Open TRI-ME: Trimetazidine to treat Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A double-blind, randomised, placebo-controlled efficacy trial

TRI-ME: Trimetazidine to treat Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A double-blind, randomised, placebo-controlled efficacy trial

Ethics application status: Submitted, not yet approved

Description of intervention(s) / exposure
1) Intervention: Trimetazidine
2) Dose: a single 35mg tablet per dose, twice daily.
3) Duration: 8 weeks.
4) Mode of Administration: Oral tablet.
5) Adherence monitoring: Participants are required to return all medication bottles for double tablet count by the trial pharmacist and trial coordinator.

Control treatment: Matched placebo tablets (pink round film-coated tablets consisting of microcrystalline cellulose, colloidal silicon dioxide, sodium starch glycolate and sodium stearyl fumarate), A single 35mg tablet per dose, twice daily, for 8 weeks.

https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12625000095460p

 

Not optimistic

https://en.wikipedia.org/wiki/Trimetazidine

 

Can we maybe do basic biomedical research before spending very limited research money trialing random pharmaceutical drugs with little to no anecdotal success stories or plausible mechanisms of action.

Urgh

 

I was going to applaud the use of blinding and placebo..

@Yann04 how is the trial funded? It might not have come out of earmarked ME/CFS-money, so the alternative cost might be zero. I still agree that it would have been better do to basic research first.

 

It’s funded by the Australian government.

 

The justification:

 

Noting that this is an entire category on the Australia New Zealand Clinical Trial Registration website

 

The narrative behind this trial is probably some vague idea in relation to ATP, similar to what is being proposed by the author here:
Metabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine.

However, it appears the trial for bipolar depression never actually got underway. So perhaps the same will happen to the trial proposed above.

 

The investigator is an author on this:
Pharm Res. 2019 Oct:148:104450.
Myalgic encephalomyelitis/chronic fatigue syndrome: From pathophysiological insights to novel therapeutic opportunities
Gerwyn Morris 1, Basant K Puri 2, Adam J Walker 1, Michael Maes 1, Andre F Carvalho 3, Ken Walder 4, Catherine Mazza 1, Michael Berk 5

It is hard to have much enthusiasm on the basis of this sort of thinking.

 

Abstract
Myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS) is a common and disabling condition with a paucity of effective and evidence-based therapies, reflecting a major unmet need.

Cognitive behavioural therapy and graded exercise are of modest benefit for only some ME/CFS patients, and many sufferers report aggravation of symptoms of fatigue with exercise.

The presence of a multiplicity of pathophysiological abnormalities in at least the subgroup of people with ME/CFS diagnosed with the current international consensus "Fukuda" criteria, points to numerous potential therapeutic targets. Such abnormalities include extensive data showing that at least a subgroup has a pro-inflammatory state, increased oxidative and nitrosative stress, disruption of gut mucosal barriers and mitochondrial dysfunction together with dysregulated bioenergetics.

In this paper, these pathways are summarised, and data regarding promising therapeutic options that target these pathways are highlighted; they include coenzyme Q10, melatonin, curcumin, molecular hydrogen and N-acetylcysteine. These data are promising yet preliminary, suggesting hopeful avenues to address this major unmet burden of illness.

 

I have to note TRI-ME is a creative name. It made me chuckle.

 

edit: Walder is not involved in this study! they're just trying their bipolar drug on me/cfs! !! fingers crossed it helps and I'm sure we will learn something but the theoretical basis is effectively absent.
Walder's in vitro work continues this year and he still hopes to get to a clinical trial for his drug screen after that.

leaving this here just for posterity but Walder isn't involved in this one: [There's a guy at Deakin University who will be involved in this. Ken Walder. He got $1 million from the National Health and Medical Research Council to look at me/cfs derived cells and run 1300 approved drugs on them to see which ones had the most promising responses.

https://www.emerge.org.au/news/professor-ken-walder/ <- this is an interview I did with him a few years ago.
https://www.nhmrc.gov.au/funding/ta...atigue-syndrome-mecfs/annual-progress-reports <- this is where his research was up to a while ago

The trial using Trimetazidine for bipolar depression is coing out of the same university, whether it looks like it has started depends where you look. The official clinical trial sites show no update but the university media site is saying yes: https://impact.deakin.edu.au/2024/0...ay-for-novel-treatment-of-bipolar-depression/

Overall trimetazidine research is showing a lot of benefits in vascular and mitochondrial domains, doesn't hurt to try it.

