Efficacy and Safety of OnabotulinumtoxinA for the Treatment of Platysma Prominence: A Randomized Phase 2 Dose-Ranging Study

Abstract

Background:

With aging, repetitive contraction of the platysma leads to an increase in platysma prominence (PP), characterized by the accentuation of vertical neck bands and blunting of the jawline contour.

Methods:

This multicenter, double-blind, phase 2 study evaluated onabotulinumtoxinA treatment in adults with moderate to severe PP. Participants were randomized to receive 1 treatment of onabotulinumtoxinA low dose (LD), onabotulinumtoxinA high dose (HD), or placebo, and were followed up for 4 months. Efficacy end points were achievement of a 1 grade or greater improvement on both the left and right sides at day 14 at maximum contraction as assessed by the investigator (primary) or by participants (secondary) using validated scales. Safety was evaluated throughout.

Results:

Participants in the modified intent-to-treat population (n = 164) had a mean age of 50 years; 95.1% were women and 93.9% were White. The primary end point was met for both onabotulinumtoxinA groups, with investigator-assessed 1 grade or greater improvement in 77.8% (LD) and 88.2% (HD) versus 12.0% (placebo) of participants on day 14 (P < 0.0001 versus placebo). Based on participant self-assessment, 75.9% (LD) and 88.2% (HD) versus 18.0% (placebo) achieved 1 grade or greater improvement on day 14 (P < 0.0001 versus placebo). Most treatment-related adverse events were procedure-related, transient, and mild in severity. The most frequent onabotulinumtoxinA-related adverse event was neck muscle weakness, reported in the HD group.

Conclusion:

OnabotulinumtoxinA was effective in improving the appearance of PP based on both investigators’ and participants’ ratings. Treatment was well tolerated.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, I.

Effective aesthetic treatment of the platysma muscle can aid in rejuvenating the appearance of the lower face and neck. The platysma originates from the upper chest fascia and proceeds upwards along the neck, crossing over the mandibular border, and inserting into the skin, overlying subcutaneous tissue and muscles of the lower face.^1–3 Contraction of the platysma muscle accentuates the appearance of vertical bands on the neck or platysma bands while depressing the skin and muscles of the lower face, resulting in blunting of the jawline contour.^1,3,4 During aging, repetitive contraction of the platysma muscle can result in more obvious or pronounced disruptions to the contours of neck and jawline.^3–7 These unaesthetic and undesired consequences of platysma contraction are known as platysma prominence (PP). PP severity can vary between patients and within the same patient, with one side presenting more severely than the other, resulting in an asymmetric appearance.⁸

PP can become noticeable during routine activities like speaking or smiling,^9,10 and adversely affect quality of life on a psychosocial and emotional level. Patients with PP can feel self-conscious and less attractive.^6,11 In addition, PP can negatively affect facial expressions due to the involvement of the platysma muscle in lower face dynamics. Contraction of this muscle results in expressions of fear, disgust, and other negative emotions.¹² Therefore, PP can cause a disconnection between the patient’s emotional state and facial expression. Left untreated, signs of aging in the neck and lower face, including PP, may become more noticeable than those in the upper face,¹³ where approved aesthetic treatments are widely used, creating imbalance and increasing the perception of advanced age.

Surgical procedures have been used to treat PP, but they carry safety risks, and can result in persistence or recurrence of platysma bands.^13,14 Therefore, interest in less invasive treatments for PP is increasing. OnabotulinumtoxinA has not been approved for treating PP. Here we report the results of a placebo-controlled, dose-ranging, phase 2 study evaluating the efficacy and safety of high and low doses of onabotulinumtoxinA for reducing the appearance of moderate to severe PP in adults.

