KPAX002 as a treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a prospective, randomized trial, 2018, Montoya et al

[Andy]

Abstract:
Mitochondrial dysfunction and a hypometabolic state are present in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). KPAX002 consists of low-dose methylphenidate hydrochloride to treat a hypometabolic state combined with key micronutrients intended to broadly support mitochondrial function.

The objective of this study was to evaluate KPAX002 as a treatment for fatigue and concentration disturbance symptoms in ME/CFS subjects. This phase 2 randomized, double-blinded, placebo-controlled trial was conducted at 4 sites in the United States. A total of 135 subjects with ME/CFS were randomly assigned to either KPAX002 (n=67) or placebo (n=68) for 12 weeks of treatment. The primary endpoint was change in the Checklist Individual Strength (CIS) total score from baseline to Week 12. Secondary measurements included visual analog scales for fatigue and concentration disturbance symptoms.

In the intent-to-treat population, the mean reduction in the CIS total score from baseline to week 12 for the KPAX002 and placebo groups was -16.9 (± 23.52) and -13.8 (± 22.15), respectively (95% confidence interval, -11.1, 4.0; P=0.359). On the visual analog scale for fatigue, the mean reduction from baseline to week 12 was -18.2 mm (± 25.05) and -11.1 mm (± 22.08) for the KPAX002 and placebo groups, respectively (95% confidence interval, -11.5, 2.3; P=0.189). The two groups demonstrating the most robust response to KPAX002 were subjects with more severe ME/CFS symptoms at baseline (P=0.086) and subjects suffering from both fatigue and pain (P=0.057). The incidence of adverse events was not statistically different between the two groups.

Treatment with KPAX002 resulted in a reduction in fatigue and concentration disturbance symptoms in multiple analyses. Two key subgroups of patients whose response approached statistical significance were identified.

Full article in PDF format here, http://www.ijcem.com/files/ijcem0065685.pdf

 

[Simon M]

Authors: Jose G Montoya1, Jill N Anderson1, Danya L Adolphs2, Lucinda Bateman3, Nancy Klimas4, Susan M Levine5, Donn W Garvert1, Jon D Kaiser

this was a double blind multi-centre trial (n=67 + 68) of a mitochondrial-function boosting treatment, using the Checklist individual Strength questionnaire as the primary end point. Secondary measures were fatigue and concentration visual analogue scales ("mark how bad it is in this line, using a pencil").

There were no significant differences between placebo and control on either primary or secondary endpoints. So it didn’t work.



In a planned subgroup comparisons, they got closer to, but still failed to reach statistical significance for more severely affected patients and those taking painkillers. Those subgroups got closer to significance because the placebo arm did worse rather than the treatment group doing better. Still no joy.



But they did it, and published the results, plaudits for that. Looks like it’s time to move on from this as a treatment (it doesn't demonstrate that the hypometabolism hypothesis is wrong, but doesn't support it either).

 

[Daisymay]

In what appears to be placed for comparisons, they got closer to, but still failed to reach sadistical significance for more severely affected patients. So still a null result.

"sadistical significance" now that sounds like a term which could be used for a BPS paper?

 

[Hoopoe]

I still believe in the hypometabolism hypothesis, even though this study suggests that (if it plays a role) it's not easily treatable.

The study also suggests that a stimulant doesn't really work either.

 

[Indigophoton]

It is further postulated that ME/CFS symptoms may be adaptive in nature in order to prevent further oxidative damage to the individual, however this comes at the cost of a substantial decrease in functional capacity [8].

The combination of mitochondrial dysfunction
coupled with the presence of a hypometabolic
state suggests that potential benefit may be achieved by a treatment combining a targeted mitochondrial support intervention with a low-dose central nervous system (CNS) stimulant.

It's curious that on the one hand they think ME/CFS (symptoms) is essentially an adaptive response to prevent damage, and on the other that trying to drive past this response with a stimulant is a good idea.

The implicit assumption seems to be that the system is staying off-kilter due simply to being in a maladaptive but stable alternative state. Hopefully that's true (as it holds out the promise of a fix), but the lack of significant results might indicate that a more or less single-point forced over-ride is too simplistic.

Methylphenidate is essentially a dopamine-reuptake inhibitor, and I'm not convinced that just upping dopamine (or serotonin) is the answer (partly because one can do this with tyrosine and 5htp respectively, and no doubt many of us have tried those).

Blockmans et al. used methylphenidate alone at the same dosage as our investigation and utilized the same primary outcome variable (change in CIS total score). One goal of the current trial was to investigate a possible potentiating effect by combining a mitochondrial modulator with methylphenidate as a treatment for ME/CFS.

Adding the mitmitochondrial modulator to the same dosage of methylphenidate used in the Blockmans trial provided an additional reduction of 4.2 points in the CIS total score at 4 weeks (16 vs. 11.8 points). However, the change in the CIS total score in the placebo arms varied greatly between the two trials. The placebo arm in the Blockmans trial declined by only 3 points compared to a placebo arm reduction of 13.1 points in the current trial [10].

One possible interpretation of this is that, while the methylphenidate is irrelevant, the mito supporting supplements made a difference.

