Box 1.

Planning a Simon two-stage (minimax) design study for primary progressive MS. ²²

Natural history: 40% of people with primary progressive MS fulfilling the inclusion criteria are expected to worsen per year* Clinically meaningful benefit: 20% of trial participants worsen per year Set threshold based on: type 1 error: 5%, type 2 error: 20% Hydroxychloroquine (HCQ) successful if < 10 of 35 participants worsen ⩾20% on timed 25-foot walk Stage 1 (interim) analysis n = 13 participants, max 4 can worsen for the trial to continue (In the HCQ in PPMS trial, 2 of 13 participants worsened, so the trial continued into the second stage) If successful, proceed to next stage. Enroll 22 more participants (total n = 35) Stage 2 (final) analysis n = 35, max 9 can worsen for the drug to be deemed non-futile (In the HCQ in PPMS trial, 8 of 35 participants worsened, so HCQ was deemed non-futile) *Based on the INFORMS and PROMISE trials