PATIENTS AND METHODS

Study Design

This was a 4-month, multicenter, randomized, double-blind, placebo-controlled, dose-ranging study to assess the efficacy and safety of a single treatment of onabotulinumtoxinA (BOTOX Cosmetic; Allergan Aesthetics, an AbbVie company) in adults with moderate to severe PP (ClinicalTrials.gov identification no. NCT03915067). The study was conducted from April of 2019 to April of 2020 at 12 centers in the United States and Canada, adhering to ethical principles derived from international guidelines, including the International Council for Harmonization Good Clinical Practice Guidelines. The protocol was amended to relax eligibility requirements (ie, removal of the upper age limit and change in maximum body mass index [BMI] from 25 kg/m² to <30 kg/m²). The study protocol and its amendment were approved by a centralized institutional review board review process, and participants provided written informed consent before procedures started.

Study Population

The study included adults with a BMI under 30 kg/m² at screening who were able to contract their platysma muscle correctly and maximally. Eligible participants had moderate (grade 3) or severe (grade 4) PP on both sides on day 1, as assessed at maximum contraction by the investigator using the Clinician Allergan Platysma Prominence Scale (C-APPS) and by the participant using the Participant Allergan Platysma Prominence Scale (P-APPS). The severity of PP on the left and right sides did not have to be identical. Eligible participants had no excessive skin laxity, abnormal variations, or abnormal anatomic features in the lower face, neck, or décolletage area (eg, predominant submental fat or jowls). Participants who had increased medical risk with exposure to onabotulinumtoxinA, any medical condition that could interfere with study assessments, or those who had previous surgical treatments were excluded from the study.

Randomization and Dosing

After the screening period (day −14 to day −7), eligible participants were randomized in a 1:1:1 ratio with interactive response technology to receive a single treatment of onabotulinumtoxinA low dose (LD), onabotulinumtoxinA high dose (HD), or placebo on day 1. Randomization was stratified by baseline C-APPS grade using central by block stratified randomization. Participants in the onabotulinumtoxinA LD group received 2 U per injection along the upper platysma and 1 U per injection along the platysma bands to a final total dose of 26 U, 31 U, or 36 U depending on the PP severity at baseline. Participants in the onabotulinumtoxinA HD group were administered 4 U per injection along the upper platysma and 2 U per injection along the platysma bands to a final total dose of 52 U, 62 U, or 72 U depending on the PP severity at baseline (Table 1). After treatment, a 120-day follow-up period was conducted, with study visits on days 7, 14, 30, 60, 90, and 120.

Table 1.

Dosing for Platysma Prominence

OnabotA Dose Group	Jawline Injection (Inferior to the Lower Mandibular Border)	Vertical Neck Band Injection (1 or 2 Bands per Side)		Total Dose, U (No. of Injection Sites)
Low dose	2 U/0.1 mL into 4 sites on each side	1 U/0.05 mL into 5 sites on each band	1 band on both sides	26 (18)
			1 band on one side and 2 bands on the other side	31 (23)
			2 bands per side	36 (28)
High dose	4 U/0.1 mL into 4 sites on each side	2 U/0.05 mL into 5 sites on each band	1 band per side	52 (18)
			1 band on one side and 2 bands on the other side	62 (23)
			2 bands per side	72 (28)

OnabotA, onabotulinumtoxinA.

Study vials with 100 U of onabotulinumtoxinA were reconstituted in 2.5 mL or 5 mL of normal saline to achieve a final concentration of 2 U/0.05 mL (onabotulinumtoxinA HD) or 1 U/0.05 mL (onabotulinumtoxinA LD). An individual with no other study involvement reconstituted the study drug and drew the required volume into the syringes for administration. Injection volume was kept the same for both onabotulinumtoxinA groups to maintain blinding of investigators and participants. Treatments were administered by the blinded investigator using superficial intramuscular injections to the upper segment of the platysma muscle along the submandibular border (0.1 mL per injection) and along each vertical neck band on each side of the neck (up to 2 bands per side, 0.05 mL per injection) (Fig. 1). Injections were spaced 1 to 2 cm apart.

Fig. 1.

Injection sites based on baseline Clinician Allergan Platysma Prominence Scale score of grade 3 (left) or grade 4 (right).

