The Treatment of Glabellar Frown Lines

• Sponsor: Merz North America, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02096081
• Collaborator: (none)
• Enrollment: 250
• Locations: 10
• Arms: 2
• Duration (Months): 9
• Patients Per Site: 25
• Patients Per Site Per Month: 2.8

Study Details

Study Description

Brief Summary

The purpose of this study is to show that two FDA-approved botulinum toxin drugs called Xeomin® and Botox® can reduce the severity of vertical lines (wrinkles) that appear between the eyebrows (glabellar frown lines).

Condition or Disease	Intervention/Treatment	Phase
Glabellar Frown Lines	Drug: IncobotulinumtoxinA; Drug: OnabotulinumtoxinA	Phase 4

Detailed Description

This is a prospective, multicenter, randomized, double-blind, parallel group clinical study to investigate the equivalence of incobotulinumtoxinA (Xeomin®) to onabotulinumtoxinA (Botox®) in the treatment of glabellar frown lines.

Study Design

• Study Type: Interventional
• Actual Enrollment: 250 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Study Start Date: Feb 1, 2014
• Actual Primary Completion Date: Aug 1, 2014
• Actual Study Completion Date: Nov 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: IncobotulinumtoxinA 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points	Drug: IncobotulinumtoxinA; 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection; Other Names: Xeomin® NT201 Botulinum toxin type A [150 kDa], free from complexing proteins
Active Comparator: OnabotulinumtoxinA 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points	Drug: OnabotulinumtoxinA; 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection; Other Names: Botox®

Outcome Measures

Primary Outcome Measures

1. Efficacy, Measured as the Percentage of Participants Who Responded to Treatment [1 Month from baseline]

   Response defined as ≥ 1 point improvement from baseline (prior to treatment) on the Facial Wrinkle Scale at maximum frown as rated by an independent masked panel of physicians specifically qualified to assess study photographs using subject photographs at 1 month from treatment.

Secondary Outcome Measures

1. Response at Maximum Frown Rated by Independent Rater [2 months from baseline]

   Response defined as ≥ 1 point improvement from baseline on the Facial Wrinkle Scale (0=None to 3=severe) at maximum frown as rated by an independent masked panel of physicians specifically qualified to assess study photographs using subject photographs at 2 months from baseline.

2. Response at Maximum Frown Rated by Independent Rater [3 months from baseline]

   Response defined as ≥ 1 point improvement from baseline on the Facial Wrinkle Scale (0=None to 3=severe) at maximum frown as rated by an independent masked panel of physicians specifically qualified to assess study photographs using subject photographs at 3 months from baseline.

3. Response at Maximum Frown Rated by Independent Rater [4 months from baseline]

   Response defined as ≥ 1 point improvement from baseline on the Facial Wrinkle Scale (0=None to 3=severe) at maximum frown as rated by an independent masked panel of physicians specifically qualified to assess study photographs using subject photographs at 4 months from baseline.

4. Response at Maximum Frown Rated by Treating Physician [1 month from baseline]

   Response defined as ≥ 1 point improvement from baseline on the Facial Wrinkle Scale (0=None to 3=severe) at maximum frown as rated by the treating physicians using subject photographs at 1 month from treatment.

5. Response at Maximum Frown Rated by Treating Physician [2 months from baseline]

   Response defined as ≥ 1 point improvement from baseline on the Facial Wrinkle Scale (0=None to 3=severe) at maximum frown as rated by the treating physicians using subject photographs at 2 months from treatment.

6. Response at Maximum Frown Rated by Treating Physician [3 months from baseline]

   Response defined as ≥ 1 point improvement from baseline on the Facial Wrinkle Scale (0=None to 3=severe) at maximum frown as rated by the treating physicians using subject photographs at 3 months from treatment.

7. Response at Maximum Frown Rated by Treating Physician [4 months from baseline]

   Response defined as ≥ 1 point improvement from baseline on the Facial Wrinkle Scale (0=None to 3=severe) at maximum frown as rated by the treating physicians using subject photographs at 4 months from treatment.

