So looking back, what do you think those earlier studies taught you that most directly shaped the design and rationale of CAP3?

Yeah, thanks, Ben.

We actually started this as a concerted action.

That's where the CA first came from, on polyposis, because at that time we didn't have the genes for what was then HNPCC.

And basically the story began with a little boy who was 12 who had extracolonic features of FAP but no polyps.

I'd just been involved in proving that folic acid prevents spina bifida in pregnant women who'd had previous babies affected with spina bifida.

and it seemed like an obvious thing to try interventions that might prevent polyps in these kids not only for them but also for us because our colon cancers also are driven by APC mutation very often so that seemed like an easy idea but it turned out to be quite challenging in 1993 we got all of the European centers together and got the money to launch in that year the CAP1 what became CAP1 And as it happened in that year, we were involved with Richard Fishel and Rick Kolodner in Boston, helping to identify the MSH2 gene in one of our big families.

So could you explain why non-inferiority was the right trial design for this question and how you arrived at the pre-specified margin of 1.5? Yeah,

Wow.

And it made me think, wouldn't it be nice if we could do something to sort of prevent these things happening rather than just waiting for an operation? And as it happened at the time, I was leading the English end of a big study, uh, which you'll probably be aware of, which we're, we're, we were doing the vitamin study on women with spina bifida babies, and we were just about to identify folic acid as a way of preventing spina bifida in pregnant women.

So I had these two thoughts in my head, maybe we could set up a trial like this folic acid trial.

And then one of my friends in Edinburgh said, "Have you seen this paper from Melbourne?" Gabriel Kuhn had just done a big study looking at people with colon cancer, seeing that people who took a lot of aspirin didn't seem to get as much bowel cancer in Melbourne as those who didn't.

So that was the design set up.

We were applying to Europe for a concerted action, so we had to think of an acronym that began with CA, so I, I came up with Concerted Action Polyپ Prevention.

But then in 1993, just as we started that trial, we were involved in finding the first of the genes for Lynch syndrome.

Right