Assessments

The efficacy of a high or low onabotulinumtoxinA dose compared with placebo was evaluated independently by investigators and participants using the C-APPS and P-APPS, respectively. These are 5-grade scales to evaluate PP severity on the left and right side independently and at maximum contraction (1 = minimal, 2 = mild, 3 = moderate, 4 = severe, 5 = extreme). The C-APPS is a static measurement designed for clinicians to assess PP severity through visual examination of the lower face and neck. The C-APPS has been validated to be reliable (reproducible) for physician ratings of PP based on inter- and intrarater agreement. The P-APPS was developed and validated as a self-assessment tool,¹⁵ which participants used to rate their PP severity with study images captured at maximum contraction. Before study onset, adequate training and instruction was provided at each site to ensure proper assessment and grading.

The primary efficacy end point was the achievement of 1 grade or greater improvement on both the right and the left sides on day 14, as assessed at maximum contraction by the investigator using the C-APPS. The secondary efficacy end point was the achievement of 1 grade or greater improvement on both the right and left sides on day 14, as assessed at maximal contraction by participants using the P-APPS.

In addition, digital photographs were taken at all study visits to assess changes in PP severity before and after treatment. Photography conditions were standardized across all photographs, including camera equipment, exposure, background, lighting, and focal length.

Adverse events (AEs) were reported by participants at each study visit and documented and recorded by the investigators or qualified designees. Safety assessments included monitoring AEs and vital signs (pulse, blood pressure, and respiration rate).

Statistical Analysis

A sample of 46 participants per treatment group (n = 138) was estimated to provide a power of 90% at the 2-sided 5% significance level to detect a difference of 30% between onabotulinumtoxinA and placebo for the primary end point.

Primary and secondary efficacy end points were analyzed for the modified intent-to-treat (mITT) population, which included all randomized participants with 1 or more postbaseline assessments for the primary efficacy end point. Safety assessments were conducted on all randomized participants who were administered study treatment. The last nonmissing assessment before study treatment served as baseline for all analyses.

Demographic and safety data were summarized descriptively. The percentage of responders was analyzed using Cochran-Mantel-Haenszel tests stratified by baseline C-APPS grade. In addition, 2-sided 95% confidence intervals for the treatment differences in response rates were provided. Between-group comparisons were performed for each onabotulinumtoxinA group against the placebo group. A serial gatekeeping multiple comparisons procedure was used to maintain the familywise type 1 error rate at 5% across the primary and secondary end points. Any tests resulting in a P value < 0.05 terminated the sequential testing, and nominal P values were subsequently reported. Statistical analyses were performed using SAS version 9.4 (SAS Institute, Inc.).

RESULTS

Study Population

A total of 171 participants were randomized, 169 received study treatment and were included in the safety population, and 164 were included in the mITT population (onabotulinumtoxinA LD [n = 58], onabotulinumtoxinA HD [n = 53], and placebo [n = 53]) (Fig. 2). Most participants completed the study (85.4%; 146 of 171 participants). Of those who discontinued, 10 participants could not attend the study exit visit because of COVID-19–related reasons. One participant in the onabotulinumtoxinA HD group withdrew because of moderate tachycardia that was not considered related to the study procedure.

Fig. 2.

Study diagram of participant flow. ^aTen participants discontinued because of COVID-19–related reasons, and 1 participant in the placebo group discontinued because of randomization with incorrect C-APPS. ^bOne participant withdrew because of an AE related to the study procedure.

Baseline demographic and clinical characteristics of the mITT population were comparable across groups (Table 2). Participants were predominantly female (95.1%) and White (93.9%), and the mean age (SD) was 50 years (9.69). Participants self-reported their race, ethnicity, and sex.

Table 2.