Here's the drug screen Walder did for bipolar depression, which identified trimetazadine as the top prospect: https://pubmed.ncbi.nlm.nih.gov/36890661/
I suspect the same general process of running drugs on a bunch of cells was used in mecfs? it's certainly odd that also apparently turned up trimetazadine! maybe it's a wonder drug?!

It's always worth remaining skeptical but I am hopeful about this research: the same team has used the same process succesfully in other diseases.]

 

Yes, I'm advocating for the research to proceed.

However I dont think it's quite in the same risk category as some drugs. It is used regularly in sports doping. Iga Swiatek was recently banned from the WTA tour for taking it!

 

To be fair, in the interview mentioned above by @Murph (thanks for sharing), they do explain they will first study ME/CFS cells using transciptomics. Maybe, if possible, it's time for another interview @Murph to see if things have headed anywhere? At least it's nice to see that someone, who's name one isn't even aware of, is working on ME/CFS.

 

I don't want to become the defender or spokesperson for this technique, but it does proceed based on that premise: we dont know what's wrong, so take an unbiased approach to see what drug makes things look like healthy cells again.

Walder used it in diabetes, he told me. Here's a couple of his papers that argue this process is useful when you're groping round in the dark (my emphasis added).

Gene expression signature: a powerful approach for drug discovery in diabetes
Smithamol Sithara 1 , Tamsyn M Crowley 2 , Ken Walder 1 , Kathryn Aston-Mourney 3
Affiliations

• PMID: 27927696
• DOI: 10.1530/JOE-16-0515

Abstract
Type 2 diabetes (T2D) is increasing in prevalence at an alarming rate around the world. Much effort has gone into the discovery and design of antidiabetic drugs; however, those already available are unable to combat the underlying causes of the disease and instead only moderate the symptoms. The reason for this is that T2D is a complex disease, and attempts to target one biological pathway are insufficient to combat the full extent of the disease. Additionally, the underlying pathophysiology of this disease is yet to be fully elucidated making it difficult to design drugs that target the mechanisms involved. Therefore, the approach of designing new drugs aimed at a specific molecular target is not optimal and a more expansive, unbiased approach is required. In this review, we will look at the current state of diabetes treatments and how these target the disease symptoms but are unable to combat the underlying causes. We will also review how the technique of gene expression signatures (GESs) has been used successfully for other complex diseases and how this may be applied as a powerful tool for the discovery of new drugs for T2D.



. 2023 Dec 31;15(1):2165368. doi: 10.1080/19382014.2023.2165368.
Identification of reversible and druggable pathways to improve beta-cell function and survival in Type 2 diabetes
Smithamol Sithara 1 , Tamsyn Crowley 2 , Ken Walder 1 , Kathryn Aston-Mourney 1
Affiliations

• PMID: 36709757
• PMCID: PMC9888462
• DOI: 10.1080/19382014.2023.2165368

Abstract
Targeting β-cell failure could prevent, delay or even partially reverse Type 2 diabetes. However, development of such drugs is limited as the molecular pathogenesis is complex and incompletely understood. Further, while β-cell failure can be modeled experimentally, only some of the molecular changes will be pathogenic. Therefore, we used a novel approach to identify molecular pathways that are not only changed in a diabetes-like state but also are reversible and can be targeted by drugs. INS1E cells were cultured in high glucose (HG, 20 mM) for 72 h or HG for an initial 24 h followed by drug addition (exendin-4, metformin and sodium salicylate) for the remaining 48 h. RNAseq (Illumina TruSeq), gene set enrichment analysis (GSEA) and pathway analysis (using Broad Institute, Reactome, KEGG and Biocarta platforms) were used to identify changes in molecular pathways. HG decreased function and increased apoptosis in INS1E cells with drugs partially reversing these effects. HG resulted in upregulation of 109 pathways while drug treatment downregulated 44 pathways with 21 pathways in common. Interestingly, while hyperglycemia extensively upregulated metabolic pathways, they were not altered with drug treatment, rather pathways involved in the cell cycle featured more heavily. GSEA for hyperglycemia identified many known pathways validating the applicability of our cell model to human disease. However, only a fraction of these pathways were downregulated with drug treatment, highlighting the importance of considering druggable pathways. Overall, this provides a powerful approach and resource for identifying appropriate targets for the development of β-cell drugs.

 

There's a small blurb here about the work Deakin are doing on me/cfs: https://med-projects.deakin.edu.au/projects-2023.php


yes, they write me/csf some of the time! Like many new studies it's being done by people who've wandered into this field from elsewhere; that lack of deep background doesn't increase the chance of success but nevertheless i'm always pleased to see new people coming in.