A few months ago, folks at Stanford were claiming miraculous recoveries after implanting stem cells directly into patients’ brains at the site of injury. An interesting concept, to be certain.
Now we have “stem cells lite”, or, at least, the slightly-fewer-holes-in-the-skull version – and it’s apparently just as miraculous.
This is a Phase 2 double-blinded dose-escalation study evaluating treatment with intravenous multipotent adult progenitor cells, with treatment initiated between 24 and 48 hours. Their trial design reflects the nature of a Phase 2 trial, with three cohorts, unbalanced allocation, and dosing differences between groups, but is otherwise fairly straightforward. Until you get to the primary outcome:
“The primary efficacy outcome was the multivariate global stroke recovery at day 90, which assesses global disability, neurological deficit, and activities of daily living and consists of mRS 2 or less; NIHSS total score improvement of 75% or more from baseline; and Barthel index of 95 or more in the multipotent adult progenitor cells treatment group, compared with the placebo treatment.”
Which is to say, they’ve conjured up their own unique black-box composite primary outcome – an outcome they changed midway through the trial.
Why would you need to change the primary efficacy outcome in 2014 for a study that started in 2011? The obvious implication is the results were unfavorable – and, the cursory review of their results table suggests this is a reasonable stance to take.
These authors screened 160 patients at several different sites for eligibility and ultimately randomized 129. Of these, three did not receive the allocated intervention – leaving the remainder for analysis. Patients in each group were generally similar based on NIHSS, time until infusion, and stroke interventions. Sticking to traditional outcomes measured by stroke trials, there was no difference between groups: mRS ≤2 in 37% of the intervention group and 36% of the placebo. However:
“exploratory analyses suggested an increase in excellent outcome in the multipotent adult progenitor cells arms in the ITT population, and a beneficial clinical effect on long-term 1 year disability.“
This “excellent” outcome is the product of the midstream outcome change combined with their post-hoc data dredging for a feasible positive finding – a combination of patients with mRS ≤1, a NIHSS ≤1, and a Barthel Index ≥95. Then, the bulk of their analysis is further restricted to one year outcomes of those who received their stem cells within 36 hours from stroke onset. With such an obvious “beneficial clinical effect”, is there any question regarding the role of the funding source?
“The funder of the study was involved in study design and in data interpretation. All data collection and analysis were overseen by Medpace. One employee of the funder (RWM) was represented on the writing committee.“
and:
“DCH received grants from Athersys, payments to his university from Medpace for patient enrolment, has a patent on the MultiStem cells through his university and has received licensing revenue through his university. LRW received grants from SanBio and Athersys, and personal fees from SanBio. GAF is a consultant for Athersys; received personal fees from Medpace; and payment from Medpace to his institution for study costs. SS received grants from Athersys. SIS received grants from Athersys, and consulting fees that were paid to the institution from Mesoblast, Aldagen, and Celgene. CAS received grants from Athersys. DC received grants from Athersys.”
The likelihood these results are valid, reproducible, and have a clinically meaningful effect size is nearly zero – but that certainly won’t stop them from throwing good money after bad.
“Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): a randomised, double-blind, placebo-controlled, phase 2 trial”
https://www.ncbi.nlm.nih.gov/pubmed/28320635
You wrote, “their analysis is further restricted to one year outcomes of those who received their stem cells within 36 hours from stroke onset.” You’re obviously lying. The 1 year results were statistically significant for all patients. There was no data mining. The 1 year results were a success for all patients, including 36-48 hours after stroke onset. The SEC should investigate your short position in ATHX as this appears to be a feeble attempt at stock manipulation.
I think the most robust reply I can suffer is: “???”
The one year results were statistically significant for all patients. Retract what you wrote.
I choose to exist in a fact-based reality. Exploratory analyses are simply that – anything other than the original primary outcome should only be considered hypothesis-generating, particularly with the heterogeneity between clinical measures.
If you’d like to understand why, despite signals of benefit, I feel their results are unlikely to be replicated, please read:
Why Most Published Research Findings are False
Read the chart you just posted. 1 year results, MAPC n=65. Those are all of the Multistem patients. There was no data mining. It was not for patients injected up to 36 hours like you stated. The one year results were for all patients and they were successful and statistically significant. Please correct your article. Primary or secondary had nothing to do with the lies/mistakes in your article. How do you not understand how to read these results? Are you really a doctor?
As you can see above, a handful of outcomes show no difference and a handful of outcomes favor the intervention. This lack of consistency across outcome measures calls into question whether there are clinically meaningful differences between groups. The sample size is small and the potential for bias and other confounders is extremely high given the clinical variability between stroke patients and response to other acute therapy. This is not a successful trial except to inform the design of future trials, as the accompanying editorial also notes.
No corrections to my original post are necessary.
Do you represent UT Houston with this blog post? You display the hospital on your blog as if you are representing them. There are some other people at your university saying the exact opposite of these cells. Interesting That a public institution is trying to play both sides of the fence especially from a financial perspective as you point out. I will try to get to the bottom of this. I hope there is no foul play on either end.
The beauty of academia absent financial conflict-of-interest is that in the setting of uncertainty, reasonable people can have reasonable disagreements over the results of published research findings. Our unifying mission is protecting patients and advancing healthcare, and innovation and dissension have each important roles to play.
Disagreement? You wrote, “their analysis is further restricted to one year outcomes of those who received their stem cells within 36 hours from stroke onset.” That is just plain wrong. Are you going to correct what you wrote?
That would be Table 4 in the article, of which it becomes increasingly clear you probably haven’t read.
By now you must know your statement is wrong. Did you intend to misinform your readers? The one year results were not data mined. Why won’t you correct your error?
You clearly haven’t read the article and its extensive discussion of which post-hoc analyses showed consistent benefit thought worthy of further investigation (hint: it’s those treated <36 hours).
I appreciate your passion and engagement for this issue, which I hope is motivated by true concern for patients suffering stroke.
Not to mention a Fragility Index of 1 for “excellent outcome.”
The likelihood that these results will stand the test of time, let alone the FDA review process, is miniscule at best.
Great post.