best ME/CFS doctors like Cheney and Goldstein. It seems counterintuitive to give sedatives to an already fatigued person but some anticonvulsant meds like clonazepam, lamotrigine and gabapentin help quite a few ME/CFS patients and actually raise their energy somewhat by raising the inhibitory tone of the brain, countering some of the excessive glutamate driven excitotoxicity going on in our brains. Giving stimulants to a brain that already cannot handle stimulation is insane and will lower the seizure threshold, worsen oxidative stress, NMDA receptor stimulation and long-term depletion of dopamine stores. For those not too severely affected who are able to take part in bogus trials, get to testing centres etc., they might feel better for a few months or years before the underlying damage becomes clinically apparent.
I believe Cort is talking about pre-publication information (http://www.cortjohnson.org/blog/201...hronic-fatigue-syndrome-study-results-are-in/).
Cort has used (is using?) at least some of the company's products.
On Health Rising someone has asked what impact Cort's use of the products had on his interpretation of the study. (I didn't find a direct answer to that question.)
I think his impression of the products may also have an impact on his interpretation of the study. (For me it would be difficult to control for that impact even in a write-up about the study.)
Snow Leopard
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I get that impression from the way the trial was designed. Cort and those who read my posts in the trial discussion thread will know what I'm talking about.
Bob
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Thanks for that. I haven't come across any discussions re gabapentin, and I didn't know people had tried lamotrigine. Seeing as clonazepam helps me so much, I should look into these others.
Well that puts things in a different light. Sounds like a conflict of interest.
Anyone have the original thread about this study? I will also do a search but if someone has it handy and could post it, it would be greatly appreciated.
Barb
I do not know if the following is the original thread but I found this quote and thread:
"
Danya
Messages:
2
Likes:
4
Hello astrea,
I am the Research Coordinator for the Synergy Trial and would be happy to answer any questions you have about the trial or the protocol. More information about the treatment can be found here: http://thesynergytrial.org/study-treatment.html. You may also view Dr. Kaiser's webinar, Mitochondrial Medicine and Chronic Fatigue Syndrome, at: to gain a better understanding of the treatment and hear results from the preliminary trial.
We are expecting to have results from the Phase II Synergy Trial in the coming months. If you would like to receive updates, please forward a request to ask@kpaxpharm.com. I am also happy to answer any questions about the treatment by phone: (855) 318-HOPE (4673).
Best wishes,
Danya Adolphs
"
thread:
http://forums.phoenixrising.me/inde...going-on-is-jon-kaiser-a-famous-doctor.35613/
"
Danya
Messages:
2
Likes:
4
Hello astrea,
I am the Research Coordinator for the Synergy Trial and would be happy to answer any questions you have about the trial or the protocol. More information about the treatment can be found here: http://thesynergytrial.org/study-treatment.html. You may also view Dr. Kaiser's webinar, Mitochondrial Medicine and Chronic Fatigue Syndrome, at: to gain a better understanding of the treatment and hear results from the preliminary trial.
We are expecting to have results from the Phase II Synergy Trial in the coming months. If you would like to receive updates, please forward a request to ask@kpaxpharm.com. I am also happy to answer any questions about the treatment by phone: (855) 318-HOPE (4673).
Best wishes,
Danya Adolphs
"
thread:
http://forums.phoenixrising.me/inde...going-on-is-jon-kaiser-a-famous-doctor.35613/
I think @Snow Leopard * summed it up nicely in the previous thread that @Denise provided. Thanks for finding it!
Barb
ETA *Just now saw you mentioned this in the above post. Facepalm!
.
Barb
ETA *Just now saw you mentioned this in the above post. Facepalm!
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@Bob
I take Lamictal for anxiety it and potentiates the AD I'm on. The AD also helps pain. I had depression before getting sick. I also take clonazepam for sleep and RLS*. They are all low dose and this combination has worked the best.
Barb
I can't take the usual med, Mirapex for RLS as I was getting up in the night eating without remembering. This stopped when I discontinued the medication.
I take Lamictal for anxiety it and potentiates the AD I'm on. The AD also helps pain. I had depression before getting sick. I also take clonazepam for sleep and RLS*. They are all low dose and this combination has worked the best.
Barb
I can't take the usual med, Mirapex for RLS as I was getting up in the night eating without remembering. This stopped when I discontinued the medication.
Undisclosed
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I do not know if the following is the original thread but I found this quote and thread:
"
Danya
Messages:
2
Likes:
4
Hello astrea,
I am the Research Coordinator for the Synergy Trial and would be happy to answer any questions you have about the trial or the protocol. More information about the treatment can be found here: http://thesynergytrial.org/study-treatment.html. You may also view Dr. Kaiser's webinar, Mitochondrial Medicine and Chronic Fatigue Syndrome, at: to gain a better understanding of the treatment and hear results from the preliminary trial.
We are expecting to have results from the Phase II Synergy Trial in the coming months. If you would like to receive updates, please forward a request to ask@kpaxpharm.com. I am also happy to answer any questions about the treatment by phone: (855) 318-HOPE (4673).
Best wishes,
Danya Adolphs
"
thread:
http://forums.phoenixrising.me/inde...going-on-is-jon-kaiser-a-famous-doctor.35613/
I have amended my statement re: employees of k-pax pharmaceuticals not saying who they were -- one employee said who she was, two other employees did not after joining the forums and quite a few posts that were advertising the supplement in question were removed as a breach of the No Advertising rule.
@barbc56, which AD are you using alongside lamotrigine? I have been tempted to try lamotrigine for a long time but Stevens-Johnson syndrome is a real concern. I have seen people develop rash on this drug. Usually it goes away if you stop the drug immediately but...
Gabapentin is safer in my opinion but the regular doses prescribed by psychiatrists are toxic. It's probably better to stay in the ~100 mg range rather than 1000+ mg for ME.
Gabapentin is safer in my opinion but the regular doses prescribed by psychiatrists are toxic. It's probably better to stay in the ~100 mg range rather than 1000+ mg for ME.