Baseline Demographic and Clinical Characteristics of the Modified Intent-to-Treat Population

Characteristics	Placebo (n = 53)	OnabotA Low Dose (n = 58)	OnabotA High Dose (n = 53)	Total (n = 164)
Age, yrs, mean (SD)	49.3 (9.59)	51.8 (9.16)	48.6 (10.21)	50 (9.69)
Sex, no. (%)
Male	1 (1.9)	4 (6.9)	3 (5.7)	8 (4.9)
Female	52 (98.1)	54 (93.1)	50 (94.3)	156 (95.1)
Race, no. (%)
American Indian or Alaskan Native	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Asian	1 (1.9)	1 (1.7)	3 (5.7)	5 (3.0)
Black or African American	1 (1.9)	0 (0.0)	1 (1.9)	2 (1.2)
Native Hawaiian or Other Pacific Islander	2 (3.8)	1 (1.7)	0 (0.0)	3 (1.8)
White	49 (92.5)	56 (96.6)	49 (92.5)	154 (93.9)
Ethnicity, no. (%)
Hispanic or Latino	5 (9.4)	6 (10.3)	6 (11.3)	17 (10.4)
Not Hispanic or Latino	48 (90.6)	52 (89.7)	47 (88.7)	147 (89.6)
BMI, kg/m2, mean (SD)	22.56 (2.577)	23.12 (2.954)	23.10 (2.713)	22.93 (2.754)
C-APPS grade, no. (%)
3 on both sides	15 (28.3)	16 (27.6)	14 (26.4)	45 (27.4)
3 on one side, 4 on the other side	15 (28.3)	18 (31.0)	14 (26.4)	47 (28.7)
4 on both sides	23 (43.4)	24 (41.4)	25 (47.2)	72 (43.9)
Other	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
P-APPS grade, no. (%)
3 on both sides	17 (32.1)	20 (34.5)	11 (20.8)	48 (29.3)
3 on one side, 4 on the other side	12 (22.6)	10 (17.2)	15 (28.3)	37 (22.6)
4 on both sides	21 (39.6)	26 (44.8)	25 (47.2)	72 (43.9)
Other	3 (5.7)	2 (3.4)	2 (3.8)	7 (4.3)

BMI, body mass index; C-APPS, Clinician Allergan Platysma Prominence Scale; OnabotA, onabotulinumtoxinA; P-APPS, Participant Allergan Platysma Prominence Scale.

Efficacy Assessments

Achievement of at Least 1 Grade Improvement on C-APPS

The percentage of participants achieving 1 grade or greater improvement at maximum contraction on day 14 using clinician-assessed C-APPS was significantly greater with onabotulinumtoxinA LD (77.8%; 95% CI, 66.7% to 88.9%; P < 0.0001) and onabotulinumtoxinA HD (88.2%; 95% CI, 79.4% to 97.1%; P < 0.0001) than with placebo (12.0%; 95% CI, 3.0% to 21.0%) (Fig. 3). The onabotulinumtoxinA peak effect was observed at the earliest postdosing time point of day 14. Treatment response declined after day 14, although onabotulinumtoxinA still showed greater improvement than placebo at day 120 (onabotulinumtoxinA LD difference versus placebo: 15.2%; 95% CI, −0.4% to 30.9%; nominal P < 0.03; onabotulinumtoxinA HD difference versus placebo: 21.9%; 95% CI, 5.5% to 38.3%; nominal P < 0.02). A dose-dependent trend favoring onabotulinumtoxinA HD was observed at all time points. Representative images of a participant before and on day 14 after treatment are provided in Figure 4.

Fig. 3.

Percentage of responders (1 grade or greater improvement from baseline at maximum contraction) in the modified intent-to-treat population as assessed by investigators. *P < 0.001 versus placebo; †P < 0.05 versus placebo. All P values except those from day 14 are nominal. Error bars indicate 95% CIs.

Fig. 4.

Standardized photographs of a 42-year-old woman with grade 4 platysma prominence on the left and the right sides at baseline (above) who achieved a 3-grade improvement (from severe to minimal severity) on the C-APPS on both sides on day 14 after treatment with 36 U of onabotulinumtoxinA (below).

