Efficacy and tolerability of an endogenous metabolic modulator (AXA1125) in fatigue-predominant long COVID: a single-centre, double-blind, randomised

Efficacy and tolerability of an endogenous metabolic modulator (AXA1125) in fatigue-predominant long COVID: a single-centre, double-blind, randomised controlled phase 2a pilot study

• Lucy E.M. Finnigan
• Mark Philip Cassar
• Margaret James Koziel
• Joel Pradines
• Hanan Lamlum
• Karim Azer
• et al.
  
  

Summary
Background
‘Long COVID’ describes persistent symptoms, commonly fatigue, lasting beyond 12 weeks following SARS-CoV-2 infection. Potential causes include reduced mitochondrial function and cellular bioenergetics. AXA1125 has previously increased β-oxidation and improved bioenergetics in preclinical models along with certain clinical conditions, and therefore may reduce fatigue associated with Long COVID. We aimed to assess the efficacy, safety and tolerability of AXA1125 in Long COVID.
Methods
Patients with fatigue dominant Long COVID were recruited in this single-centre, double-blind, randomised controlled phase 2a pilot study completed in the UK. Patients were randomly assigned (1:1) using an Interactive Response Technology to receive either AXA1125 or matching placebo in a clinical based setting. Each dose (33.9 g) of AXA1125 or placebo was administered orally in a liquid suspension twice daily for four weeks with a two week follow-up period. The primary endpoint was the mean change from baseline to day 28 in the phosphocreatine (PCr) recovery rate following moderate exercise, assessed by 31P-magnetic resonance spectroscopy (MRS). All patients were included in the intention to treat analysis. This trial was registered at ClinicalTrials.gov, NCT05152849.
Findings
Between December 15th 2021, and May 23th 2022, 60 participants were screened and 41 participants were randomised and included in the final analysis. Changes in skeletal muscle phosphocreatine recovery time constant (τPCr) and 6-min walk test (6MWT) did not significantly differ between treatment (n = 21) and placebo group (n = 20). However, treatment with AXA1125 was associated with significantly reduced day 28 Chalder Fatigue Questionnaire [CFQ-11] fatigue score when compared with placebo (least squares mean difference [LSMD] −4.30, 95% confidence interval (95% CI) −7.14, −1.47; P = 0.0039). Eleven (52.4%, AXA1125) and four (20.0%, placebo) patients reported treatment-emergent adverse events; none were serious, or led to treatment discontinuation.
Interpretation
Although treatment with AXA1125 did not improve the primary endpoint (τPCr-measure of mitochondrial respiration), when compared to placebo, there was a significant improvement in fatigue-based symptoms among patients living with Long COVID following a four week treatment period. Further multicentre studies are needed to validate our findings in a larger cohort of patients with fatigue-dominant Long COVID.
Funding
Axcella Therapeutics.

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00123-2/fulltext

 

I would be very surprised if a blend of amino acids does anything significant. Only significant result is based on subjective outcome (Chalder Fatigue Scale), but of course this study is placebo-controlled. Some of these amino acids can be used to affect mood, so perhaps that is playing a role.

 

I'm not familiar with this: τPCr-measure of mitochondrial respiration

Has this been used in ME/CFS research?

 

Wow, I'm surprised. (But still skeptical)

 

Sky News article:

https://news.sky.com/story/new-long-covid-drug-may-significantly-reduce-fatigue-in-patients-12856906

 

Agree I felt a lot better about this when I read 'double-blinded'.

Not sure about the 4 weeks if LC is a condition like ME, given that there are so many things we could consume or do or have done to us that might just 'jolly the adrenaline' or 'give a sense we are suddenly on top of it' followed by a big old crash when we realise that whilst we were managing to do 10-20% each day bla and getting away with it, that catches up in a horrible way.

To me this just flags the question about the CHalder Fatigue Scale. Putting aside whether it is even a valid measure of the illness or checking the right things, I mean whether it diminishes/concertinas effects in one direction and amplifies non-changes in the other.

I also don't really know about fatigue scales' validity without triangulating them to things that are actually meaningful anyway. BY which I mean taking these fatigue scales, taking patients of different severities and logging whether a 2 point increase means being able to eat your 3 meals a day when normally that isn't possible, or that people can do a 20min walk one day and then not have reduction in activity for the rest of the week, or what.

PS we get a few of these calibrated and maybe we start rocking and rolling on those who create and use these scales having them measured up against each other. I suspect we need scales that are probably honed for appropriate severity for a start (contextualised) otherwise the sensitivity is in the wrong place. And probably if you did do it by severity (let's be honest most researchers are mainly using mild or moderate anyway) then you could look at calibrating load and timings. It's almost impossible to even answer a medics q of how you got on without describing whether it has been a difficult week with things you had on your plate. So there is a lot to unbundle under these things.

Floor vs ceiling effects are really important. It's all very well using the marketing spiel of these various intervals whilst missing the point completely regardin 'effect size'. One one of these scales could you decline so much you are bed-bound one more day a week and still it doesn't go down by any significance and yet ticking the box on feeling more positive on something that is more inconsequential could increase it by enough it claims significance?

