Abstract
Background
A novel botulinum toxin type A (Protoxin; Protox Inc.) has been developed.
Objective
To evaluate the efficacy and safety of the newly developed Protoxin compared to the approved drug onabotulinumtoxinA (OBoNT) in moderate to severe glabellar lines.
Methods
Adults with a glabellar line Facial Wrinkle Scale (FWS) score of 2 (moderate) or 3 (severe) were enrolled in the study. Subjects were randomized in a 1:1 ratio to receive either Protoxin or OBoNT. A total of 20 units of botulinum toxin was injected at five sites in the glabellar region (4 units at each site). FWS scores were assessed at baseline and at weeks 4, 8, 12, and 16 post-injection. The primary endpoint was the proportion of subjects at week 4 who had a reduction of 2 or more points in FWS and a final score of 0 (none) or 1 (mild).
Results
A total of 274 subjects were randomized, of whom 78.1% were female. At week 4 post-treatment, the improvement rate of glabellar lines was 62.22% in the Protoxin group and 62.96% in the OBoNT group. The lower limit of the two-sided 95% confidence interval (−12.24%) exceeded the −15% margin, confirming the non-inferiority of the new drug. Safety profiles were comparable between the two groups.
Conclusion
Protoxin demonstrated efficacy and safety profiles comparable to those of OBoNT in the treatment of moderate to severe glabellar lines.
Trial Registration
ClinicalTrials.gov Identifier: NCT05364580
Keywords: Aging, Botulinum toxins, Neurotoxins
INTRODUCTION
Glabellar lines are primarily formed by the repeated contraction of the centrally located procerus muscle and the bilateral corrugator supercilii muscles1. These lines typically begin to appear noticeable in individuals during their 30s to 40s, indicating an association with the aging process. Additionally, prominent glabellar lines may convey an impression of anger or irritation, potentially influencing social perception.
Botulinum toxin type A, a neurotoxin produced by Clostridium botulinum, blocks the release of acetylcholine at motor nerve terminals and temporarily induces muscle relaxation, thereby reducing dynamic facial wrinkles2. Since the initial observation in 1987—when botulinum toxin used to treat blepharospasm was also found to smooth the facial wrinkles3—research into its cosmetic applications has expanded significantly.
To date, efficacy of the various botulinum toxins for improvement of glabellar lines has been demonstrated in numerous randomized controlled studies4,5,6,7,8. Furthermore, several studies have reported that patient satisfaction following treatment of glabellar lines with botulinum toxin is associated with reduced psychological burden, and improvement of depressive symptoms9,10,11.
Protoxin (Protox Inc., Hwaseong, Korea) is a botulinum toxin type A product derived from a master cell bank of C. botulinum type A (strain ATCC-3502). During manufacturing, the active ingredient undergoes purification and formulation processes. While many commercially available botulinum toxin type A products are manufactured using the conventional lyophilization (freeze-drying) method, Protoxin is distinguished by its use of a vacuum drying process. This process removes moisture through direct evaporation under reduced pressure, thereby eliminating the freezing step that could result in protein destabilization and potential loss of biological activity12. By avoiding this step, vacuum drying may help better preserve the molecular integrity and biological potency of the toxin. Additionally, the vacuum drying process significantly reduces manufacturing time, which could improve production efficiency. These advantages may contribute to high product quality and enhanced cost-effectiveness.
OnabotulinumtoxinA (OBoNT), the first botulinum toxin product approved for the temporary improvement of glabellar lines, was used as the active comparator in this study. The objective of this study was to evaluate whether Protoxin demonstrates efficacy and safety profiles comparable to those of OBoNT at a 1:1 dosage ratio in subjects with moderate to severe glabellar lines.
MATERIALS AND METHODS
Study design
This clinical trial is a multicenter, randomized, double-blind, active-controlled, phase III clinical trial targeting adult subjects with moderate to severe glabellar lines (NCT05364580). Five medical centers in South Korea participated in the trial, and subjects were recruited from March 2023 to October 2023. The study protocol was approved by Institutional Review Board at Konkuk University Medical Center (IRB protocol approval number KUMC 2022-05-035). After obtaining written informed consent from the subjects, screening tests were conducted.
This clinical trial was conducted ethically and scientifically in accordance with Korea Good Clinical Practice and all relevant regulations. Furthermore, the trial respected the dignity and rights of participants and was conducted in accordance with the Declaration of Helsinki, ensuring that subjects were not subjected to any undue harm.