8. Subject Satisfaction [1 month from baseline]

   Assessment of subject treatment satisfaction by subject questionnaire and diary at 1 month from treatment. Extremely satisfied, satisfied, and slightly satisfied were categorized as "Satisfaction" and extremely dissatisfied, dissatisfied, and slightly dissatisfied were categorized as "Dissatisfaction." Subjects with missing data were categorized as "Missing."

9. Subject Satisfaction [2 months from baseline]

   Assessment of subject treatment satisfaction by subject questionnaire and diary at 2 months from treatment. Extremely satisfied, satisfied, and slightly satisfied were categorized as "Satisfaction" and extremely dissatisfied, dissatisfied, and slightly dissatisfied were categorized as "Dissatisfaction." Subjects with missing data were categorized as "Missing."

10. Subject Satisfaction [3 months from baseline]

    Assessment of subject treatment satisfaction by subject questionnaire and diary at 3 months from treatment. Extremely satisfied, satisfied, and slightly satisfied were categorized as "Satisfaction" and extremely dissatisfied, dissatisfied, and slightly dissatisfied were categorized as "Dissatisfaction." Subjects with missing data were categorized as "Missing."

11. Subject Satisfaction [4 months from baseline]

    Assessment of subject treatment satisfaction by subject questionnaire and diary at 4 months from treatment. Extremely satisfied, satisfied, and slightly satisfied were categorized as "Satisfaction" and extremely dissatisfied, dissatisfied, and slightly dissatisfied were categorized as "Dissatisfaction." Subjects with missing data were categorized as "Missing."

12. Subject Perception of Treatment Onset [Open-ended time frame for the 4 month study duration. Data for onset and peak effect is recorded in the subject diary.]

    Assessment of subject perception of date of treatment onset using a take-home diary

13. Subject Perception of Treatment Peak Effect [Open-ended time frame for the 4 month study duration. Data for onset and peak effect is recorded in the subject diary.]

    Assessment of subject perception of date of treatment peak effect using a take-home diary

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Outpatient females 18 to 50 years of age

• Moderate to severe glabellar frown lines

Exclusion Criteria:

• Glabellar Frown Lines at rest rating 3 on the 4-point Facial Wrinkle Scale

• Previous treatment with botulinum toxin

• Previous treatment with biodegradable fillers in glabellar area within last 12 months

• Any severe or uncontrolled systemic disease, malignant tumor, or medical history of HIV infection

• Known hypersensitivity to incobotulinumtoxinA or onabotulinumtoxinA or to any of their excipients

• Intake of any of the forbidden concomitant medication or other agents that might interfere with neuromuscular function or might interfere with the action of botulinum toxin type within 14 days prior to injection

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Merz Investigative Site #001099	Los Angeles	California	United States	90069
2	Merz Investigative Site #001300	Sacramento	California	United States	95819
3	Merz Investigative Site #001299	Santa Monica	California	United States	90404
4	Merz Investigative Site #001298	Washington, D.C.	District of Columbia	United States	20005
5	Merz Investigative Site #001170	Washington, D.C.	District of Columbia	United States	20037
6	Merz Investigative Site #001101	Coral Gables	Florida	United States	33146
7	Merz Investigative Site #001105	Metairie	Louisiana	United States	70006
8	Merz Investigative Site #001098	Chestnut Hill	Massachusetts	United States	02467
9	Merz Investigative Site #001297	New York	New York	United States	10065
10	Merz Investigative Site #001097	Nashville	Tennessee	United States	37215

Sponsors and Collaborators

• Merz North America, Inc.

