Background TNX-102 SL, 2.8mg tablet is a novel sublingual investigational formulation of low dose cyclobenzaprine designed for rapid absorption and bedtime use. The use of TNX-102 SL at bedtime is thought to improve sleep quality in patients diagnosed with fibromyalgia (FM). A recently completed Phase 2b trial (BESTFIT) of TNX-102 SL in FM patients explored various approaches to the evaluation of changes in patient reported symptoms.
Objectives The BESTFIT study was designed to evaluate whether the sleep quality improvement associated with TNX-102 SL treatment would lead to improvement in the pain and other symptoms of FM.
Methods Under a US Investigational New Drug Application, 205 FM patients from 17 US investigational sites were randomized in a double-blinded fashion to placebo (n=102) or 2.8 mg of TNX-102 SL (n=103) for 12 weeks. Symptoms assessed in this study included daily pain and sleep quality assessed on a daily diary, the patient global impression of change (PGIC), the Fibromyalgia Impact Questionnaire-Revised (FIQ-R), and the PROMIS sleep disturbance instrument.
Results TNX-102 SL was well tolerated, with 86% of patients randomized to TNX-102 SL completing the full 12 weeks of study participation vs. 83% in the placebo group. This low dose of CBP was chosen to improve the tolerability and side-effect profile in the FM population who are typically sensitive to drug therapy. Consistent with a “gentle” therapeutic approach, pain improvement was clinically meaningful, but typically not dramatic in most patients. For example, while 34% of patients achieved a 30% reduction in reported pain from baseline (significant at p=0.03), only 19% achieved a 50% reduction (NS). Due to the absence of very large responders in the study population, the therapeutic effects when expressed as a comparison of group mean change from baseline was a less favorable approach to therapeutic assessment (-1.6 vs -1.1 units, p=0.086, pre-specified primary endpoint). PGIC results, also analyzed as a responder analysis, were consistent with the pain responder results with a response rate of 30.1% (p=0.025). As expected, sleep quality was statistically improved by all measures, including the daily assessment, the PROMIS sleep instrument and the FIQ-R sleep item.
Conclusions TNX-102 SL at bedtime has proven to have a very low systemic adverse event burden in a FM population known to be particularly sensitive to drug therapy. The most common local adverse event was transient tongue or mouth numbness occurring in 42% of treated patients. No systemic adverse events were noted in >5% of treated patients. Results from BESTFIT suggest that responder analyses, where individual patients are analyzed for benefit as opposed to the assessment of group mean changes, are the preferred method by which to assess clinical results with this particular treatment approach. In agreement with the US FDA, the sponsor is currently initiating a confirmatory study that will utilize pain responder analyses as the pre-specified primary endpoint.
Clauw, DJ. JAMA 2014;311(15):1547-1555.
Acknowledgements Study sponsored by Tonix Pharmaceuticals. TNX-102 SL is an Investigational New Drug and has not been approved for any indication.
Disclosure of Interest None declared
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