Efficacy and safety of flupirtine modified release for the management of moderate to severe chronic low back pain: results of SUPREME, a prospective randomized, double-blind, placebo- and active-controlled parallel-group phase IV study.

To demonstrate non-inferior/superior efficacy of flupirtine modified release (MR) compared with tramadol/placebo for the management of moderate to severe chronic low back pain (LBP). Randomized, double-blind, active-/placebo-controlled double-dummy multicenter study, performed in 31 German study centers. LBP patients (n = 363) with moderate pain intensity were randomized 1:1:1 to receive flupirtine MR 400 mg, tramadol extended release (ER) 200 mg, or matching placebo (each given OD in the evening) over 4 weeks. EudraCT 2009-013268-38. Primary endpoint was change from baseline in the LBP intensity index (LBPIX; 11-point NRS) at week 4; last observation carried forward was used to impute missing scores. Least square (LS) mean ± SD LBPIX changes from baseline at week 4 were clinically significant for all three treatment groups of the intent-to-treat (ITT) and the per-protocol (PP) population (n = 326/276): placebo (n = 110/96): -1.81 ± 1.65/-1.77 ± 1.59; flupirtine MR (n = 109/95): -2.23 ± 1.73/-2.28 ± 1.68; and tramadol ER (n = 107/85): -1.92 ± 1.84/2.03 ± 1.83 (p < 0.001 for each). ITT/PP treatment effects for flupirtine MR were non-inferior when compared with tramadol ER and superior when compared with placebo (p = 0.003/0.033). Significantly more ITT patients treated with flupirtine MR (59.6/37.6 showed a ≥30/50% LBPIX relief in comparison to placebo (46.4/24.6%; p vs. flupirtine MR: 0.049/0.037). Treatment contrasts for tramadol failed to reach significance vs. placebo. Within the safety population (n = 355), flupirtine MR (n = 119) was associated with a significantly lower incidence of treatment emergent AEs (TEAEs; 21.0%) and TEAE-related study discontinuations (3.4%) than tramadol ER (n = 116; 34.5/12.0%; p = 0.039/0.017) and exhibited an overall safety/tolerability profile non-inferior to placebo (n = 120; 15.8/3.3%; p = ns for each). Major limitations of this study were the short treatment duration, the comparison of different drug classes and the lack of a titration phase. The analgesic efficacy of flupirtine MR 400 mg OD was comparable to that of tramadol ER 200 mg OD and superior to that of placebo.