Investigators

• Study Director: Andrea Schlӧbe, MD, Merz North America, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merz North America, Inc.
• ClinicalTrials.gov Identifier: NCT02096081
• Other Study ID Numbers: MUS 60201_4096_1
• First Posted: Mar 26, 2014
• Last Update Posted: Oct 19, 2017
• Last Verified: Sep 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Merz North America, Inc.: Glabellar Frown Lines; Frown Lines; Facial Wrinkles
• Additional relevant MeSH terms: Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA; incobotulinumtoxinA

Study Results

Participant Flow

Arm/Group Title	IncobotulinumtoxinA	OnabotulinumtoxinA
Arm/Group Description	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. IncobotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. OnabotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection
Period Title: Overall Study
STARTED	122	128
COMPLETED	119	124
NOT COMPLETED	3	4

Baseline Characteristics

Arm/Group Title	IncobotulinumtoxinA	OnabotulinumtoxinA	Total
Arm/Group Description	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. IncobotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. OnabotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection	Total of all reporting groups
Overall Participants	122	128	250
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39.3 (7.4)	39.4 (7.8)	39.3 (7.6)
Sex: Female, Male (Count of Participants)
Female	122 100%	128 100%	250 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	23 18.9%	35 27.3%	58 23.2%
Not Hispanic or Latino	99 81.1%	93 72.7%	192 76.8%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 0.8%	1 0.4%
Asian	4 3.3%	4 3.1%	8 3.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	14 11.5%	13 10.2%	27 10.8%
White	104 85.2%	107 83.6%	211 84.4%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	3 2.3%	3 1.2%

Outcome Measures

1. Primary Outcome

Title	Efficacy, Measured as the Percentage of Participants Who Responded to Treatment
Description	Response defined as ≥ 1 point improvement from baseline (prior to treatment) on the Facial Wrinkle Scale at maximum frown as rated by an independent masked panel of physicians specifically qualified to assess study photographs using subject photographs at 1 month from treatment.
Time Frame	1 Month from baseline

Outcome Measure Data

Analysis Population Description

All efficacy analyses were performed on the per protocol set (PPS) defined as the subset of subjects in the FAS for whom no major protocol deviations were identified.

Arm/Group Title	IncobotulinumtoxinA	OnabotulinumtoxinA
Arm/Group Description	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. IncobotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. OnabotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection
Measure Participants	116	119
Number [percentage of participants]	95.7 78.4%	99.2 77.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IncobotulinumtoxinA, OnabotulinumtoxinA
	Comments	With assumptions of an alpha of 5%, an equivalence margin of 15% for each side, the real response rate expected as 90% for incobotulinumtoxinA and onabotulinumtoxinA at day 30 and a 1:1 allocation ratio, a total of 225 subjects were needed to achieve a statistical power of 90% in order to make an equivalence conclusion at day 30. Results are based on the Newcombe-Wilson confidence interval. To account for exclusions from the PPS of about 10%, approximately 250 subjects were enrolled.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The analysis of response defined as the difference (D) in response rates between two treatment groups at 1 month was as follows: D = response rate in the incobotulinumtoxinA group minus the response rate in the onabotulinumtoxinA group. The hypothesis testing procedure to test the equivalence of the two products is as follows: Ho (null): D ≤ -∆ OR D ≥ ∆ versus Ha (alternate): -∆ < D < ∆, where ∆ is the margin of equivalence = 0.15.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in proportions of response
	Estimated Value	-3.5
	Confidence Interval	(2-Sided) 95%; -7.5 to 0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	If the confidence interval lies within the limits of ±0.15, then Ho is rejected in favor of Ha (i.e., equivalence of incobotulinumtoxinA and onabotulinumtoxinA can be concluded); otherwise, treatment equivalence cannot be concluded.

2. Secondary Outcome

Title	Response at Maximum Frown Rated by Independent Rater
Description	Response defined as ≥ 1 point improvement from baseline on the Facial Wrinkle Scale (0=None to 3=severe) at maximum frown as rated by an independent masked panel of physicians specifically qualified to assess study photographs using subject photographs at 2 months from baseline.
Time Frame	2 months from baseline

Outcome Measure Data

Analysis Population Description

All efficacy analyses were performed on the per protocol set (PPS) defined as the subset of subjects in the FAS for whom no major protocol deviations were identified.

