A mixed treatment comparison of gabapentin enacarbil, pramipexole, ropinirole and rotigotine in moderate-to-severe restless legs syndrome

Abstract

Objective:

A mixed treatment comparison (MTC) was performed to investigate the relative efficacy and safety of licensed pharmaceuticals for moderate-to-severe restless legs syndrome (RLS).

Methods:

RLS trials published over the past 10 years were identified via systematic literature searches of MEDLINE, Embase, Cochrane CENTRAL, and manufacturers’ websites. MTC was performed with WinBUGS software using a Bayesian approach. Identified primary outcomes: change in International RLS Study Group Rating Scale (IRLS) at week 12 and end of maintenance (EoM). Secondary outcomes: IRLS and Clinical Global Impression – Improvement Scale (CGI-I) responders, RLS-6 items and adverse events (AEs).

Results:

Twenty-eight clinical trials were identified. Fifteen were included in the primary analysis. Indirect comparisons were established among gabapentin enacarbil, pramipexole, ropinirole, rotigotine and placebo. Overall, the four active treatments showed similar efficacies as assessed by changes in IRLS scores, IRLS responders, CGI-I responders, and RLS-6 scores. The sole exception was change in IRLS at week 12, for which rotigotine was likely more efficacious than ropinirole (mean difference: −2.52 [95% CrI: −4.74, −0.40]). Indirect comparisons on safety endpoints indicated ropinirole was associated with a higher risk of nausea than the other agents, and was more likely to result in discontinuations due to lack of efficacy than pramipexole. Nausea was likely more frequent with pramipexole than gabapentin enacarbil, and rotigotine was more likely to result in discontinuation due to AEs than ropinirole and pramipexole.

Conclusions:

This MTC confirmed the superiority of gabapentin enacarbil, pramipexole, ropinirole, and rotigotine above placebo in alleviating RLS symptoms. Compared to ropinirole, rotigotine showed some additional benefit in terms of change in IRLS at Week 12. Choice of RLS drugs requires careful evaluation of effectiveness and safety profiles in clinical practice. Due to lack of head-to-head trials, inconsistency could not be assessed in our analysis. Head-to-head trials on a more homogeneous population are needed to validate the MTC results.

Keywords::

• Bayesian approach
• Dopamine agonist
• Mixed treatment comparison
• Restless legs syndrome

Transparency

Declaration of funding

This study was supported by UCB Pharma, Brussels, Belgium. The sponsor had no role in study design, data collection, or analysis and interpretation of data. The sponsor was given the opportunity to review the manuscript prior to submission.

Declaration of financial/other relationships

Y.S. and T.M. have disclosed that, at the time the study was conducted, they were employees of Deloitte Financial Advisory Services which has received professional consulting fees from various companies including UCB Pharma. Y.S. and T.M. have disclosed that they are now employees of UCB Pharma. G.v.V. has disclosed that he was a subcontractor to Deloitte for this project.

CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

Editorial support was provided by Hannah Carney (Evidence Scientific Solutions, Horsham, UK) and was contracted by UCB Pharma, Brussels, Belgium.

Previous presentations: Abstract and poster presentation at ISPOR-EU: Sun Y, van Valkenhoef G, Morel T. A mixed treatment comparison of gabapentin enacarbil, pramipexole, ropinirole and rotigotine in moderate-to-severe restless legs syndrome (RLS). International Society for Pharmacoeconomics and Outcomes Research – 15th Annual European Congress. Value Health 2012;15:A546.