WSC 2025 | Effect of colchicine on cognitive outcomes after acute ICH: secondary analysis of COVASC-ICH

This was a really interesting study that my colleague and friend, Aristeidis Katsanos, and I led testing colchicine, which is a drug that has been shown in patients with atherosclerotic disease and symptomatic atherosclerotic disease like PAD, CAD, to be able to reduce ischemic vascular events and major adverse cardiovascular events without increasing bleeding again. And one of the ways it does this, although we don’t know exactly, there’s many pleiotropic effects of this agent, but we know that it affects inflammation. So we think the pathway is a reduction in thrombo-inflammation. And an etiology or disease state where we have a lot of thrombo-inflammation that affects both acute outcomes but also long-term outcomes is intracerebral hemorrhage. When patients have bleeding in the brain, there’s a large wave of thrombo-inflammation that occurs that affects short-term endpoints and long-term outcomes and functional outcomes and death. But also the underlying small vessel disease that results in bleeding in the brain, that also has chronic thromboinflammation associated with it. So a drug like colchicine that may be safe and not increase bleeding while reducing thromboinflammation seems to be perhaps a very promising agent for this disease population. So we first conducted an animal study which is the first kind of murine collagenase-induced ICH model of using colchicine where we showed that colchicine pretreatment or treatment shortly after a bleed does not exacerbate hematoma expansion. The reason we wanted to just double check this even though there was no sign of excess bleeding in the clinical trials to date with colchicine and other disease states is that there may be some pleiotropic antiplatelet properties of colchicine and we just want to make sure it doesn’t exacerbate bleeding. We didn’t see that in the animal models and then most importantly we provide proof of concept that you can reduce inflammation in the brain with colchicine and in these animals there was reduction in perihematomal inflammation with colchicine treatment. So subsequent to that we led the COVASC-ICH trial. This was a small vanguard study conducted only in Canada of a hundred patients with ICH. This was a double-blind randomized trial. These patients were randomized to colchicine versus placebo. The dosing of colchicine was 0.5 milligrams. And we follow these patients just to get some feasibility metrics to be able to then design a larger Phase III trial. This is going to be a global one that we’re now leading, Aristides and I, that’s COVASC-ICH2 that I won’t get into in any great detail. But even though, so we met all our feasibility metrics, we actually exceeded our recruitment targets, our retention was great, our compliance was great. But another question was, well, even though our exploratory kind of primary clinical endpoint was MACE and there was very few events there and we didn’t have any power to really get any good signal. One thing that we were able to look at that where we could have had some power is cognitive function. Patients with ICH have a high rate of cognitive decline, 40% rate of new dementia as kind of four years after their ICH and that chronic inflammatory process in addition to the acute inflammation that we discussed earlier, probably plays into that. So we had a pre-planned secondary analysis of cognitive outcomes in this population. We estimated that with 100 patients, we should have 80% power to detect a 20% improvement in cognition as measured by a telephone MOCA scale, which is the Montreal cognitive assessment scale, but an abbreviated version that you could do over the phone. And so if we had 100 patients, we were empowered to detect 20% reduction at that endpoint at six months when comparing those that got colchicine versus placebo. Unfortunately, patients with ICH are sick. So we were not able to get 100 patients to complete the cognitive screening. Many of them will have aphasia or have reduced level of consciousness. So at the time of randomization or shortly after randomization, we were only able to get cognitive assessments in about 60% of the population. So we were underpowered. And also because we only had 100 patients, 50 people in each arm roughly, we didn’t have perfect randomization. So at baseline, those randomized to colchicine, their MOCA score was 30% less than those that got placebo. So not only did they have to beat placebo, but they had to catch up that 30% to actually show a difference. So ultimately, a primary endpoint was negative. We were underpowered. There was this imbalance in baseline cognitive functions that put colchicine at a disadvantage. But what was interesting is an exploratory analysis. When we looked at the delta, how much did one group, not at the absolute at six months, but what was how much did one group improve their cognitive function versus the other at six months and also at the end of study, which was about a year, the colchicine group improved their cognitive scores by 60%, whereas the placebo group only improved by 10 to 20%. So that was quite promising. This was a numerical trend. It’s exploratory, of course, but really a promising signal, a preliminary signal, that perhaps a very low-cost, widely available drug like colchicine could actually improve cognition in these patients who need it the most. Now, one thing that was also interesting was that we also looked at another scale of cognition. This was the mental alternation test. One problem with the telephone MOCA is that it doesn’t have a TRAILS test. The TRAILS test in the MOCA is important for assessing executive function. Executive function is the kind of domain that’s most affected in vascular cognitive impairment, at least one of them. So we actually did the mental alternation test and added that to our cognitive battery to be able to supplement that which is basically an oral version of the trails test and what we saw there is continued improvement in a very high slope in those that got assigned to colchicine and really a flat line in those that got placebo so basically if you look at the cognitive scores when you look this is the placebo arm this is the colchicine arm this this is how their cognition improved over time. But again, underpowered and only preliminary signals that we hope to validate in our now ongoing global COVASC-ICH-2 trial that’s funded by the Canadian Institute of Health Research. My colleague, Aristeidis Katsanos, is going to be at the helm driving this and I’ll be supporting them in any way I can.

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