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100x jump in query time with IN operator
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SQLite NGQP is a cost based query planner. The IN () operator with a list of literal values gets implemented as a kind of temporary table; sometimes SQLite decides to create an index and do lookups, other times it decides to use that table as the outermost loop of the query.

EXPLAIN QUERY PLAN should show that in a more concise manner.

If compiled in DEBUG mode mith WHERETRACE enabled, the .wheretrace command will show how SQLite NGQP reaches its plan. Essential input is the return values from the xBestIndex method of your virtual table, especially the "number of rows" and the "estimated cost". It is paramount to deliver accurate estimates. Cost should reflect processing cost relative to SQLite native tables.

Note that you can name the IN table by making it a CTE and CROSS JOIN to force the query plan that works fast.