Simmaron Research study on low-dose rapamycin may be overhyped?

General
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The study paper’s title begins with: “Low Dose Rapamycin Alleviates Clinical Symptoms
of Fatigue and PEM in ME/CFS Patients […]”. It sounds good… the title is saying that the treatment reduces symptoms.

But if you start skimming through the pre-print paper, you will see that only 40 out of 86 patients actually completed the study. Unfortunately, the study didn’t go so well and the number of people dropping out is much higher than what’s ideal.

Now suppose that there is a treatment that does nothing and that patients have a roughly 50/50 chance of getting better/worse over time. If the patients who get worse all drop out of the study, then the final cohort will have an overrepresentation of people who got ‘better’. This is why I would not draw conclusions from this study design (which is not ideal) when the dropout rate is so high.

Possible reasons why the dropout rate was so high

The preprint states that study participants had to pay to stay in the trial. While Simmaron Research’s charitable mission is to conduct research, it seems that they didn’t fund higher-quality research despite raising six figures every year since 2011. (Note: charities have overhead and have to find a way to pull in enough money to survive.)

Importantly, discontinuation from the study was most commonly attributed to financial barriers as this pilot trial did not cover the cost of the study drug or safety laboratory tests.

The pre-print also explains that patients sometimes left the trial if they weren’t getting better:

A secondary reason for discontinuation was a lack of perceived clinical benefit or a clinical decision to initiate a different therapy that may or may not interact with the study protocol.

Twitter thread by one of the paper’s authors

Patients have had bad experiences with antibiotics

Survey data that I collected show that patients (LC, MECFS, and vax) are more likely to report bad experiences with antibiotics than other treatments.

Caveats:

  • Survey data is unreliable in certain ways. (I don’t want to type out a nuanced deep dive on that though.)
  • What is true for antibiotics in general doesn’t necessarily apply to rapamycain.
  • While people did try rapamycin (or other macrolides), rapamycin wasn’t very popular among the survey respondents.

Sources:

Survey data suggests actual response rates are in the 1-20% range (maybe around 2%), and that human trials should ideally have many participants and a control group (because there is very little signal in the survey results and a lot of noise from reporting biases).

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My take on ME/CFS research in general: it looks like ME/CFS has multiple underlying causes which is why treatment response rates will be very low. This means that treatment trials need to be on the bigger side (which is expensive).

When most of the issues are self-reported, there is a tendency for studies to measure the patients’ reporting biases (which are quite significant). The reporting biases usually drown out whatever signal there is. So, randomized controlled trials are ideal. This will make treatment trials pretty expensive.

Asking patients about their health (or asking people on Reddit about what worked) will generate a lot of unreliable results. It won’t lead to much progress.

Perhaps a way around all of that is to find the causes first (so that hopefully we can get tests to predict treatment outcomes) and/or build an animal model.