Subject selection
Subjects were adult men and women aged 19 to 65 years who had a moderate to severe glabellar lines based on 4-point Facial Wrinkle Scale (FWS) (Table 1). The exclusion criteria were as follows: a history of neuromuscular junction disorders; a history of facial nerve palsy or ptosis; skin abnormalities at the injection site; current use of medications with muscle relaxing effects, a history of taking aspirin or non-steroidal anti-inflammatory drugs; a history of any facial procedures or surgery that may influence the study results; a known hypersensitivity to the components of injection (e.g., botulinum toxin, albumin); a history of alcohol or drug abuse, or other significant mental disorders; pregnancy or lactation; individuals of reproductive potential unwilling to use adequate contraception; and any individual deemed unsuitable for participation as judged by the by the investigator.
Table 1. Description of 4-point FWS and 7-point subjects’ self-assessment scale.
| Scale | Score | Severity | Definition |
|---|---|---|---|
| FWS (At maximal frown) | 3 | Severe | Facial lines are prominent, and the base of the deepest wrinkle is not visible from the surface |
| 2 | Moderate | Facial lines are prominent, and the base of the deepest wrinkle is visible from the surface | |
| 1 | Mild | Some facial lines are visible | |
| 0 | None | No lines are visible | |
| FWS (At rest) | 3 | Severe | Lines are very clearly visible |
| 2 | Moderate | Lines are clearly visible | |
| 1 | Mild | Some lines are visible | |
| 0 | None | No lines are visible | |
| Subjects’ Self-Assessment Scale | +4 | Almost 100% improved | |
| +3 | 75% improved | ||
| +2 | 50% improved | ||
| +1 | 25% improved | ||
| 0 | Neither improved nor worsened | ||
| −1 | 25% worsened | ||
| −2 | 50% worsened | ||
| −3 | 75% worsened | ||
| −4 | Almost 100% worsened | ||
Drug administration
Eligible subjects who met the inclusion and exclusion criteria were randomly assigned to either the Protoxin group or OBoNT group. Randomization was performed by an independent statistician using a stratified block randomization method, with glabellar lines severity as a stratification factor. The randomization sequence was generated using SAS® Version 9.4 (SAS Institute, Cary, NC, USA). One vial (100 U) of Protoxin or OBoNT was diluted with 2.5 ml of 0.9% sterile saline solution (resulting in a concentration of 4 U/0.1 ml). The diluted solution was then injected—0.1 ml at each of 5 sites. Four injection sites targeted the bilateral corrugator supercilii muscles and one site targeted the procerus muscle (Fig. 1). To reduce the risk of blepharoptosis, injections into the corrugator supercilii muscle were performed at least 1 cm above the bony supraorbital margin to avoid diffusion to the levator palpebrae superioris muscle.
Fig. 1. Injection sites of the botulinum toxin.
Blinding was maintained for both the investigator and the subjects to minimize the potential bias in evaluation of treatment effects and adverse reactions. Each subject was identified only by the assigned code during randomization, and allocation details remained undisclosed until the end of the clinical trial. To address the difference in drug vial appearance, dilution was performed by trained and designated research personnel who were not involved in subject assessment or injection. Identical syringes were prepared and delivered to the investigator who were responsible for the injection, thereby maintaining blinding.
Assessments
The glabellar lines evaluation by investigators was conducted at screening visits, at 4, 8, 12, and 16-weeks post-administration. Glabellar lines, both at maximum frown and at rest, were evaluated using the FWS. In addition to on-site evaluations, an independent investigator assessed glabellar lines using the FWS by reviewing photographs of the subjects. At maximum frown, “improvement” was defined as FWS score of 0 or 1 and a decrease of two or more grades from the baseline. At rest, “improvement” was defined as FWS score 0 or 1.
Subjects self-assessed the improvement of their glabellar lines at 4, 8, 12, and 16 weeks post-administration using a 7-point scale (Table 1). An improvement was defined as a score increase of 2 or more points. Subject satisfaction with the appearance of their glabellar lines was also assessed at the same time points. They were asked to rate their satisfaction with the improvement due to the treatment, using a 7-point scale ranging from grade 1 (very dissatisfied) to grade 7 (very satisfied). Scores of grade 6 or 7 were considered indicative of satisfaction.
The primary efficacy endpoint was the improvement rate of glabellar lines at maximum frown, as evaluated by the on-site investigator at 4 weeks post-administration. Secondary efficacy endpoints included improvement rates of glabellar lines under the following conditions:
1) Maximum frown, evaluated by the on-site investigator at weeks 8, 12, and 16.
