Background/Purpose: The importance of nonrestorative sleep in the pathophysiology of fibromyalgia (FM) suggests that treatments that improve sleep quality would address global symptoms.  TNX-102 SL¹a proprietary eutectic sublingual (SL) tablet formulation of low dose cyclobenzaprine HCl (2.8 mg) tablet designed for rapid absorption and long-term bedtime use.  TNX-102 SL was assessed for its safety and efficacy in a phase 2b study of FM (the BESTFIT study).

Methods: A total of 205  FM patients who satisfied  the ACR 2010 FM criteria were enrolled at 17 sites in a 12-week, double-blind, placebo-controlled trial in which participants were randomized 1:1 to receive TNX-102 SL (N=103) or placebo (N=102). Outcome measures included daily diary assessments of pain and sleep (0-10 NRS), the Fibromyalgia Impact Questionnaire-Revised (FIQ-R), Patient Global Impression of Change (PGIC), and the PROMIS Sleep Disturbance scale (PROMIS).

Results: Subjects treated with TNX-102 SL improved in all measures of sleep quality, as well as pain, FIQ-R and PGIC ratings over the 12 weeks. The PROMIS sleep disturbance scale reached statistical significance by week 4, p = 0.021, and had sustained benefit through week 12, p = 0.005 (-8.96 on TNX-102 SL v -5.13 on placebo).  Daily sleep diary (change from baseline to endpoint) reached statistical significance at week 1, regained significance at week 6, p = 0.015, and was sustained through week 12; p < 0.001 (-1.85 v -0.88). The sleep quality item on the FIQ-R reached significance at week 2, p=0.012, and was sustained through week 12; p <0.001 (-2.9 v 1.2). The improvements in sleep quality preceded other FM changes. The responder analysis of daily diary pain (with =>30% improvement from baseline defined as response) was significant at week 12 p = 0.033 (34.0% response rate v 20.6%) and reached initial statistical significance at week 9, p = 0.042 (logistic regression). Improvement in sleep by PROMIS correlated with improvement in pain by 30% responder analysis (r=0.3, p=<0.001).  PGIC favorable response was significant at week 12 (30.1% vs. 16.7%, p = 0.025 by logistic regression).  PGIC correlated with improvement in PROMIS sleep (r=0.6, p=<0.001) and sleep diary (r=0.5, p=<0.001).  FIQ-R total score became significant at week 8, p = 0.041, and was sustained through week 12, p = 0.014 (-15.6 v -8.5). FIQ-R correlated with improvement in PROMIS sleep (r=0.5, p=<0.001) and with sleep diary (r=0.6, p=<0.001). 

Systemic adverse events (AEs) were infrequent. Weight gain was negligible.  Local administration site reactions (transient tongue or sublingual numbness) occurred in 42% of treated patients.

Conclusion: Bedtime TNX-102 SL improved sleep quality by multiple measures of FM which is consistent with the antagonistic activity of cyclobenzaprine at 5HT2A, alpha-1 adrenergic and H-1 receptors. The improvement in sleep quality temporally preceded improvements in pain, PGIC and FIQ-R, with which sleep quality improvements were correlated. Together, these data suggest TNX-102 SL targets non-restorative sleep and provides a novel approach to treating FM.

¹TNX-102 SL is an Investigational New Drug and has not been approved for any indication.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/relationship-of-sleep-quality-and-fibromyalgia-outcomes-in-a-phase-2b-randomized-double-blind-placebo-controlled-study-of-bedtime-rapidly-absorbed-sublingual-cyclobenzaprine-tnx-102-sl/