To explain how I came to the conclusion that CrashPlan is causing the problem:
When I got the I/O error earlier this evening I almost immediately tried to delete the database from within Duplicati. This resulted in an error message telling me the file was locked by another process. I then used Process Explorer from Sysinternals to see what process was holding that lock, and it turns out it was CrashPlanService.exe.
This is why I am so confident this is the root cause.