Good afternoon everybody thanks for the invitation pleasure to be here and to talk about ivy glyburide in acute stroke to prevent cerebral edema these are my disclosures and cerebral edema an acute stroke is a common problem 70,000 patients in the us alone have malignant infraction each year and as many of you know or all of you know it is a fatal often fatal
Disorder but 60 to 80 percent fatality rates and the only treatment we currently have for it is the compressive craniotomy obviously a quite invasive procedure and there aren’t any good medical approach is no good medicines to prevent edema this is a example of typical patient who underwent decompressive craniectomy they they won there’s some hypo density day 2 to
3 you see some midline shift and faceman of the ventricles and then the midline shift is resolves with with the hema craniectomy so that treatment was shown in multiple trials that were pulled a small number of patients in these three trials together 93 to be quite effective at avoiding a very severe disability mrs for dichotomies a team of 75 versus 24% in favor of
Hema craniectomy but it was also benefit if you dichotomize the ranking at the amorous three and it was a survival benefit as well so these are outcomes at one year and so a very effective treatment but can we do more with medications and can we avoid these hema craniectomy well in order to figure that out we need to first know what the causes of cerebral edema and
And this seems to be a key player it is the t rpm for channel that was discovered in early 2000 and it’s a very interesting channel that lives in multiple cells within the brain so this channel is regulated by a by sir one that is associated with this channel and after ischemia when there’s atp depletion there’s up regulation of this channel so the channel usually
Doesn’t really exist in the cells but is up regulated soon after ischemia and and the channel is activated by atp depletion it allows sodium to flow into the cell and that leads to cerebral edema and as i mentioned it’s present in many cells in the brain neurons astrocytes endothelium and oligodendrocytes so this is from 2006 paper from shimmered in nature medicine
Really nice paper that shows in all of these cells neurons astrocytes capillary and the thulium and oligodendrocytes you’re shown in red staining for that molecule that is associated with the with the channel serve one that it’s present in all of those cells in green the specific cells are labeled and then on the far right you see the co labeling of this cell for
Example the neuron in the top row as well as the red labeling for serve one in an mca stroke model so they demonstrated one that serve one was present that it was up regulated after mca strokes and they later also showed the same in a patient who underwent hema craniectomy and tissue was taken from the brain and they serve one the trp m4 channel was present also
In human tissue this is what looks like under electron micro and microscopy control cell on the very left a and then after atp depletion the cell starts to swell up after five minutes 25 minutes later there’s even more swelling so you get these large edematous cells that are the cause of of eventually the malignant edema so what if we blocked that channel well
It turns out that there is a molecule or a medication glib right and that can block the t rpm channel quite effectively and so they went out in that same paper that was published in 2006 to try to block the channel and see what the effect was on infarct volume as well as on survival and so this was in an animal study in fact volume was reduced by about 50% in the
Animals treated with glyburide versus the control patients only enormous treatment effect there on the radiological outcome and as animal research is always do they show a nice example of the histology and so here on the left the control rat with a large in fact or mouse sorry i don’t know what of us and on the right minimal swelling so the this also led to great
Survival advantage among the animals traded with glyburide but the mortality was 24% versus animals treated with sale and 65 percent mortality 29 breaths per group and this were was a rat study so those encouraging results in animal studies led to the games rp trial and that was a randomized controlled trial multicenter that was published in 2016 so the design was
The patients were included 18 to 80 years old they needed to have a large anterior circulation stroke and that was defined as a diffusion lesion between 82 and three hundred ccs they needed to be randomized within ten hours after stroke onset iv tpa was permitted up to four and a half hours thrombectomy was not permitted in this trial randomization was 1 to 118
Centers were included and eighty-three patients were involved in the trial the the the trial was supposed to enroll more patients but was stopped early for financial reasons these are the baseline characteristics which were well matched between the patients the 41 in the glyburide arm and the 36 in the placebo arm and this is the per protocol sample notably the
Baseline diffusion lesions were matched 157 versus 163 and and quite large the minimum again was 82 ccs these were almost double so these were fairly substantial strokes in the study the primary efficacy outcome was interesting endpoint was the composite of an mrs zero to four and avoidance of hemi craniectomy and the primary endpoint was not significant 42% in
The glib right arm versus third 39% in the placebo arm and p-value of 0.8 the primary safety outcome was there any serious adverse event and that was equal also in both arm 68 percent versus 72 percent p value of 0.7 and so they looked further in what you know if there was any efficacy on their secondary or tertiary endpoint so i’ll show some of those and i think
That those are encouraging even though the primary end point of the study was not so here’s the 90-day mrs and oddly for an acute stroke trial that was not chosen as one of their even their secondary endpoint but if you look at the benefit on mrs 0 to 4 you see a difference in the control arm 47% achieved mr 0 to 4 versus 61% in the glyburide arm not statistically
Significant but a good trend in favor of the glyburide odds ratio was 1.7 for this deck atomization and the p-value of 0.2 if you do is shift analysis over the entire spectrum of the mr-s distribution it’s also in favor of glib right as you can see on this slide with a p-value of 0.1 and so the difference is that there were some sites that did hema critiqued me
Prophylactically basically in the study and that high percentage of prophylactic hema craniectomy hurt them in their primary endpoint so rather than waiting until patients decompensated and and truly needed hema craniectomy it was offered prophylactically in about half of the centers that were participating some other endpoints here mortality a p-value of 0.06
In favor of the intravenous glyburide treatment treated arm midline shift at 72 to 96 hours four point six millimeters in the glyburide arm versus eight point five millimeters in the placebo arm and that was highly statistically significant so on their imaging endpoint and here the safety endpoint they were particularly interested in severe hypoglycemia defined
As blood glucose less than 55 occurred in nine percent of the patients in the glyburide arm versus no patients in the placebo arm so that was increased p-value of 0.1 and you see here in the in the graph the shaded area and blue at the bottom indicates time points individual time points when patients dipped below that fifty five milligrams per deciliter threshold
So those encouraging secondary and tertiary endpoints in terms of their imaging endpoint the ranking shift and the safety led the investigators to actually the drug and that was it with a small company was bought by by region and by gen decided and two that these data were encouraging enough to start a larger phase three trial that’s called term it’s supposed to
Enroll six hundred and eighty patients started its now enrolled 116 patients for november first and it had very similar inclusion criteria as the phase 2 trial lesion volumes now 80 to 300 milliliters that can be a patient can be enrolled either based on diffusion-weighted imaging or ctp ak or they can also be enrolled based on a low aspect score age range is 18
To 85 time again less than 10 hours after stroke onset and this time thrombectomy is permitted but patients need to get an imaging study after thrombectomy to confirm their final lesion volume for inclusion thank you very much
Transcribed from video
SVIN 2019: IV Glyburide for Brain Swelling in Large Hemispheric Infarcts By SVIN
