MSB’s ARDS trial and C-Reactive Protein (CRP) enrolmentcriteria
Whencommencing the ARDS trail in March 2020, MSB set enrolment criteria for theARDS trial of, amongst other things, a High sensitivity C-Reactive Protein(hs-CRP) or CRP serum level >4.0 mg/dL (which equates to a lower limit of40mg/L).
MSB’sannouncement on 10 March drew a comparison between common inflammatory biomarkersChronic Obstructive Pulmonary Disease (COPD) and Covid-19 ARDS. It inferredthat success shown in treating the former chronic disease with inflammation,might predict success in treating the latter acute disease with inflammation.Studies have shown that CRP > 3-5 mg/L is associated with higher rates of mortality in COPD (e.g. https://www.atsjournals.org/doi/10.1164/rccm.200605-713OC; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2080712/). MSB’s enrolment criteria of 40mg/L when viewed in this context make sense as a (possibly conservatively high) criteria.
Butin hindsight:
1, Was the CRP criteria set high enough to prove efficacy given the acute nature of this disease? and
2, Should CRP have been the main criteria (as it is consistent with Rem-L's mechanism of action), without adding ventilation requirements as another (potentially confounding) enrolment criteria?
At least one study has more recently been published which indicate CRP levels in severe acutecases of COVID-19 (MSB’s target population) are significantly higher than 40mg/L
InAugust 2020 The Lancet published a study on Covid-19 cases from March 2020(n=269) which drew comparisons between CRP (and also ferritin concentrations)with clinical outcomes. It showed severe cases associated with death or a need to ventilate with CRP significantly exceeding 40mg/L and in the range of 100-300mg/L (https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(20)30275-7/fulltext).
The study produces interesting graphs (see copies at end of this post) which indicate that rising levels of CRP >150mg/Lare associated with death. In cases of those who died, CRP was rapidly rising to about day 12 afterthe onset of symptoms, and then CRP levels declined thereafter.
Thegraphs in these studies also show that, during March (about the time of the MtSinai pilot study), it was common practice to move patients onto ventilators atabout the time when CRP levels were high and increasing (i.e. about day 12after onset of symptoms). However, the standard of care seems to have shiftedin the later months of 2020 to delay the commencement of ventilators, perhapsdue to health concerns for the use of ventilators, learning of effectiveness ofother treatments such as proning, oxygenation or other treatments.
Asone of the key enrolment criteria for MSB’s ARDS trial relates to ventilation,it might be that this criterion actually caused many candidates to be dosed too late in the course of their disease for Rem-L to be effective in stopping damagefrom inflammation (i.e. after CRP had already peaked).
Maybethis is why interim trials at 30% and 45% passed (when ventilators were usedearly when CRP was high) but the 60% interim trial did not (Rem-L applied toolate).
Itwould be interesting to see the results of MSB’s trial stratified by CRP profiles(and particularly those with rapidly increasing CRP levels above 150mg/L) at orabout the time when Rem-L was dosed.
Toapply the analogy to @LeftYahoo's excellent Christmas greeting post, maybe the CRP criteria of40mg/L reduces the apparent efficacy of the “Rem-L life-preserver” by including too many candidates from 'the airport' whereas a criteria of 150mg/L might reveal efficacyfor those in 'the banana boats'. Or perhaps another way of looking at it is thatthe ventilation criteria resulted in applying the Rem-L life-preserver too lateand in the latter part of the trial resulted in only throwing the life-preserver to candidates after they had more or less drowned.
Graph from study in the Lancet showing days from onset ofsymptoms
Graph from study in the Lancet synchronised to point ofventilation
(20min delay)