Achievement of at Least 1 Grade Improvement on P-APPS

The percentage of participants achieving 1 grade or greater improvement at maximum contraction on day 14 using participant-assessed P-APPS was significantly greater with onabotulinumtoxinA LD (75.9%; 95% CI, 64.5% to 87.3%; P < 0.0001) and onabotulinumtoxinA HD (88.2%; 95% CI, 79.4 to 97.1; P < 0.0001) than with placebo (18%; 95% CI, 7.4% to 28.6%) (Fig. 5). OnabotulinumtoxinA, either at low or high doses, showed greater effects than placebo continuing at day 120 (onabotulinumtoxinA LD difference versus placebo: 24.9%; 95% CI, 7.1% to 42.6%; nominal P < 0.009; onabotulinumtoxinA HD difference versus placebo: 31.9%; 95% CI, 13.9% to 49.8%; nominal P < 0.001). There was a dose-dependent trend across all time points favoring onabotulinumtoxinA HD.

Fig. 5.

Percentage of responders (1 grade or greater improvement from baseline at maximum contraction) in the modified intent-to-treat population as assessed by participants. *P < 0.001 versus placebo; †P < 0.05 versus placebo. All P values except those from day 14 are nominal. Error bars indicate 95% CIs.

Safety and Tolerability

The percentage of participants experiencing any treatment-emergent adverse event (TEAE) was similar across groups (onabotulinumtoxinA LD: 23.7%; onabotulinumtoxinA HD: 25.9%; placebo: 23.2%) (Table 3). The majority of TEAEs were mild or moderate, transient, and resolved spontaneously. The most common TEAE was injection site bruising (onabotulinumtoxinA LD: 6.8%; onabotulinumtoxinA HD: 5.6%; placebo: 7.1%).

Table 3.

Percentage of Participants in the Safety Population with TEAEs

Category	Placebo(n = 56), No. (%)	OnabotA Low Dose (n = 59), No. (%)	OnabotA High Dose (n = 54), No. (%)
TEAEs	13 (23.2)	14 (23.7)	14 (25.9)
Treatment-related TEAEs	7 (12.5)	8 (13.6)a	10 (18.5)a
Study procedure–related TEAEs	7 (12.5)	8 (13.6)	6 (11.1)
Study drug–related TEAEs	0 (0.0)	1 (1.7)	9 (16.7)
Serious TEAEs	0 (0.0)	2 (3.4)	0 (0.0)
Treatment-related serious TEAEs	0 (0.0)	0 (0.0)	0 (0.0)
TEAEs leading to discontinuation	0 (0.0)	0 (0.0)	1 (1.9)
Deaths	0 (0.0)	0 (0.0)	0 (0.0)
TEAE of possible distant spread of toxinb	0 (0.0)	1 (1.7)	9 (16.7)a

OnabotA, onabotulinumtoxinA.

^aOne participant experienced 2 or more TEAEs.

^bAll possible distant spread of toxin TEAEs were deemed local.

Study drug–related TEAEs occurred in 16.7% of onabotulinumtoxinA HD participants and 1.7% of onabotulinumtoxinA LD participants. No study drug–related TEAEs were reported in the placebo group. The most commonly reported study drug–related TEAEs were muscular weakness (investigator term: neck muscle weakness) (onabotulinumtoxinA HD: 9.3%) and dysphagia (onabotulinumtoxinA HD: 3.7%), and all occurred in the onabotulinumtoxinA HD group (Table 4). None of the study drug–related TEAEs led to study discontinuation.

Table 4.

Percentage of Participants in the Safety Population with Study Drug–Related TEAEs by OnabotulinumtoxinA Dose

