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.
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.“
“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”