Tolperisone for the Treatment of Acute Muscle Spasm of the Back: Results from the Dose-Ranging Phase 2 STAR Study (NCT03802565)

Figures & data

Figure 1 Subject disposition. AE, adverse event; TID, three times daily.

Table 1 Subject Demographics

	Placebo (n=78)	Tolperisone
		50 mg TID (n=82)	100 mg TID (n=87)	150 mg TID (n=83)	200 mg TID (n=85)	Total (n=337)
Mean age (SD), years	41.6 (12.37)	43.5 (12.58)	44.4 (12.20)	44.3 (12.09)	42.0 (11.96)	43.6 (12.19)
Age category, n (%)
18–49 years	52 (66.7)	54 (65.9)	52 (59.8)	50 (60.2)	61 (71.8)	217 (64.4)
50–65 years	26 (33.3)	28 (34.1)	35 (40.2)	33 (39.8)	24 (28.2)	120 (35.6)
Sex, n (%)
Male	29 (37.2)	37 (45.1)	30 (34.5)	42 (50.6)	44 (51.8)	153 (45.4)
Female	49 (62.8)	45 (54.9)	57 (65.5)	41 (49.4)	41 (48.2)	184 (54.6)
Ethnicity, n (%)
Hispanic or Latino	16 (20.5)	13 (15.9)	18 (20.7)	22 (26.5)	20 (23.5)	73 (21.7)
Not Hispanic or Latino	62 (79.5)	69 (84.1)	69 (79.3)	61 (73.5)	65 (76.5)	264 (78.3)
Race,^a n (%)
American Indian/Alaska Native	3 (3.8)	1 (1.2)	0	1 (1.2)	0	2 (0.6)
Asian	4 (5.1)	1 (1.2)	4 (4.6)	2 (2.4)	4 (4.7)	11 (3.3)
Black or African American	30 (38.5)	29 (35.4)	32 (36.8)	30 (36.1)	35 (41.2)	126 (37.4)
Native Hawaiian/Pacific Islander	0	1 (1.2)	1 (1.1)	1 (1.2)	0	3 (0.9)
White	44 (56.4)	50 (61.0)	50 (57.5)	50 (60.2)	45 (52.9)	195 (57.9)
Other	0	0	0	0	1 (1.2)	1 (0.3)
Body mass index (kg/m^2)
Mean (SD)	28.53 (4.33)	28.23 (4.27)	28.48 (4.10)	28.34 (3.99)	28.45 (4.35)	28.38 (4.16)
Range	19.5–35.0	19.4–35.0	20.9–35.0	19.8–35.0	20.0–35.0	19.4–35.0

Note: ^aSubjects may have been included in >1 race category.

Abbreviation: SD, standard deviation.

Table 2 Summary of Adverse Events

	Placebo (n=78)	Tolperisone
		50 mg TID (n=82)	100 mg TID (n=87)	150 mg TID (n=83)	200 mg TID (n=85)	Total (n=337)
Total number of AEs, n	13	13	22	21	36	92
Subjects with ≥1 AE, n (%)	11 (14.1)	10 (12.2)	16 (18.4)	15 (18.1)	20 (23.5)	61 (18.1)
Mild^a	8 (10.3)	6 (7.3)	13 (14.9)	8 (9.6)	12 (14.1)	39 (11.6)
Moderate^a	3 (3.8)	4 (4.9)	3 (3.4)	5 (6.0)	6 (7.1)	18 (5.3)
Severe^a	0	0	0	2 (2.4)	2 (2.4)	4 (1.2)
AE, n (%)
Related to study drug^b	5 (6.4)	5 (6.1)	13 (14.9)	13 (15.7)	14 (16.5)	45 (13.4)
Leading to study drug discontinuation^c	1 (1.3)	0	1 (1.1)	2 (2.4)	2 (2.4)	5 (1.5)
Requiring study drug dose interruption	0	0	0	0	1 (1.2)	1 (0.3)
Requiring study drug dose reduction	0	0	0	0	1 (1.2)	1 (0.3)
Death	0	0	0	0	0	0
Serious AEs, n	0	0	0	0	0	0

Notes: ^aSubjects reporting >1 AE were counted only once using the highest severity. ^bSubjects reporting >1 AE were counted only once using the closest relationship to study drug. Related events included those reported as “possibly related” or “definitely related” to study drug. ^cOne placebo subject discontinued treatment due to an AE of blurred vision. Five tolperisone recipients discontinued treatment with a total of eight AEs (vertigo [n=2], headache, nausea, vomiting, withdrawal syndrome, urticaria, and maculopapular rash).

Abbreviations: AE, adverse event; TID, three times daily.