Arm/Group Title	IncobotulinumtoxinA	OnabotulinumtoxinA
Arm/Group Description	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. IncobotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. OnabotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection
Measure Participants	116	119
Number [percentage of participants]	89.7 73.5%	95.0 74.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IncobotulinumtoxinA, OnabotulinumtoxinA
	Comments	The study was not powered for this secondary endpoint.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	This secondary analysis was performed for exploratory purposes. The analysis of response defined as the difference (D) in response rates between two treatment groups at 2 months was as follows: D = response rate in the incobotulinumtoxinA group minus the response rate in the onabotulinumtoxinA group.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in proportion of responders
	Estimated Value	-5.3
	Confidence Interval	(2-Sided) 95%; -12.1 to 1.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	If the confidence interval lies within the limits of ±0.15, then both incobotulinumtoxinA and onabotulinumtoxinA have similar efficacy profiles.

3. Secondary Outcome

Title	Response at Maximum Frown Rated by Independent Rater
Description	Response defined as ≥ 1 point improvement from baseline on the Facial Wrinkle Scale (0=None to 3=severe) at maximum frown as rated by an independent masked panel of physicians specifically qualified to assess study photographs using subject photographs at 3 months from baseline.
Time Frame	3 months from baseline

Outcome Measure Data

Analysis Population Description

All efficacy analyses were performed on the per protocol set (PPS) defined as the subset of subjects in the FAS for whom no major protocol deviations were identified.

Arm/Group Title	IncobotulinumtoxinA	OnabotulinumtoxinA
Arm/Group Description	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. IncobotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. OnabotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection
Measure Participants	116	119
Number [percentage of participants]	80.2 65.7%	80.7 63%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IncobotulinumtoxinA, OnabotulinumtoxinA
	Comments	The study was not powered for this secondary endpoint.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	This secondary analysis was performed for exploratory purposes. The analysis of response defined as the difference (D) in response rates between two treatment groups at 3 months was as follows: D = response rate in the incobotulinumtoxinA group minus the response rate in the onabotulinumtoxinA group.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in proportion of responders
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 95%; -10.6 to 9.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	If the confidence interval lies within the limits of ±0.15, then both incobotulinumtoxinA and onabotulinumtoxinA have similar efficacy profiles.

4. Secondary Outcome

Title	Response at Maximum Frown Rated by Independent Rater
Description	Response defined as ≥ 1 point improvement from baseline on the Facial Wrinkle Scale (0=None to 3=severe) at maximum frown as rated by an independent masked panel of physicians specifically qualified to assess study photographs using subject photographs at 4 months from baseline.
Time Frame	4 months from baseline

Outcome Measure Data

Analysis Population Description

All efficacy analyses were performed on the per protocol set (PPS) defined as the subset of subjects in the FAS for whom no major protocol deviations were identified.

Arm/Group Title	IncobotulinumtoxinA	OnabotulinumtoxinA
Arm/Group Description	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. IncobotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. OnabotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection
Measure Participants	116	119
Number [percentage of participants]	62.1 50.9%	67.2 52.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IncobotulinumtoxinA, OnabotulinumtoxinA
	Comments	The study was not powered for this secondary endpoint.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	This secondary analysis was performed for exploratory purposes. The analysis of response defined as the difference (D) in response rates between two treatment groups at 4 months was as follows: D = response rate in the incobotulinumtoxinA group minus the response rate in the onabotulinumtoxinA group.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in proportion of responders
	Estimated Value	-5.2
	Confidence Interval	(2-Sided) 95%; -17.4 to 7.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	If the confidence interval lies within the limits of ±0.15, then both incobotulinumtoxinA and onabotulinumtoxinA have similar efficacy profiles.

5. Secondary Outcome

Title	Response at Maximum Frown Rated by Treating Physician
Description	Response defined as ≥ 1 point improvement from baseline on the Facial Wrinkle Scale (0=None to 3=severe) at maximum frown as rated by the treating physicians using subject photographs at 1 month from treatment.
Time Frame	1 month from baseline

Outcome Measure Data

Analysis Population Description

All efficacy analyses were performed on the per protocol set (PPS) defined as the subset of subjects in the FAS for whom no major protocol deviations were identified.