2) Maximum frown, evaluated by the independent investigator at weeks 4, 8, 12, and 16.
3) At rest, evaluated by the on-site investigator at weeks 4, 8, 12, and 16.
4) At rest, evaluated by the independent investigator at weeks 4, 8, 12, and 16.
5) Maximum frown, evaluated by subjects at weeks 4, 8, 12, and 16.
6) At rest, evaluated by subjects at weeks 4, 8, 12, and 16.
Subjects’ overall satisfaction rates at weeks 4, 8, 12, and 16 were also included as secondary endpoints.
Adverse events were categorized and assessed as either localized (related to the forehead area) or systemic reactions. In case of adverse events, details such as symptoms, onset and resolution dates, severity, course, management, and causality were comprehensively recorded in the case report form. All adverse events were classified according to the Medical Dictionary for Regulatory Activities version 26.0, based on System Organ Class and Preferred Term.
Statistical methods
For efficacy evaluation, the primary analysis was conducted on the Per-Protocol Set (PPS), and supplementary analysis was performed on the Full Analysis Set (FAS). The safety analysis was conducted on the Safety Set (SS), which included all subjects who received at least one dose of the drug. Demographic characteristics, baseline medical history, and prior medication use were analyzed based on the Intention-To-Treat principle, including all randomly assigned subjects.
For analysis of primary efficacy endpoint, a 95% two-sided confidence interval (CI) was calculated using the Mantel-Haenszel method. Non-inferiority of the investigational drug compared to the active comparator was established if the lower limit of the 95% CI exceeded −15%. For the analysis of secondary efficacy endpoints, the frequency and percentage for each group were presented, and difference between groups were analyzed using the Cochran-Mantel-Haenszel test. All statistical tests were two-sided and performed at a significance level of 5%. Statistical analyses were performed using SAS® Version 9.4 (SAS Institute).
RESULTS
Demographics
A total of 274 subjects were randomly assigned to two groups (137 in Protoxin group and 137 in OBoNT group). Of 274 subjects, five subjects dropped out, and 269 subjects completed the clinical trial (Fig. 2).
Fig. 2. Flow diagram of the study participants.
The demographic characteristics of the subjects are presented in Table 2. The mean age (mean ± standard deviation) was 46.61±9.26 years, and 78.1% were female. There was no significant difference between the two groups in terms of the age, gender, height, history of previous botulinum toxin injection. There was a statistically significant difference in weight distribution between the groups (p=0.0461). The distribution of FWS scores at maximum frown at baseline was not significantly different between the Protoxin and OBoNT group. The proportion of subjects with a score of 2 (moderate) was 67.15% in Protoxin group and 66.42% in OBoNT group.
Table 2. Demographic characteristics of all randomized subjects.
| Characteristics | OBoNT (n=137) | Protoxin (n=137) | Total (n=274) | p-value* | |
|---|---|---|---|---|---|
| Age (yr) | 0.359 | ||||
| Number of subjects | 137 | 137 | 274 | ||
| Mean ± SD | 47.12±9.28 | 46.09±9.26 | 46.6±9.26 | ||
| Median (min–max) | 47.0 (24.0–65.0) | 45.0 (24.0–64.0) | 46.0 (24.0–65.0) | ||
| Age group | 0.921 | ||||
| Number of subjects | 137 | 137 | 274 | ||
| 18–19 yr | 0 | 0 | 0 | ||
| 20–29 yr | 7 (5.11) | 7 (5.11) | 14 (5.11) | ||
| 30–39 yr | 18 (13.14) | 22 (16.06) | 40 (14.60) | ||
| 40–49 yr | 62 (45.26) | 63 (45.99) | 125 (45.62) | ||
| 50–59 yr | 32 (23.36) | 31 (22.63) | 63 (22.99) | ||
| 60–65 yr | 18 (13.14) | 14 (10.22) | 32 (11.68) | ||
| Sex | 0.080 | ||||
| Number of subjects | 137 | 137 | 274 | ||
| Male | 24 (17.52) | 36 (26.28) | 60 (21.90) | ||
| Female | 113 (82.48) | 101 (73.72) | 214 (78.10) | ||
| Previous botulinum toxin injection | 0.715 | ||||
| Number of subjects | 137 | 137 | 274 | ||
| Yes | 78 (56.93) | 75 (54.74) | 153 (55.84) | ||
| No | 59 (43.07) | 62 (45.26) | 121 (44.16) | ||
| Height (cm) | 0.067 | ||||
| Number of subjects | 137 | 137 | 274 | ||
| Mean ± SD | 163.04±7.60 | 164.79±8.18 | 163.92±7.93 | ||
| Median (min–max) | 162.1 (148.3–185.7) | 163.1 (145.5–187.6) | 162.5 (145.5–187.6) | ||
| Weight (kg) | 0.046 | ||||
| Number of subjects | 137 | 137 | 274 | ||
| Mean ± SD | 60.72±11.29 | 63.67±13.04 | 62.20±12.26 | ||
| Median (min–max) | 59.2 (41.6–98.5) | 60.0 (42.7–112.2) | 59.5 (41.6–112.2) | ||
| Baseline severity of glabellar lines (at maximum frown) | 0.898 | ||||
| Number of subjects | 137 | 137 | 274 | ||
| 2 points (moderate) | 92 (67.15) | 91 (66.42) | 183 (66.79) | ||
| 3 points (severe) | 45 (32.85) | 46 (33.58) | 91 (33.21) | ||
Values are presented as number (%).