Treatment	OnabotA Low Dose (n = 59), No. (%)			OnabotA High Dose (n = 54), No. (%)
	26 U (n = 16)	31 U (n = 18)	36 U (n = 25)	52 U (n = 14)	62 U (n = 15)	72 U (n = 25)
At least 1 TEAE	1 (6.3)	0 (0)	0 (0)	2 (14.3)	2 (13.3)	5 (20)
Gastrointestinal disorders	0 (0)	0 (0)	0 (0)	1 (7.1)	1 (6.7)	0 (0)
Dysphagia	0 (0)	0 (0)	0 (0)	1 (7.1)	1 (6.7)	0 (0)
Musculoskeletal and connective tissue disorders	0 (0)	0 (0)	0 (0)	0 (0)	2 (13.3)	5 (20)
Muscle spasms	0 (0)	0 (0)	0 (0)	0 (0)	1 (6.7)	0 (0)
Muscular weakness	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	5 (20)
Musculoskeletal stiffness	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (4)
Myalgia	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (4)
Neck pain	0 (0)	0 (0)	0 (0)	0 (0)	1 (6.7)	0 (0)
Nervous system disorders	1 (6.3)	0 (0)	0 (0)	1 (7.1)	0 (0)	0 (0)
Facial paresis	1 (6.3)	0 (0)	0 (0)	1 (7.1)	0 (0)	0 (0)

OnabotA, onabotulinumtoxinA.

Five participants receiving 72 U of onabotulinumtoxinA experienced neck muscle weakness. Most of these events were mild or moderate, with onset between 4 and 45 days after treatment and duration ranging from 4 to 68 days. One of the 5 participants experienced severe neck muscle weakness for 10 days, which progressed to moderate for 22 days, and ultimately transformed into a mild condition for 36 days.

Mild dysphagia was reported by 1 participant treated with onabotulinumtoxinA 52 U and 1 participant treated with onabotulinumtoxinA 62 U; these events started 5 and 14 days after study treatment and lasted for 9 days. Dysphagia interfered neither with successful swallowing nor with the ability to get the food down to the stomach in the 2 participants affected. In addition, mild facial paresis (or mild depressor labii inferioris weakness) was reported by 1 participant treated with onabotulinumtoxinA 26 U (which lasted for 133 days) and 1 participant treated with onabotulinumtoxinA 52 U (which lasted for 19 days), with the onset of symptoms occurring 24 and 15 days, respectively, after study treatment.

Two serious TEAEs (thrombocythemia and appendicitis) occurred in the onabotulinumtoxinA LD group, which were considered unrelated to the study drug. During the study, 15 events of possible distant spread of toxin were identified, but none was confirmed as distant spread of toxin events (Table 3). Among the possible distant spread of toxin events, 13 were attributed to localized toxin effects, and 2 were determined to be confounded by concurrent conditions. No new safety concerns or signals were detected through monitoring of vital signs.

DISCUSSION

This randomized placebo-controlled trial evaluated the safety and effectiveness of onabotulinumtoxinA in adults with moderate to severe PP. Investigators and participants rated PP severity by holistically looking at the platysma area of interest. Treatment experience, satisfaction with treatment outcomes, and psychologic impact were also evaluated by participants. Results demonstrated that onabotulinumtoxinA is safe and effective for treating moderate to severe PP. TEAE rates were similar across groups, mostly mild to moderate, and resolved during the study. Furthermore, in the primary and secondary end point analyses, greater improvements in PP severity were observed on day 14 with onabotulinumtoxinA compared with placebo.

Medical literature reports vary in safe and effective dosing of onabotulinumtoxinA for PP treatment (10 to 100 U, with doses up to 250 U reported).^16–19 This is the first randomized, multicenter, placebo-controlled study with a sample size of more than 160 participants to evaluate the efficacy and safety of various doses of onabotulinumtoxinA for treating PP (26 to 72 U). In addition, this is the first randomized placebo-controlled study to adjust dosing based on participant PP severity on each side of the neck, accounting for asymmetry between the left and right sides to maximize the aesthetic outcome. The platysma muscle was treated as a unit, with onabotulinumtoxinA injected along the submandibular border and neck bands. Treating the upper segment of the platysma muscle eases the downward pull on the lower face, improving the appearance of the jawline and lower face while minimizing dosing in vulnerable neck areas.

Excessive submental fat or skin laxity are important exclusion criteria, as they may mask PP. A thorough evaluation and selection of participants is essential to ensure optimal results. Variability in platysma contraction or inaccurate estimates of PP severity at baseline could lead to reduced efficacy.