 

[Melanie]

I don't like studying drugs on us because we don't fully understand what has gone wrong. I would rather continue studying Dr. Davis' metabolic findings and Dr. Montoya's brain scans. I wouldn't mind studying Ampligen because we already know it is working on a good percentage of us and we need to find out why and implement it in our care but outside of that I don't care about studying drugs.

If we had tons of money then yes, we could study drugs while studying metabolism, brain scans, and more but we just don't have the money to spare. We have to find out what went wrong.

I also want more studies focused on Natural Killer cells and Cytokines. Expand and replicate on these four and maybe we can get somewhere.

 

[Andy]

The implicit assumption seems to be that the system is staying off-kilter due simply to being in a maladaptive but stable alternative state. Hopefully that's true (as it holds out the promise of a fix), but the lack of significant results might indicate that a more or less single-point forced over-ride is too simplistic.

Interestingly this, from memory, is what Nancy Klimas believes she has found with GWI and can successfully treat, and that she suggests might be the case in ME/CFS.

 

[Londinium]

I found it interesting they discussed the large placebo response, as that was what first came to mind when I looked their first chart (Figure 2, which Simon has posted above). It does appear that ME/CFS studies generate an abnormally large placebo response - my guess is that is to be expected in a patient group that has otherwise been given little hope, interest or even belief by doctors. However this does provide an additional challenge in properly sizing adequately powered studies an an already underfunded field.

 

[arewenearlythereyet]

Not unexpected.... if it was that easy we would now about it by now, but good that these are being tested and reported. I do wonder whether 12 weeks is a sufficient amount of time to check these things, particularly when placebo response on self reported questionnaires are involved. It might be just showing that studies using these measures really need larger samples and longer time periods.

 

[unicorn7]

I think the placebo effect is pretty big in this disease, because there is a lot of fluctuation in symptoms. Maybe not with severe patients, but with mild-moderate.

If you really believe you will get better, you can also push yourself a bit more. When the amount of time of the study is short, you could think you are a bit better, only to have a crash later.

I know someone who participated in some sort op LP-type study. She was mildly affected and still worked 20 hours a week. She really pumped herself up with that therapy and even worked full time for half a year. She was "counted" as recovered for that study, which she really hates now. She crashed after that half year of working full time, has been housebound for 4 years now...

 

[Trish]

A side issue, but one that I think should apply in all scientific publications.

The graphs of CIS score show an apparently large effect of both placebo and treatment.

If you read the information more closely, you see that the CIS score is measured on a scale from 20 to 140, so that is what they should show on the graph, in my opinion.

By only showing the bit from 90 to 120, the visual effect is wildly exaggerated.

The group averages started at approximately 112 on this scale, and dropped by approximately 17 (treatment) and 14 (placebo) respectively.

On a scale from 20 to 140 these drops are probably clinically insignificant, especially for a fluctuating condition that varies probably by more than this from one day to the next.

 

[Indigophoton]

On a scale from 20 to 140 these drops are probably clinically insignificant, especially for a fluctuating condition that varies probably by more than this from one day to the next.

I wonder why they didn't have a control group. Control vs placebo vs treatment would have gone some way towards answering that.

 

[Snow Leopard]

I'm not at all impressed by either of the KPAX studies, I think it is time to conclude this treatment is not effective. If you need huge sample sizes to even achieve p<0.05 it means the treatment barely works at all.

I think the placebo effect is pretty big in this disease, because there is a lot of fluctuation in symptoms. Maybe not with severe patients, but with mild-moderate.

If you really believe you will get better, you can also push yourself a bit more. When the amount of time of the study is short, you could think you are a bit better, only to have a crash later.

There is a difference between how patients may report symptoms and their underlying capacity and as you suggest, in the long term there is a regression back to their true capacity.

My opinion is all these biases (not merely "placebo effect") are similar to patients with other medical conditions, despite a systematic review claiming that CFS patients have a "lower than predicted" placebo response. (https://www.ncbi.nlm.nih.gov/pubmed/15784798)

 

[Flying Dutchman]

KPAX is a bog-standard stimulant, Ritalin, mixed with some (presumably useless) over-the-counter supplements. Adding these "herbs & spices" allows them to claim the combo is a proprietary medicine.

That is, KPAX can be patented, whereas the active ingredient (Ritalin) is out of patent.

The sponsour of the trial is - wait for it - the promotor of KPAX.

He (Jon Kaiser) has publicly hyped the therapeutic value of KPAX in ME/CFS:
“More than two-thirds of them experienced clinically significant improvement in both fatigue and concentration symptoms. One woman had been out of work for six years due to her symptoms and went back to work six weeks after starting this treatment.”

This is not the first occasion of Dr Kaiser or his for-profit company hyping their secret herbs & spices.
Eg
"This signature formula was developed by Jon D. Kaiser, M.D. during the height of the AIDS epidemic to help his patients significantly outlive the prognosis of a quick demise. Combining this formula with the appropriate use of medications, the vast majority of Dr. Kaiser’s HIV/AIDS patients have lived normal, healthy lives."
http://kpaxpharm.com/about-us/

Dr Kaiser also claims to have had CFS and recovered, and that supplements aided his recovery.

