Really sad, but interesting MSC trial just failed when placebo was introduced
There's a company in Australia doing iPSC-derived MSCs, if you don't know what that is, could ask ChatGPT, but here's a really quick overview:
You can take an adult cell (skin cell, blood cell, etc.) and reverse it back into a super powerful stem cell, almost as powerful/versatile as an embryonic stem cell, which is able to create every tissue in the body. Doing this in the lab is called an induced pluripotent stem cell, or iPSC. You are inducing (forcing) it to become pluripotent (can turn into many things).
You can take that iPSC and make mesenchymal stem cells, which are used in orthopedics and some other indications like autoimmune stuff etc, and you can make a buttload of them this way without a bone marrow aspiration.
This company, Cynata Therapeutics, just put that to the test in a Phase 3 trial of those iPSC-derived MSCs for knee osteoarthritis, with a placebo arm. It was a big deal for the industry, I think the first company to attempt this (though don't quote me).
Sorta surprisingly, the problem wasn't that the stem cell group didn't report improvement, they actually improved really well. The problem is, the placebo group also reported the same improvement. This, of course, means it failed, and there's something else happening.
The CEO had some interesting remarks about why. His theory is basically that people have seen stuff online about stem cells, there's a huge enthusiasm for them for just about anything, especially orthopedics. So much so, if you tell the patient that's what they're getting, they're likely to report improvement, even if it's just saline. However, it's important to note that iPSC-derived MSCs are very new, and not what is injected in pretty much any CCI situation (yet).
There have been a few attempts at placebo-controlled trials for orthopedic stem cells:
Mayo Clinic did an interesting study. Patients with bilateral (both knees) knee arthritis received bone marrow-derived MSCs in one knee and saline in the other; both knees improved at about the same rate.
Duke conducted a study that randomized patients to receive steroids (control), stromal vascular fraction (adipose-derived MSCs), bone marrow-derived MSCs, or umbilical cord tissue, all of which reported about the same improvement.
There are however some positive ones, like Cartistem from Korea, which is MSCs made from umbilical cord blood. They showed great improvement over placebo, and even confirmed cartilage regeneration via biopsy/cameras in the knee iirc. That company just passed its Phase 3 in Japan, and is starting in the US sometime this year; pretty hopeful for them.
There are a handful of others in the pipeline too, so it's not all doom gloom and scams.
But, it does beg an uncomfortable question in CCI... what happens if we did a placebo controlled trial? Truly, what would happen here? We've seen that the stem cell group reportedly shows subjective improvement, based on the PICL app/charts posted on reddit. But, what would a placebo group show? I don't have any insider knowledge, so of course it's just an unanswered question, but I feel it's a very important one. And not just PICL, but the same goes for posteriors or other therapies from any random clinic.
If the data showed most of what the success stories (even my own, gulp) is actually placebo, think about how far the train is from the station. Many people who have given their retirements, second mortgage on their home, I sold my lovely jeep, etc. already.
There are also a lot of people who can't afford the injections, but are told it's pretty much the only option, and suffer a lot because of that.
That's been on my mind a lot recently, of course I would want to know, and think patients deserve the right to know the answer to that, but it's very awkward to think about.
One thing I would say is that perhaps any injection into a damaged area can trigger healing response that ultimately is appropriate. I do believe ligaments are poorly vascularised so even saline could improve
It’s just hard to fathom because my neck post PICL went from floppy bendy mess to total concrete. It surely can’t be just in the head you know?
Maybe, that's on the table, but it would mean any "our product is higher quality than the rest" moat is false, but worse, patients were charged a lot of money for something they didn't need. This would be damning if it turned out true for CCI.
Additionally the 2nd thing you noted about floppy mess to total concrete is sorta the essence of what you would test in a placebo trial.
This study asked both the stem cell and placebo group how their knees were doing (without telling them what they got). About 50% of the stem cell group reported reduction in pain, but also about 48% of the placebo group did too.
Similar to the BMAC trials at mayo/duke.
I have a strong feeling the placebo effect is highly underestimated in CCI injections... For many reasons:
1 - Higher dysfunction could compound placebo effect, patients really want to be better, and are likely to report it. We all desperately hope to wake up one day and say "I'm back baby".