The research into fatigue is so so bad. It doesn't even seem to be done by people who experienced it enough in their life to understand the different concepts and ins and outs of it.

Physical over-exertion can give me cognitive PEM as well as physical PEM, cognitive exertion tends to lead to cognitive PEM and both types of exertion lead to things I might call 'central PEM' ie can't wake up. Noone has even been intrigued enough to unbundle how those different PEMs fit into this central thing. We all probably have different types of fatigue and PEMs within ourselves (different things,different circumstances such as when you go 'really over' and can't sleep because of over-exertion) and between ourselves.

 

Well, yeah, the CFQ is known to be lousy like this. Exactly for the purpose of giving a false positive even when there's nothing, it's what it was invented for.

So at best, this study has to be redone, competently this time. Otherwise this is useless. Using useless tools and assessments give useless results.

Also there isn't a fatigue-dominant sub-type that is fixed. I've never seen professionals struggle so hard with such easy stuff. They can't process that the outcomes are not universal, if everyone doesn't have the exact same outcome, they freeze. Then they can't process that the sub-types aren't fixed, but they try to force the square thing in the round hole anyway.

Really this is something I keep seeing: since everyone doesn't have the same outcome, it can't be real. What an incredible waste of resources. And people. And money. And more.

 

I probably haven't thought through the words for the analogy being relevant well enough but I have a picture in my mind of those kits you used to get many years ago as kids where you poured a certain liquid onto cardboard and it 'grew a furry tree': https://www.fizzicseducation.com.au/product/magic-crystal-tree-science-kit-copy/

Ahh this one which has a make your own experiment section at the bottom is probably getting closer to where my mind is thinking:

https://sciencenotes.org/magic-crystal-tree-experiment/

What happens when you drop a certain amount of actual 'no change', improvement or worsening onto different scales/reactors.

 

Was this the same drug they pulled the plug on with Dr Systrom?

 

No, totally different. That was bocidelpar AKA ASP0367.

 

These are things that really need to be accounted for in trial protocols. It's not easy—it might even be impossible in a short trial, because any intervention is likely to result in some behavioural changes at the outset—and researchers almost certainly underestimate just how much difference small factors can make.

 

The paper does not seem to say what the placebo was made up from. All I could find was “matched placebo which were identical in colour and flavour (orange) with a closely matched aroma and appearance”.

Without being aware consciously of what was and what was not the active treatment and what was the placebo, if there were differences not directly related to the amino acids, such as total calorific value, this could still impact on how the body responded in the treatment group compared to the control not caused by the supposed active ingredient.

 

The essence of a good trial or experiment is: all other things being equal. There has to be certainty that one thing is being evaluated, and one thing only. Most of the effort in conducting a reliable experiment is in achieving this, in eliminating all possible noises.

It's important enough that in economics, technically a less scientifically rigorous discipline than medicine, it's used all the time. In intro classes it's almost a mantra, repeating it so that it sticks. More often than not, it's impossible, and then that qualifier signifies that the result is only as good as the evaluation, and it's not possible to evaluate the evaluation, it's turtles all the way down.

The entire paradigm of clinical trials is extremely lousy at testing with all other things being equal. It's hard to do, but then that should naturally lead to an understanding that any result out of this paradigm is at best a crapshoot, and given how heavy biases are, it's possible that almost nothing in evidence-based medicine is actually better than a completely random process.

The lack of actual real-life results speak for itself. When an entire discipline essentially uses the null comparator as the most effective thing they have, I'm sorry but everything is already lost. The belief in the cebo stuff is truly unique in the modern world, no different than any religious-based system in its fanatical, even coercive, application.

 

I asked Betty Raman (the corresponding author) whether they were planning to use a better measure than CFQ for the phase III study.

Here is her response:
https://twitter.com/user/status/1646949442795216898


Although I doubt they looked very hard for an alternative measure, as she is also involved with PHOSP-COVID and other LC studies that Chalder herself is likely advising [edit: is actually a co-author on!].
She's also a fellow at the same college as Michael Sharpe. I would imagine that might make things difficult if there is a difference in opinion about the validity of the scale.

And before anyone says it, just because she's a fellow at the same college as Sharpe, doesn't mean she automatically shares his views. Academic institutions aren't religious sects (mostly).

Anyway, I replied with info about other fatigue scales, including Whitehead's review, Prof Jason's studies, and the S4ME critique of CFQ.

 

That's a pretty bad answer. There are other scales with published research. Choosing the worst one is a deliberate choice. Maybe not the choice of the worst one, so much as the choice of one that is basically 3 biases in a suit and has the magical ability of giving expected results every time it's used, because only people who seek out a specific outcome will ever use it.

 

https://news.sky.com/story/new-long..._3znIhoXZPA5Wzb0vrAuZKhUdjgBcDluz6t_16lA6A0-Q