Arm/Group Title	IncobotulinumtoxinA	OnabotulinumtoxinA
Arm/Group Description	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. IncobotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. OnabotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection
Measure Participants	116	119
Number [percentage of participants]	93.1 76.3%	95.8 74.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IncobotulinumtoxinA, OnabotulinumtoxinA
	Comments	The study was not powered for this secondary endpoint.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	This secondary analysis was performed for exploratory purposes. The analysis of response defined as the difference (D) in response rates between two treatment groups at 1 month was as follows: D = response rate in the incobotulinumtoxinA group minus the response rate in the onabotulinumtoxinA group.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in proportion of responders
	Estimated Value	-2.7
	Confidence Interval	(2-Sided) 95%; -8.5 to 3.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	If the confidence interval lies within the limits of ±0.15, then both incobotulinumtoxinA and onabotulinumtoxinA have similar efficacy profiles.

6. Secondary Outcome

Title	Response at Maximum Frown Rated by Treating Physician
Description	Response defined as ≥ 1 point improvement from baseline on the Facial Wrinkle Scale (0=None to 3=severe) at maximum frown as rated by the treating physicians using subject photographs at 2 months from treatment.
Time Frame	2 months from baseline

Outcome Measure Data

Analysis Population Description

All efficacy analyses were performed on the per protocol set (PPS) defined as the subset of subjects in the FAS for whom no major protocol deviations were identified.

Arm/Group Title	IncobotulinumtoxinA	OnabotulinumtoxinA
Arm/Group Description	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. IncobotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. OnabotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection
Measure Participants	116	119
Number [percentage of participants]	87.1 71.4%	89.9 70.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IncobotulinumtoxinA, OnabotulinumtoxinA
	Comments	The study was not powered for this secondary endpoint.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	This secondary analysis was performed for exploratory purposes. The analysis of response defined as the difference (D) in response rates between two treatment groups at 2 months was as follows: D = response rate in the incobotulinumtoxinA group minus the response rate in the onabotulinumtoxinA group.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in proportion of responders
	Estimated Value	-2.8
	Confidence Interval	(2-Sided) 95%; -11.0 to 5.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	If the confidence interval lies within the limits of ±0.15, then both incobotulinumtoxinA and onabotulinumtoxinA have similar efficacy profiles.

7. Secondary Outcome

Title	Response at Maximum Frown Rated by Treating Physician
Description	Response defined as ≥ 1 point improvement from baseline on the Facial Wrinkle Scale (0=None to 3=severe) at maximum frown as rated by the treating physicians using subject photographs at 3 months from treatment.
Time Frame	3 months from baseline

Outcome Measure Data

Analysis Population Description

All efficacy analyses were performed on the per protocol set (PPS) defined as the subset of subjects in the FAS for whom no major protocol deviations were identified.

Arm/Group Title	IncobotulinumtoxinA	OnabotulinumtoxinA
Arm/Group Description	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. IncobotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. OnabotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection
Measure Participants	116	119
Number [percentage of participants]	75.0 61.5%	76.5 59.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IncobotulinumtoxinA, OnabotulinumtoxinA
	Comments	The study was not powered for this secondary endpoint.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	This secondary analysis was performed for exploratory purposes. The analysis of response defined as the difference (D) in response rates between two treatment groups at 3 months was as follows: D = response rate in the incobotulinumtoxinA group minus the response rate in the onabotulinumtoxinA group.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in proportion of responders
	Estimated Value	-1.5
	Confidence Interval	(2-Sided) 95%; -12.4 to 9.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	If the confidence interval lies within the limits of ±0.15, then both incobotulinumtoxinA and onabotulinumtoxinA have similar efficacy profiles.