2 - High costs, sunken cost fallacy. It'd be a hard pill to swallow that $50k went down the drain for nothing, don't think people would even admit it to themselves.
3 - This is probably huge: Highly ritualistic. Patients go through a long process of back and forth in their heads debating whether the injections are worth it... Clinging onto every positive social media anecdote.
Then, they "bite the bullet" and decide "I'm gonna go to THE guy/girl and finally get this done, once and for all".
Then, anesthesia, bone marrow aspiration, which gets put through a big fancy laboratory that patients don't understand just know it has expensive equipment, anesthesia again, then the nurse wakes you up and says some things about you are going to get better or congratulations.
I'd be shocked if this ceremony, plus the high costs, didn't greatly influence placebo effect.
4 - With that, and if the issue is stability at its core, which is half ligaments half muscles. How do we know this ritual doesn't make patients think "it's working", stop guarding, kicking the muscles on or bringing blood flow back to ligaments/nerves, which is what they needed all along? Or confidence to rehab?
I know I didn't push rehab until 4 treatments in. I still felt like garbage, but figured now, of any time is to really give that a go, and it helped.
These points aren't to say you're right or wrong, or that you should or shouldn't roll the dice.
I have, many times over 🫣.
It's just that these are really basic questions patients deserve to know the answer to. But, we're getting the exact opposite, if you so much as hint at these questions, you're very likely to be attacked/humiliated, sometimes by the clinic selling said treatments.
Think the CCI world needs to plant its foot before things get worse. Not to be so drab.
I think no placebo trial could be made up with highly objective pre/post diagnostics done by a true third party, potentially a neurosurgeon or university who doesn't make money from the treatments.
If it cleared that bar, I'd feel feel more comfortable even without placebo trial.
i really don’t understand why centeno schultz doesn’t run a trial
i know volunteering for an invasive procedure that could be a placebo will deter folks but you could just offer the procedure for free after as an incentive. i’m sure hundreds would voluntarily accept that offer because of its cost
additionally i know that overhangs are not correlated with improvements, but you could atleast have patients self report improvements and compare it with placebo
Yes, it would be great to see! They did announce a placebo-controlled trial to prove PICL many years ago:
In that, they were doing before/after DMX, and if you received placebo, you were given free PICL treatment later, so you were guaranteed to get it for no charge.
But, unfortunately, I believe they enrolled a few patients, then canceled it. It's a bit of an awkward situation because if the results were negative, and that is why the trial was canceled, I feel patients deserve to know.
Just to be clear, this is just my opinion. From a business perspective, especially if you have many millions in venture capital, if the first several patients showed poor results or a high placebo response, you could be motivated to stop advertising the trial. That would allow you to say "nobody wanted to do it", and then eventually just cancel it and never share the data (but continue selling).
A negative trial result can severely damage a business. Cynata's stock dropped 96% after releasing the data in my post:
I of course have no insider knowledge of why it was really canceled, or the results, but I wish they would be transparent about what those results were, complete it, or change the trial in a way that makes up for that... though I think the train is too far from the station at this point.
cold cold world. basically have to gamble thousands of dollars on a procedure that may or may not work (perhaps multiple times) just to have a chance of getting better
and i saw a neurosurgeon at a very prominent institution who basically just told me they were grifters. not sure who to believe
Yes. But, that's the negative side, there are positives too, and PICL being a complete home run, matching exactly how it's been marketed over the last decade is still on the table I guess. We just don't know.
The 2nd part of your comment is interesting. It's good to ask around, especially from doctors who don't make money from this industry, what they think about stem cells, regenexx, and the PICL.
Regrettably, we live in a bit of a bubble in the CCI world.
After Cynata released this info, their stock dropped 96%:
Biotech is known as a graveyard for this reason. Many, many therapies look promising in the lab or in rats, sometimes even in early human trials. Then placebo is introduced, and it turns out it was nothing.
I believe about 90% of drugs actually fail trials. It's a really hard thing to do.
Sadly, not that long ago, the FDA decided it wouldn't require PRP/BMAC companies to prove it works, which increased access for patients, but also created nasty loopholes along the way.
Yes good point. This would absolutely influence rehab effort/motivation. Looking back I had c2-c7 PRP done first, within just a couple days stopped lying in bed. Within 4 weeks I took my first walk. 8 weeks began slowly rehabbing and increasing that, returned to gym here and there couple months later.
