65 - Tolperisone 100 and 200 mg Three Times Daily (TID) for Acute Muscle Spasm of the Back: A Double-Blind, Randomized, Placebo-Controlled, Multicenter Phase 3 Study
Randall Kaye1, Henry Riordan2, Srinivas Nalamachu3, Joseph Pergolizzi4, Sanam Ara Vaughn1
1Neurana Pharmaceuticals, Inc., San Diego, CA, USA. 2Worldwide Clinical Trials, Morrisville, NC, USA. 3Mid America PolyClinic, Overland Park, KS, USA. 4NEMA Research, Naples, FL, USA
Purpose Back pain, one of the most common reasons for a physician visit and a leading cause of disability worldwide, is typically due to acute musculoskeletal spasm. Skeletal muscle relaxants (SMRs) can be an effective treatment for the relief of pain due to acute muscle spasm. However, there are barriers to prescribing SMRs, including side effects such as somnolence and cognitive function impairment. Tolperisone, a centrally acting, nonopioid SMR in clinical development in the United States, does not have these untoward effects. The recently completed dose-ranging phase 2 STAR study (NCT03802565) evaluated tolperisone administered at 50, 100, 150, and 200 mg TID for 14 days in subjects with acute muscle spasm of the back. Tolperisone was effective for the relief of pain, with the greatest efficacy seen in the highest dose (200 mg TID). The primary efficacy endpoint, subject-rated pain “right now” using a numerical rating scale (NRS) on day 14, was significantly lower (p=0.0040) in the tolperisone 200 mg TID group compared with the placebo group. Although the study was not sufficiently powered, a number of secondary efficacy endpoints also trended toward statistical significance at the tolperisone 200 mg TID dose. Tolperisone was well tolerated and its treatment-related adverse events (AEs) were similar to those of placebo; the most common AEs were headache (7.1%) and diarrhea (2.4%). Importantly, the incidence of somnolence was comparable between subjects treated with tolperisone versus placebo (0%, 3.4%, 0%, and 1.2% of subjects in the tolperisone 50 mg TID, 100 mg TID, 150 mg TID, and 200 mg TID dose groups, respectively, compared with 2.6% of those in the placebo group). Based on the design of the phase 2 STAR study, the safety and efficacy demonstrated by tolperisone, and an earlier phase 1 driving simulation study, a pivotal phase 3 study has recently been launched to evaluate the safety and efficacy of tolperisone (100 and 200 mg TID) for the relief of pain due to acute muscle spasm of the back. Methods This is a double-blind, randomized, placebo-controlled, parallel-group, multicenter phase 3 study of tolperisone (100 and 200 mg TID) in subjects experiencing pain due to acute muscle spasm of the back. Subjects are randomized 1:1:1 to tolperisone 100 mg TID or tolperisone 200 mg TID or placebo for 14 days. Male or female subjects aged 18-64 years with current back pain and/or stiffness due to acute and painful muscle spasm starting within 7 days prior to study entry and at least 8 weeks after the last episode of back pain are eligible for enrollment. Eligible subjects must also have a subject-rated "pain right now” NRS score of ≥4 at baseline. Subjects can receive acetaminophen 500 mg TID as rescue medication, with use documented daily through day 14. The primary efficacy endpoint is subject-rated pain “right now” using NRS score (0=no pain to 10=worst possible pain) on day 14. Secondary endpoints include onset of action, time to relief, Clinician’s and Patient’s Global Impression of Change, and the Oswestry Disability Index questionnaire. Use of rescue medication and subject responses to the satisfaction questions “Would you take this medication again?” and “Were you able to resume your usual activities?" are exploratory efficacy endpoints. Safety assessments include AEs, a visual analog scale for subject-reported sleepiness, the Epworth Sleepiness Scale, and the Columbia-Suicide Severity Rating Scale. The study will be approved by an institutional review board at each site. Results Approximately 750 subjects will be enrolled at about 60 clinical sites in the United States, and the first subject is expected to be enrolled in October 2020. A second replicate phase 3 study will be initiated at a later date. Conclusions Pain due to acute muscle spasm of the back represents a common and disabling condition. Given the widespread clinical use of SMRs for acute muscle spasm of the back, physicians and patients must have a safe and effective alternative option that is not associated with somnolence or cognitive function impairment. In studies to date, tolperisone does not exhibit the CNS effects typically seen with currently available SMRs and is both effective and well tolerated with somnolence rates comparable to placebo-treated subjects. This pivotal phase 3 study is based on the promising results from the STAR phase 2 study and is sponsored by Neurana Pharmaceuticals, Inc. The phase 3 study will be conducted in a similar patient population as the phase 2 STAR study, and is designed to confirm the safety and efficacy of tolperisone for the management of acute muscle spasm of the back in a registration setting.