8. Secondary Outcome

Title	Response at Maximum Frown Rated by Treating Physician
Description	Response defined as ≥ 1 point improvement from baseline on the Facial Wrinkle Scale (0=None to 3=severe) at maximum frown as rated by the treating physicians using subject photographs at 4 months from treatment.
Time Frame	4 months from baseline

Outcome Measure Data

Analysis Population Description

All efficacy analyses were performed on the per protocol set (PPS) defined as the subset of subjects in the FAS for whom no major protocol deviations were identified.

Arm/Group Title	IncobotulinumtoxinA	OnabotulinumtoxinA
Arm/Group Description	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. IncobotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. OnabotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection
Measure Participants	116	119
Number [percentage of participants]	58.6 48%	60.5 47.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IncobotulinumtoxinA, OnabotulinumtoxinA
	Comments	The study was not powered for this secondary endpoint.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	This secondary analysis was performed for exploratory purposes. The analysis of response defined as the difference (D) in response rates between two treatment groups at 4 months was as follows: D = response rate in the incobotulinumtoxinA group minus the response rate in the onabotulinumtoxinA group.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in proportion of responders
	Estimated Value	-1.9
	Confidence Interval	(2-Sided) 95%; -14.4 to 10.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	If the confidence interval lies within the limits of ±0.15, then both incobotulinumtoxinA and onabotulinumtoxinA have similar efficacy profiles.

9. Secondary Outcome

Title	Subject Satisfaction
Description	Assessment of subject treatment satisfaction by subject questionnaire and diary at 1 month from treatment. Extremely satisfied, satisfied, and slightly satisfied were categorized as "Satisfaction" and extremely dissatisfied, dissatisfied, and slightly dissatisfied were categorized as "Dissatisfaction." Subjects with missing data were categorized as "Missing."
Time Frame	1 month from baseline

Outcome Measure Data

Analysis Population Description

This endpoint was analyzed using observed cases in the per protocol set (PPS), defined as the subset of subjects in the FAS from whom no major protocol deviations were identified.

Arm/Group Title	IncobotulinumtoxinA	OnabotulinumtoxinA
Arm/Group Description	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. IncobotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. OnabotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection
Measure Participants	116	119
Satisfaction	112 91.8%	116 90.6%
Dissatifaction	3 2.5%	3 2.3%
Missing	1 0.8%	0 0%

10. Secondary Outcome

Title	Subject Satisfaction
Description	Assessment of subject treatment satisfaction by subject questionnaire and diary at 2 months from treatment. Extremely satisfied, satisfied, and slightly satisfied were categorized as "Satisfaction" and extremely dissatisfied, dissatisfied, and slightly dissatisfied were categorized as "Dissatisfaction." Subjects with missing data were categorized as "Missing."
Time Frame	2 months from baseline

Outcome Measure Data

Analysis Population Description

This endpoint was analyzed using observed cases in the per protocol set (PPS), defined as the subset of subjects in the FAS from whom no major protocol deviations were identified.

Arm/Group Title	IncobotulinumtoxinA	OnabotulinumtoxinA
Arm/Group Description	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. IncobotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. OnabotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection
Measure Participants	116	119
Satisfied	110 90.2%	113 88.3%
Dissatisfied	5 4.1%	6 4.7%
Missing	1 0.8%	0 0%

11. Secondary Outcome

Title	Subject Satisfaction
Description	Assessment of subject treatment satisfaction by subject questionnaire and diary at 3 months from treatment. Extremely satisfied, satisfied, and slightly satisfied were categorized as "Satisfaction" and extremely dissatisfied, dissatisfied, and slightly dissatisfied were categorized as "Dissatisfaction." Subjects with missing data were categorized as "Missing."
Time Frame	3 months from baseline

Outcome Measure Data

Analysis Population Description

This endpoint was analyzed using observed cases in the per protocol set (PPS), defined as the subset of subjects in the FAS from whom no major protocol deviations were identified.