The text in bold indicates p<0.05.
OBoNT: onabotulinumtoxinA, SD: standard deviation.
*Two sample t-test, Pearson’s χ2 test or Fisher’s exact test. Statistically significant at a two-sided 5% significance level.
The drug was administered at least once in all randomized 274 subjects, and they were included in the SS. In FAS, one subject was excluded due to the omission of evaluation after baseline. In PPS, which was used for primary efficacy analysis, four subjects were excluded due to protocol violation. Thus, a total of 270 subjects were included in the PPS (Fig. 2).
Primary endpoint
The results of the primary endpoint are shown in Table 3. In the analysis of the PPS, the improvement rate of glabellar lines at maximum frown at 4 weeks after administration according to the investigator’s on-site evaluation, was 62.22% (84/135 subjects) in the test group and 62.96% (85/135 subjects) in the control group. The difference in improvement rates between the test and control groups was −0.88% (95% two-sided CI,−12.24%, 10.49%). The lower limit of the CI (−12.24%) exceeded −15%, demonstrating the non-inferiority of the test group compared to the control group. The FAS analysis results showed similar results to the PPS analysis.
Table 3. Comparison of the improvement rates at maximum frown, as evaluated by the on-site investigator at week 4.
| Per Protocol Set | Full Analysis Set | |||
|---|---|---|---|---|
| OBoNT (n=135) | Protoxin (n=135) | OBoNT (n=137) | Protoxin (n=136) | |
| Number of subjects | 135 | 135 | 137 | 136 |
| Improvement | 85 (62.96) | 84 (62.22) | 87 (63.50) | 85 (62.50) |
| No improvement | 50 (37.04) | 51 (37.78) | 50 (36.50) | 51 (37.50) |
| Treatment difference (%)* | −0.88 | −1.18 | ||
| 95% confidence interval† | −12.24, 10.49 | −12.47, 10.11 | ||
| Non-inferiority | Yes | Yes | ||
Values are presented as number (%).
OBoNT: onabotulinumtoxinA.
*Treatment difference (%): Protoxin − OBoNT.
†Mantel-Haenszel (adjusted for facial wrinkle scale score as a stratification covariate).
Secondary endpoints
1) Evaluation by on-site investigator
At weeks 8, 12, and 16, at maximum frown, the improvement rates were 39.55%, 22.90%, 19.23% in the Protoxin group, and 34.81%, 22.96%, 19.23% in the OBoNT group (Supplementary Table 1). The differences were not statistically significant at any time point (all p>0.05). At weeks 4, 8, 12, and 16, at rest, the improvement rates were 87.41%, 85.82%, 85.50%, and 80.77% in the Protoxin group, and 85.93%, 81.48%, 80.00%, and 78.52% in the OBoNT group (Supplementary Table 2). No statistically significant differences were observed between the groups at any time point (all p>0.05).
2) Evaluation by independent investigator
At weeks 4, 8, 12, and 16, at maximum frown, the improvement rates were 82.22%, 68.42%, 50.38%, and 43.08% in the Protoxin group, and 91.11%, 69.63%, 51.85%, and 42.96% in the OBoNT group (Supplementary Table 3). At week 4, the improvement rate was significantly higher in the control group compared to the test group (91.11% vs. 82.22%, p=0.033). Except for week 4, no statistically significant differences were observed between the groups (all p>0.05). At weeks 4, 8, 12, 16 weeks, at rest, the improvement rate was 74.07%, 74.44%, 74.81%, and 73.08% in the Protoxin group, and 74.07%, 76.30%, 74.07%, and 74.07% in the OBoNT group (Supplementary Table 4). The differences were not statistically significant at any time points (all p>0.05).