In this trial, a 1 grade or greater improvement in the C-APPS was reported by 77.8% of participants in the onabotulinumtoxinA LD group and 88.2% in the onabotulinumtoxinA HD group on day 14 (P < 0.0001 versus placebo). OnabotulinumtoxinA effects in the neck are often more rapid than in the face, with a peak effect 14 days after treatment or earlier, which is consistent with the study primary time point.^18,20 Less pronounced improvement was observed at later time points, in agreement with the reported duration of onabotulinumtoxinA in the platysma, which usually lasts about 3 to 4 months.²¹ Notwithstanding, at day 120, there was still a greater percentage of 1 grade or greater responders by C-APPS in the onabotulinumtoxinA groups compared with placebo (both with nominal P ≤ 0.03 versus placebo). P-APPS results were similar to investigator ratings, with 75.9% and 88.2% of 1 grade or greater responders in the onabotulinumtoxinA LD and onabotulinumtoxinA HD groups, respectively, on day 14 (P < 0.0001 versus placebo). Likewise, improvements in both onabotulinumtoxinA groups peaked at day 14 but remained greater than placebo through day 120. These findings further confirmed that participants observed an improvement in PP severity. Moreover, in both investigator and participant assessments, there was a dose-dependent trend favoring onabotulinumtoxinA HD across all time points.

A dose trend was observed in the incidence of study drug–related TEAEs. Mild dysphagia occurred in 2 participants in the onabotulinumtoxinA HD group, with no events in the onabotulinumtoxinA LD group. Dysphagia refers to difficulty in swallowing, leading to delays in the transit of solids or liquids to the stomach. Assessing dysphagia can be challenging, as it is a subjective symptom and may not be evident in objective tests.²² One of the participants who experienced dysphagia had a history of gastroesophageal reflux disease, which could have predisposed him to swallowing dysfunction.²³ In addition, 5 participants in the onabotulinumtoxinA HD group experienced neck muscular weakness events, which were mainly mild to moderate; this TEAE was not observed in the LD group. Neck muscle weakness may manifest as inability to lift the head from a recumbent position or during physical activity, but it is typically transient and not considered serious.^8,16

Cases of dysphagia and muscle weakness have been reported before, frequently associated with onabotulinumtoxinA doses above 50 U.^{10,16,18,20,24} In a study with more than 1500 participants treated with onabotulinumtoxinA doses ranging from 50 to 250 U for platysma bands, fewer than 10% reported transient, mild neck discomfort, and 1% experienced neck weakness while exercising or lifting the head. One case of dysphagia after injection of 100 U of onabotulinumtoxinA resolved spontaneously within 2 weeks.¹⁸ High doses of onabotulinumtoxinA can potentially lead to toxin diffusion to adjacent structures, and deep injections can cause misplacement of the toxin.^19,21 Lower doses, precise placement, and understanding the area’s anatomy are important in reducing complications.

The phase 2 study findings have guided the establishment of an appropriate dose for the phase 3 trials, with a maximum of 36 U selected to optimize treatment efficacy and prioritize patient safety. Limitations of this study include using an injection paradigm (based on PP severity) that may not reflect the full spectrum of clinical practice and a minimal representation of male participants and racial groups other than White, which may affect the generalization of results. In addition, this study was not powered to analyze differences in efficacy between onabotulinumtoxinA groups.

CONCLUSIONS

OnabotulinumtoxinA treatment revealed significantly greater improvement compared with placebo in PP severity at day 14, with effects lasting up to day 120, as measured by investigators using the C-APPS and participants using the P-APPS. Moreover, onabotulinumtoxinA was well tolerated after a single treatment at doses ranging from 26 to 72 U, although higher onabotulinumtoxinA doses were associated with a greater incidence of TEAEs.