Arm/Group Title	IncobotulinumtoxinA	OnabotulinumtoxinA
Arm/Group Description	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. IncobotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. OnabotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection
Measure Participants	116	119
Satisfaction	108 88.5%	108 84.4%
Dissatisfaction	7 5.7%	10 7.8%
Missing	1 0.8%	1 0.8%

12. Secondary Outcome

Title	Subject Satisfaction
Description	Assessment of subject treatment satisfaction by subject questionnaire and diary at 4 months from treatment. Extremely satisfied, satisfied, and slightly satisfied were categorized as "Satisfaction" and extremely dissatisfied, dissatisfied, and slightly dissatisfied were categorized as "Dissatisfaction." Subjects with missing data were categorized as "Missing."
Time Frame	4 months from baseline

Outcome Measure Data

Analysis Population Description

This endpoint was analyzed using observed cases in the per protocol set (PPS), defined as the subset of subjects in the FAS from whom no major protocol deviations were identified.

Arm/Group Title	IncobotulinumtoxinA	OnabotulinumtoxinA
Arm/Group Description	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. IncobotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. OnabotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection
Measure Participants	116	119
Satisfaction	107 87.7%	104 81.3%
Dissatisfaction	8 6.6%	11 8.6%
Missing	1 0.8%	4 3.1%

13. Secondary Outcome

Title	Subject Perception of Treatment Onset
Description	Assessment of subject perception of date of treatment onset using a take-home diary
Time Frame	Open-ended time frame for the 4 month study duration. Data for onset and peak effect is recorded in the subject diary.

Outcome Measure Data

Analysis Population Description

This endpoint was analyzed using observed cases in the per protocol set (PPS), defined as the subset of subjects in the FAS from whom no major protocol deviations were identified.

Arm/Group Title	IncobotulinumtoxinA	OnabotulinumtoxinA
Arm/Group Description	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. IncobotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. OnabotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection
Measure Participants	116	119
Median (Full Range) [days]	3.0	3.0

14. Secondary Outcome

Title	Subject Perception of Treatment Peak Effect
Description	Assessment of subject perception of date of treatment peak effect using a take-home diary
Time Frame	Open-ended time frame for the 4 month study duration. Data for onset and peak effect is recorded in the subject diary.

Outcome Measure Data

Analysis Population Description

This endpoint was analyzed using observed cases in the per protocol set (PPS), defined as the subset of subjects in the FAS from whom no major protocol deviations were identified.

Arm/Group Title	IncobotulinumtoxinA	OnabotulinumtoxinA
Arm/Group Description	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. IncobotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. OnabotulinumtoxinA: 20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection
Measure Participants	116	119
Within 4 weeks	108 88.5%	113 88.3%
Longer than 4 weeks	7 5.7%	4 3.1%
Missing	1 0.8%	2 1.6%

Adverse Events

Time Frame	Adverse events were collected during the entire study period (4 months). Adverse events were not followed-up after the final study visit/safety visit, which was scheduled for 4 months post-treatment.
Arm/Group Title	IncobotulinumtoxinA		OnabotulinumtoxinA
Arm/Group Description	20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. IncobotulinumtoxinA: 20U/injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection		20U injection: equal aliquots of 0.1 mL (4U) to 5 injection points. OnabotulinumtoxinA: 20U/injection: equal aliquots of 0.1 mL (4U) to 5 injection points; mode of application: intramuscular injection
All Cause Mortality
	IncobotulinumtoxinA		OnabotulinumtoxinA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	IncobotulinumtoxinA		OnabotulinumtoxinA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/122 (0.8%)		1/128 (0.8%)
Infections and infestations
Human ehrlichiosis	1/122 (0.8%)	1	0/128 (0%)	0
Atypical pneumonia	0/122 (0%)	0	1/128 (0.8%)	1
Other (Not Including Serious) Adverse Events
	IncobotulinumtoxinA		OnabotulinumtoxinA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/122 (7.4%)		8/128 (6.3%)
Musculoskeletal and connective tissue disorders
Facial Asymmetry	2/122 (1.6%)	2	3/128 (2.3%)	3
Nervous system disorders
Headache	7/122 (5.7%)	7	5/128 (3.9%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.