Chris -
calibre plugins and
windows safe mode have no connection with one another, if running calibre with the --noplugins option makes no difference in Normal mode, it will make no difference in Safe Mode. From what you've written, plugins are not the issue.
I've also just seen that CCleaner can also disable shell extensions (I think that must have been added since I last looked), so there's no need for the nirsoft utility, other than to get a second opinion. Manufacturers also run bloat as scheduled tasks, CCleaner can enable/disable them too.
Dell installs some of its bloat in services, you'll need to find them via services.msc module, you can disable them in Properties (one at a time). Other manufacturers probably do the same, here's an example of Dell services I have disabled.
If you're apprehensive in doing changes to Windows, create system restore point at appropriate times. WinKey+S then 'restore point' will get you to the right place to do that.
BR