3) Evaluation by subjects
At weeks 4, 8, 12, and 16, at maximum frown, the improvement rates were 95.56%, 91.04%, 76.34%, and 65.38% in the Protoxin group and 94.81%, 91.11%, 77.78%, and 62.22% in the OBoNT group (Supplementary Table 5). The differences were not statistically significant at all time points (all p>0.05). At weeks 4, 8, 12, and 16, at rest, the improvement rates were 91.11%, 89.55%, 74.81%, and 63.85% in the Protoxin group and 93.33%, 91.85%, 81.48%, and 67.41% in the OBoNT group (Supplementary Table 6). No statistically significant differences were observed between the groups at any time point (all p>0.05).
4) Subjects’ overall satisfaction rates
Satisfaction was defined as subjects reporting scores of 6 (satisfied) or 7 (very satisfied). At weeks 4, 8, 12, and 16, the satisfaction rates were 91.11%, 85.82%, 77.10%, and 73.08% in the Protoxin group, and 85.93%, 82.22%, 73.33%, and 65.93% in the OBoNT group (Fig. 3). There were no statistically significant differences between the groups at any time point (all p>0.05).
Fig. 3. Subjects’ overall satisfaction rates at weeks 4, 8, 12, and 16.
Safety evaluation
The overall incidence of treatment-emergent adverse events after drug administration was reported as 10.22% (14/137 persons, 16 events) in the test group and 8.03% (11/137 persons, 13 events) in the control group. Among these, adverse drug reactions with a potential causal relationship to the investigational drug were observed in 2.19% of the test group (3/137 subjects). These reactions were headache, injection site pruritus, and injection site reaction. In the control group, such reactions were observed in 1.46% (2/137 subjects), which were headache and injection site paresthesia. All drug-related adverse reactions were mild. Additionally, no acute adverse reactions were observed within 30 minutes after administration of the investigational drug.
No deaths or severe adverse reactions were reported after the administration of the drug. There were no clinically significant changes observed in vital signs, hematological tests, blood chemistry test, or urinalysis.
DISCUSSION
The difference in improvement rates at maximum frown between the groups at week 4, which was our primary endpoint, was −0.88%, confirming the non-inferiority of Protoxin. Up to week 16, there were no significant differences in improvement rate between the two groups. Both groups exhibited a decreasing trend in improvement rates over time, and the proportion of subjects with improvement at week 16 was under 20% in both groups. This can be attributed to gradual functional recovery of cholinergic synapses after blockade by botulinum toxin. In a meta-analysis of OBoNT in the treatment of glabellar lines13, the median duration effect was 120 days, which was consistent with our study results.
The improvement rate for the primary outcome observed in this study was slightly lower than that reported in previous studies evaluating the same outcome—defined as an improvement of ≥2 points from baseline and an FWS score of 0 or 1. In the two phase III placebo-controlled studies of prabotulinumtoxinA14, the improvement rate at week 4 was 77.5% and 82.5%, and in the phase III placebo-controlled study of letibotulinumtoxinA15, the week 4 improvement rate was 78.6%. Similarly, the phase III placebo-controlled study of incobotulinumtoxinA7 reported a week 4 improvement rate of 76.6%. In contrast, the improvement rate in this study was 62.22% in the Protoxin group and 62.96% in the OBoNT group. This discrepancy may be attributable to differences in the sex distribution of the study populations. While the proportion of male subjects in the three aforementioned studies ranged from 6.8% to 12%, nearly 20% of subjects in the present study were male. Several reports suggest that male subjects require higher doses of botulinum toxin than female subjects, as men generally have greater muscle mass16,17,18. As a fixed dose (20U) was administered, the relatively higher proportion of male participants may have contributed to the lower responder rates observed in this study. Importantly, subgroup analysis identified sex as a statistically significant predictor of treatment outcome in this cohort. After controlling for confounding factors, female subjects had 2.22 times higher odds of experiencing clinical improvement at week 4 (primary endpoint) compared to male subjects (reference group; 95% CI, 1.21, 4.07, p=0.0099), supporting the hypothesis that the higher proportion of males in our study population likely contributed to the reduced overall improvement rate.