And, here's the really good bit: If you have ME/CFS, or cancer, or heart disease, or HIV, or another immune disease, you can buy a treatment to cure you direct from Dr Kaiser's company.

If his ME/CFS initiative wanted the pretense of looking plausibly "sciency", they would have compared the efficacy of KPAX to that of Ritalin.

Low-dose stimulants have already been trialled in ME, without much demonstrated efficacy.

The only part of this process I find interesting is that 4 of the leading ME clinicians (Bateman, Klimas, Levine & Montoya) are taking part and enrolling their patients.
I wonder why they all agreed to do so?
Pure speculation: it's possible money (eg generous funding) may have something to do with it.

I also suspect it's good for Dr Kaiser's business to be able to associate these clinicians' names with his product, and to claim his "treatment" is undergoing a clinical trial at Stanford. I further suspect that drawing out clinical trials over a period of years, even if they all produce null findings, might be good for business.

 

[Milo]

“More than two-thirds of them experienced clinically significant improvement in both fatigue and concentration symptoms. One woman had been out of work for six years due to her symptoms and went back to work six weeks after starting this treatment.”

The placebo response is a powerful thing... especially when there are no biomarkers to begin with.

secret herbs & spices

Uh huh. Herb and spices. Hasn’t cured anybody with any kind of diseases. That is why medicine and naturopathy don’t mix.

And we already know that meditation, yoga and even ‘the good kind of CBT’ is not going to change the course of our disease. I hope no one dare researching that.

The only part of this process I find interesting is that 4 of the leading ME clinicians (Bateman, Klimas, Levine & Montoya) are taking part and enrolling their patients.
I wonder why?

Gain experience in clinical trials maybe? Practice run for the real thing?

I further suspect that drawing out clinical trials over a period of years, even if they all produce null findings, might be good for business

Honestly, research and clinical trials take much time and money. It’s ridiculously slow in the best of times. Our field, it’s exponentially slower.

Looking forward to the next discovery. Hanging on to hope is needed but we also need to act and do our share to advance research, fundraise, support our researchers, encourage physicians to enter the field etc.

 

[Alvin]

The only part of this process I find interesting is that 4 of the leading ME clinicians (Bateman, Klimas, Levine & Montoya) are taking part and enrolling their patients.
I wonder why they all agreed to do so?
Pure speculation: it's possible money may have something to do with it.

I also suspect it's good for Dr Kaiser's business to be able to associate these clinicians' names with his product, and to claim his "treatment" is undergoing a clinical trial at Stanford. I further suspect that drawing out clinical trials over a period of years, even if they all produce null findings, might be good for business.

Indeed, i am surprised they want their names associated with supplements plus Ritalin. Also we know that many things give us a slight boost for a short period, likely measuring that and selling a drug based on it is a waste of money and patients hope.
I believe there have been some threads on this product that have been picked apart already

 

[Milo]

Indeed, i am surprised they want their names associated with supplements plus Ritalin. Also we know that many things give us a slight boost for a short period, likely measuring that and selling a drug based on it is a waste of money and patients hope.
I believe there have been some threads on this product that have been picked apart already

Look, there will always be volunteers to try out things. There is value in performing a double blinded clinical trial, the value being knowing whether it is effective and treatment is safe, or whether it is ineffective. Now we know. And for the zealous doctors actually suggesting Ritalin, you can now bring this paper and show them this paper. That will shut them up.

But it is more than the Ritalin. It is the supplements. They don’t perform, at least not this specific one. Save yourself hundreds of dollars.

 

[Alvin]

Look, there will always be volunteers to try out things. There is value in performing a double blinded clinical trial, the value being knowing whether it is effective and treatment is safe, or whether it is ineffective. Now we know. And for the zealous doctors actually suggesting Ritalin, you can now bring this paper and show them this paper. That will shut them up.

But it is more than the Ritalin. It is the supplements. They don’t perform, at least not this specific one. Save yourself hundreds of dollars.

I have no intention of buying this product, you can read my scathing words on the other thread.
My biggest surprise is that these good researchers want their name associated with it though it only approaches significance

 

[Milo]

I have no intention of buying this product, you can read my scathing words on the other thread.
My biggest surprise is that these good researchers want their name associated with it though it only approaches significance

But it is important to publish negative studies. This is part of the scientific process. They tested a theory, and it’s been disproven. Now can all move on.

It reminds me of the XMRV saga. Retrovirologists were curious. They tested that hypothesis and it didn’t work out. (I will leave the dirty details behind, no need to revisit that)- they moved on and it was the right thing to do.

 

[Alvin]

But it is important to publish negative studies. This is part of the scientific process. They tested a theory, and it’s been disproven. Now can all move on.

It reminds me of the XMRV saga. Retrovirologists were curious. They tested that hypothesis and it didn’t work out. (I will leave the dirty details behind, no need to revisit that)- they moved on an dit was the right thing to do.

I completely agree, but random chance could have caused it to just hit significance and led us down the road of legitimizing snake oil