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

Abstract

Objective:

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).

Research design:

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.

Clinical trial registration:

EudraCT 2009-013268-38.

Main outcome measures:

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.

Results:

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.

Conclusions:

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.

Keywords::

• Analgesic
• Chronic low back pain
• Flupirtine
• Placebo
• Randomized controlled trial
• Tramadol

Transparency

Declaration of funding

This study was sponsored by TEVA, Germany.

Declaration of financial/other relationships

M.A.Ü. is a consultant to and has received expenses and speakers’ honoraria from Astellas, Bene-Arzneimittel, Eisai, Grünenthal, Janssen-Cilag, Mundipharma, Nycomed, Pfizer, PharmAllergan, ProStrakan and TEVA. G.H.H.M.-S. is a consultant to and has received expenses and speakers’ honoraria from Cephalon, Eisai, Grünenthal, Janssen-Cilag, Mundipharma, Pfizer, PharmAllergan and TEVA. B.T. was a full-time employee of TEVA/AWD.pharma GmbH at the time of the study and is now retired.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.

Acknowledgments

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors read and approved the final manuscript to be published.

M.A.Ü. had access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Data from this study have been presented at the Annual Meeting of the German IASP Chapter, 17–20 October 2011, Mannheim, Germany; the 6th World Congress of the World Institute for Pain, 4–6 February 2012, Miami Beach, FL, USA; and the 23rd Annual Meeting of the German Pain Society, 14–17 March 2012, Frankfurt/Main, Germany.