Regarding secondary endpoints, the improvement rate recorded by independent investigators was not significantly different between the two groups, except for the photographic evaluation at week 4 (82.22% in the Protoxin group vs. 91.11% in the OBoNT group). No differences were observed at weeks 8, 12, and 16. The subjects’ self-evaluation also showed no significant differences between the two groups at any time point. Although the independent photographic evaluation at week 4 showed a statistically higher improvement rate with OBoNT compared to Protoxin, this isolated difference should be interpreted with caution. Possible explanations include 1) slight variation in the timing of maximal clinical effect between the formulations, 2) a chance finding due to inter-individual variability and random variation—especially given multiple assessments at different timepoints, and 3) inherent differences between 2-dimensional photographic evaluations versus 3-dimensional on-site evaluations of wrinkle severity. Notably, the difference was not maintained at subsequent visits, and no difference was observed in on-site investigator evaluation or subject self-assessment at all timepoints, suggesting that the week-4 finding does not represent a consistent or clinically meaningful inferiority of Protoxin.
In procedures or surgical interventions conducted for cosmetic purposes, meeting the expectations of the subjects is also an important criterion for assessing efficacy19,20. Up to the 16-week time point, the subject-reported overall satisfaction rate exceeded 70% in both the test and control groups, with slightly higher satisfaction observed in the test group. Botulinum toxin injection is generally well tolerated, and produces immediate effects following the procedure, with minimal pain.
From a safety perspective, the new drug demonstrated a safety profile comparable to that of the control drug. There were no statistically significant differences between the groups in the incidence rates of local adverse reactions at the injection site, overall adverse reactions, adverse drug reactions. All adverse events were considered mild, and no serious adverse events were reported.
Historically, botulinum toxin type A formulations have progressively improved in purity, stability, and reduction of immunogenicity by employing advanced manufacturing techniques. Protoxin utilizes a relatively newer vacuum drying method, which mitigates several limitations associated with conventional lyophilization, including protein damage and extended manufacturing times. This process can contribute to enhanced product stability, production efficiency and cost-effectiveness. These manufacturing improvements support Protoxin’s clinical value as a reliable alternative to existing neurotoxins.
This clinical trial has several limitations. First, study population consisted entirely of Koreans, which may limit the generalizability of the study findings. Second, anatomic variability of the target muscles was not considered. Various glabellar contraction patterns have been reported in previous studies21,22,23, and classification by subtype along with subgroup analysis may help determine the optimal injection method, thereby maximizing efficacy and minimizing unwanted adverse events. Lastly, the data were limited to 16 week-period following injection; the long-term duration of drug effectiveness was not investigated.
In conclusion, based on its demonstrated equivalence to OBoNT, Protoxin may be considered a satisfying treatment option for adult subjects with moderate to severe glabellar lines.
Footnotes
FUNDING SOURCE: This study was sponsored by Protox Inc.
CONFLICTS OF INTEREST: The authors have nothing to disclose.
DATA SHARING STATEMENT: The data that support the findings of this study are available from the corresponding author upon reasonable request.
SUPPLEMENTARY MATERIALS
Comparison of the improvement rates at maximum frown, as evaluated by the on-site investigator at week 8, 12, and 16
Comparison of the improvement rates at rest, as evaluated by the on-site investigator at week 4, 8, 12, and 16
Comparison of the improvement rates at maximum frown, as evaluated by the independent investigator at week 4, 8, 12, and 16
Comparison of the improvement rates at rest, as evaluated by the independent investigator at week 4, 8, 12, and 16
Comparison of the improvement rates at maximum frown, as evaluated by the subjects at week 4, 8, 12, and 16
Comparison of the improvement rates at rest, as evaluated by the subjects at week 4, 8, 12, and 16
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Associated Data
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Supplementary Materials
Comparison of the improvement rates at maximum frown, as evaluated by the on-site investigator at week 8, 12, and 16
Comparison of the improvement rates at rest, as evaluated by the on-site investigator at week 4, 8, 12, and 16
Comparison of the improvement rates at maximum frown, as evaluated by the independent investigator at week 4, 8, 12, and 16
Comparison of the improvement rates at rest, as evaluated by the independent investigator at week 4, 8, 12, and 16
Comparison of the improvement rates at maximum frown, as evaluated by the subjects at week 4, 8, 12, and 16
Comparison of the improvement rates at rest, as evaluated by the subjects at week 4, 8, 12, and 16