Cyclobenzaprine tablets fail phase 3 trial for fibromyalgia pain
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A sublingual tablet form of the muscle relaxant cyclobenzaprine hydrochloride failed to achieve statistical significance in reducing fibromyalgia pain vs. placebo in a phase 3 trial, according to a press release.
Tonix Pharmaceuticals reported that its patented form of the drug, TNX-102 SL, failed its primary endpoint in the phase 3 RALLY study, a 14-week, randomized, double-blind, placebo-controlled trial. The company in December 2020 reported positive results for the drug in the phase 3 RELIEF study. However, between the two studies, researchers reported a 79% increase in participant discontinuations due to adverse events in the cyclobenzaprine group, as well as a 77% increase in adverse event-related discontinuations in the placebo group.
“The positive outcome of the earlier RELIEF study stands in contrast to the missed primary endpoint in RALLY,” Gregory Sullivan, MD, chief medical officer of Tonix, said in the company press release. “We believe the difference between these study results may be driven in large part by a 79% increase in adverse event-related participant discontinuations in the drug treatment group in RALLY as compared to RELIEF. Similarly, a 77% increase of adverse event-related participant discontinuations was observed in the placebo group in RALLY as compared to RELIEF.”
Missing data
According to Tonix, missing data for the primary and secondary endpoints were accounted for using multiple imputation (MI). The company added that discontinuations due to adverse events can negatively impact the statistical outcome when using this approach.
“When the data are analyzed without MI, the results of RALLY appear consistent with the previous RELIEF study,” Sullivan said in the release. “The mixed model repeated measures (MMRM) results without MI method are presented to illustrate the impact of the increased discontinuations on the results when using MI as the primary analytic approach. At this time, the anticipated analytic approach for the upcoming phase 3 RESILIENT study is MMRM with MI.”
Tonix CEO Seth Lederman, MD, added that the increased rate of discontinuations due to adverse events may have been related to COVID-19. According to the company, the first interim cohort of the study was enrolled between September 2020 and March 2021, while the post-interim cohort was enrolled between third week of March and the last week of July 2021.
“Without knowing the precise reasons, we postulate the increased rate of adverse event-related discontinuations may be related to conducting the study during the peak phase of the COVID-19 pandemic in the U.S., during which time vaccines were being rolled out,” Lederman said in the release.
“Since the pandemic phase of COVID-19 appears to be transitioning to an endemic phase, we believe that starting the new RESILIENT phase 3 study imminently is justified based on the expectation that rates of adverse event-related discontinuations will return toward the levels of RELIEF and our PTSD studies,” he added. “We are grateful to the individuals who participated in the RALLY study, and to their families, particularly because of the many challenges presented by different phases of the COVID-19 pandemic.”
The RALLY study
Tonix reported interim analysis results of RALLY in July 2021, at which time an independent data monitoring committee recommended stopping the study as it was unlikely to succeed on the primary endpoint for the planned full sample. Enrollment of new participants was then ceased while those already in the study continued to completion.
The two-arm trial enrolled a total of 514 patients with fibromyalgia across 36 U.S. sites. Participants started on 2.8 mg of TNX-102 SL, or placebo, during the trial’s first two weeks. After the run-in period, all participants had their dose increased to 5.6 mg, or two placebo tablets, for 12 weeks. The primary endpoint was daily diary pain severity score change from baseline to Week 14, based on numerical rating scale (NRS) scores for the 5.6 mg dosage vs. placebo.
According to the company, The RALLY study missed statistical significance on the primary efficacy endpoint, with a least squares mean of –1.6 units (standard error = 0.11), compared with –1.3 units (0.11) for placebo, analyzed by mixed model repeated measures with multiple imputation, resulting in a least squares mean difference of –0.2 units (P = .115).
Adverse events resulted in premature study discontinuation in 15.2% of those who received TNX-102 SL, compared with 6.2% of those in the placebo group. Oral administration site reactions were higher in the drug treatment group, including rates of tongue/mouth numbness, pain/discomfort of tongue/mouth, and abnormal product taste.
“Tonix remains dedicated to improving the lives of the millions suffering from fibromyalgia,” Lederman said in the release. “[Fibromyalgia] is a complex syndrome, and while TNX-102 SL at 5.6 mg missed the primary endpoint in RALLY, it continued to show strong activity on sleep disturbance (P = .004) and on the Patient Global Impression of Change (P = .038), which is a patient-reported assessment of overall improvement during the trial.”
He added: “These findings and our general understanding of TNX-102 SL tolerability encourage us to move forward with our plans to initiate our new F307 RESILIENT phase 3 study for fibromyalgia in the first half of 2022.”
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