DISCLOSURE

Dr. Rohrich is an advisory board member, consultant, investigator, and/or speaker for Allergan Aesthetics, an AbbVie company; Galderma; and the Musculoskeletal Transplant Foundation. Dr. Bertucci is an advisory board member, consultant, investigator, and/or speaker for Allergan Aesthetics, an AbbVie company; Cutera; Evolus; Galderma; MedyTox; Merz; Prollenium; Revance; and Teoxane. Dr. Dayan is an advisory board member, consultant, investigator, and/or speaker for Allergan Aesthetics, an AbbVie company; Galderma; and Merz. Dr. Jones is an investigator, consultant, and/or advisory board member for Allergan Aesthetics, an AbbVie company; and Galderma. Dr. Solish is a consultant, an advisory board member, and a speaker's bureau member for Allergan Aesthetics, an AbbVie company; Galderma; and Revance Therapeutics. Dr. Rivers is an advisory board member, speakers’ bureau member, and an investigator for AbbVie/Allergan; an investigator and a speaker's bureau member for Galderma; an advisory board member, a speaker's bureau member, paid consultant, and investigator for Leo Pharma; an investigator for Pfizer; and a founder and stockholder of Riversol Skin Care Solutions, Inc. Dr. Weiss is an advisory board member, consultant, investigator, and/or speaker for Allergan Aesthetics, an AbbVie company; and Galderma. Dr. Muhn is an advisory board member, consultant, investigator, or speaker for Allergan Aesthetics, an AbbVie company; Galderma; and Merz. Dr. Harutunian is an investigator for Allergan Aesthetics, an AbbVie company. Dr. Park, Dr. Shimoga, Ms. Lee, and Mr. Tong are employees of Allergan Aesthetics, an AbbVie company, and may own AbbVie stock. Allergan Aesthetics, an AbbVie company, funded this study and participated in the study design, research, analysis, data collection, interpretation of data, review, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria were received or payments made for authorship. Medical writing support was provided by Ana Vicente Sanchez, PhD, of AbbVie, Inc., and editorial support was provided by Angela T. Hadsell of AbbVie, Inc.; both were funded by AbbVie, Inc.

ACKNOWLEDGMENT

Allergan Aesthetics, an AbbVie company, and the authors thank the participants, study sites, and investigators who participated in this clinical trial.

MEETING PRESENTATIONS

Presented at the Annual Meeting of the American Academy of Dermatology, in Tampa, FL, August 5 through 8, 2021; Aesthetic and Anti-Aging Medicine World Congress, in Monaco, September 16 through 18, 2021; Beauty through Science Congress, in Stockholm, Sweden, June 17 through 19, 2021; Middle East International Dermatology and Aesthetic Medicine, in Dubai, United Arab Emirates, September 23 through 25, 2021; World Congress of Aesthetic Medicine, in Bangkok, Thailand, March 25 through 27, 2022; Aesthetic Plastic Surgery, in Seoul, Korea, April 16 and 17, 2022; Australasian Society of Aesthetic Plastic Surgeons–Nonsurgical Symposium, in Broadbeach, Australia, June 3 through 5, 2022; Regional Conference of Dermatology, in Manila, the Philippines, October 26 through 28, 2022; Aesthetic Medicine and Surgery Conference, in Kuala Lumpur, Malaysia, August 20 and 21, 2022; International Caucasian Congress on Plastic Surgery and Dermatology (Kolkhida), in Tbilisi, Georgia, July 1 through 3, 2022; Aesthetic Medicine Congress, in Dubrovnik, Croatia, October 6 through 8, 2022; Sociedad Española de Medicina Estética, in Malaga, Spain, February 23 through 25, 2023; and Societa Italiana di Medicina Estetica, in Rome, Italy, May 19 through 21, 2023.

DATA SHARING STATEMENT

AbbVie is committed to responsible data sharing regarding the clinical trials they sponsor. This includes access to anonymized, individual, and trial-level data (analysis data sets), as well as other information (eg, protocols, clinical study reports, or analysis plans), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. The clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal, statistical analysis plan, and execution of a data sharing agreement. The data will be accessible for 12 months, with possible extensions considered. For more information on the process or to submit a request, visit https://vivli.org/ourmember/abbvie and select “Home.”