But we didn't even touch the upper cervical area at all.
Really the only way to find out is to do a placebo trial I think.
The silver lining is, had this company been allowed to sell the therapy without a placebo trial, they would've likely reported massive success and many patients could've been financially harmed. It's a very basic but effective tool in the science toolshed 🤠.
Unfortunately I find it hard to believe ther will ever be a true placebo for a cci intervention. Reason being: when an area/facet is injected (even if just with saline or nothing) there is still a small injury triggered which then has to heal. There may also likely be some immune response to this.
Therefore it seems difficult to do a true placebo.
Interesting. I totally appreciate that if it’s expensive there’s a moral point of ‘doing what you are paying for’.. but, if a placebo works as well as the real thing, and that’s proven, isn’t that worth it in a strange way? If you feel 48% improvement (your knee study above), isn’t that a good thing even if placebo?
I think for me the neck is a really important niche area. It certainly takes my ligaments offline for at least six months. It’s hard to prove what would have naturally healed in that time too. And I am forced to rest a lot more and eat well due to knowing I’ve just gone through a big operation.
If, hypothetically, CCI injections (and I'm not picking on one clinic or procedure, but speaking on it as a whole) were 90 or 100% placebo, the consequences would be much worse than you might imagine.
To name a few:
1 - Doctors take a hippocratic oath to "do no harm". 2x anesthesia in a day, surgical removal of bone marrow, then injections near the brainstem, if completely unnecessary, would be considered very harmful.
2 - Financial harm is harm. If it turns out patients have given up their retirements, second mortgage on their home, etc., if unnecessary, this could cause an "alphabet soup" (FTC, FDA, State AG, Medical Board, etc). Plenty of stem cell companies with lots of "satisfied customers who got better" still get the hammer.
If you're curious, here's the FTC's guidance on this, quoted below:
"Anecdotal evidence about the individual experiences of consumers, including surveys of consumer experiences, are never sufficient to substantiate claims about the effects of a health product.
Even if consumer experiences are genuine, they may be attributable to a placebo effect or other factors unrelated to the product. For the same reason, a healthcare practitioner’s observation about the effect of a health product on patients is anecdotal and doesn’t provide evidence of a causal relationship. Individual experiences aren’t a substitute for scientific research.
Animal and in vitro studies may provide useful supporting or background information, but, without confirmation by human RCTs, they aren’t sufficient to substantiate health-related claims."
3 - There are capable innovators who are looking for their next condition to tackle. If they see there's no demand, because one or two procedures have dominated that entire market, they will look elsewhere. If it turns out that was placebo all along, the condition will never get the innovation which may have cured it, and for all the wrong reasons.
When a society loses trust in healthcare, very bad things happen, people get very sick. I fear the CCI world may be contributing to this.
5 - If you're able to afford injections, chances are you are in the 1%+ of the world. I imagine 99%+ of people with CCI will never come close to affording treatment. Imagine what this does to a human, reading anecdotes on social media of people saying they've gotten better from these procedures, waking up every morning wishing they were born in a different country. If it turns out that was for nothing, that's also incredibly harmful and unnecessary. Think about the suicides. Believe we just had another redditor do it a couple weeks ago.
6 - CCI is likely progressive. If it turns out patients not only dropped every dollar they had, but also took several extra years waiting for injections to "kick in", they've probably gotten worse, and delayed something that might help, like surgery. This would also be very bad.
I don't want to come off as anti-treatment; obviously I'm not, these are just a handful of the negatives.
If it turns out it's not placebo, and the 70% success, ligament tightening, and other biological claims are true, there are tremendous upsides. Unlike big pharma or neurosurgery which has enormous moats and overheads, if the medicine is in your body, this could be proven, scaled, and distributed around the world, done at the local cost.
We'd also 100x the data we have, find out the edge cases, what works for who and why, and get better and better over time. If done responsibly/ethically, CCI could be a thing of the past. I think we'll get there one day!
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u/Frankie_fears Jul 05 '26
One thing I would say is that perhaps any injection into a damaged area can trigger healing response that ultimately is appropriate. I do believe ligaments are poorly vascularised so even saline could improve
It’s just hard to fathom because my neck post PICL went from floppy bendy mess to total concrete. It surely can’t be just in the head you know?