Table 3 Adverse Events Typically Associated with Skeletal Muscle Relaxants

Category, n (%)  Preferred Term, n (%)	Placebo (n=78)	Tolperisone
		50 mg TID (n=82)	100 mg TID (n=87)	150 mg TID (n=83)	200 mg TID (n=85)	Total (n=337)
Somnolence	2 (2.6)	0	3 (3.4)	0	1 (1.2)	4 (1.2)
Hypersensitivity^a	0	0	1 (1.1)	1 (1.2)	2 (2.4)	4 (1.2)
Dermatitis allergic	0	0	1 (1.1)	0	0	1 (0.3)
Pruritus	0	0	0	0	1 (1.2)	1 (0.3)
Maculopapular rash	0	0	0	0	1 (1.2)	1 (0.3)
Urticaria	0	0	0	1 (1.2)	0	1 (0.3)

Note: ^aAEs were coded to preferred term using the Medical Dictionary for Regulatory Activities, version 21.1.

Figure 2 Change from baseline NRS “right now” scores. NRS, numerical rating scale; TID, three times daily.

Figure 3 Numerical rating scale (NRS) “right now” least-squares mean difference (treatment-placebo) mixed-effect model for repeated measures estimate of NRS (95% CI).

Abbreviations: CI, confidence interval; TID, three times daily; LSMD, least-squares mean difference.

Table 4 Secondary Efficacy Analyses

	Placebo	Tolperisone
		50 mg TID	100 mg TID	150 mg TID	200 mg TID
Time to pain relief^a	n=78	n=81	n=84	n=81	n=85
Median, days (range)	14 (2, 14)	12 (2, 14)	10 (2, 14)	14 (2, 14)	14 (2, 14)
Hazard ratio		1.31	1.47	1.14	1.22
95% CI		0.85, 2.03	0.96, 2.25	0.72, 1.79	0.79, 1.89
P value		0.1975	0.0609	0.3098	0.2177
CGI-C (day 14)	n=72	n=76	n=82	n=74	n=76
Worse	3 (4.2)	0	4 (4.9)	2 (2.7)	1 (1.3)
No change	7 (9.7)	10 (13.2)	11 (13.4)	9 (12.2)	9 (11.8)
Minimally improved	23 (31.9)	20 (26.3)	16 (19.5)	19 (25.7)	21 (27.6)
Much/very much improved	39 (54.2)	46 (60.5)	51 (62.2)	44 (59.5)	45 (59.2)
P value		0.2133	0.2982	0.7210	0.2646
Fingers to floor distance (day 14)^b	n=72	n=77	n=83	n=74	n=77
LSM (SE)	13.9 (0.89)	13.8 (0.86)	13.0 (0.83)	14.8 (0.88)	12.4 (0.86)
LSMD (treatment minus placebo) (SE)		–0.1 (1.24)	–1.0 (1.22)	0.8 (1.25)	–1.5 (1.24)
95% CI		–2.5, 2.4	–3.4, 1.4	–1.6, 3.3	–3.9, 0.9
P value		0.9493	0.4332	0.5069	0.2250
ODI (day 14)^b	n=71	n=77	n=81	n=74	n=74
LSM (SE)	21.3 (1.64)	17.7 (1.57)	19.0 (1.53)	19.8 (1.60)	17.9 (1.60)
LSMD (Tx - placebo) (SE)		–3.6 (2.27)	–2.3 (2.24)	–1.6 (2.29)	–3.4 (2.29)
95% CI		–8.1, 0.9	–6.7, 2.1	–6.1, 2.9	–7.9, 1.1
P value		0.1123	0.3020	0.4961	0.1376
Use of rescue medication	n=77	n=79	n=82	n=79	n=84
Caplets/day, mean (SD)	3.9 (6.55)	3.9 (6.95)	3.0 (6.03)	3.6 (6.99)	3.0 (5.46)
P value^c		0.8942	0.2436	0.4782	0.5065

Notes: ^aKaplan-Meier hazard ratio (treatment/placebo) and 95% CI are based on a Cox regression model with treatment as the main effect. A hazard ratio >1 was favorable to treatment. Time to pain relief was assessed based on the NRS assessment of subject rating of pain over the past 12 hours starting at day 2. Pain relief was defined as an NRS rating ≤2 where 0 = no pain and 10 = worst possible pain. ^bEstimates for p-values, LSM, LSMD, and 95% CI are from an analysis of covariance model with observed total ODI score as the response, main effects for treatment group, and a covariate adjustment for baseline value. ^cWilcoxon rank-sum test pairwise comparison versus placebo.

Abbreviations: CGI-C, Clinician’s Global Impression of Change; CI, confidence interval; LSMD, least-squares mean difference; LSM, least-squares mean; ODI, Oswestry Disability Index; SE, standard error; TID, three times daily.

Figure 4 Rating of medication helpfulness at day 14.

Abbreviation: TID, three times daily.

Figure 5 Patient’s Global Impression of Change at day 14.

Abbreviation: TID, three times daily.