Trial Outcomes & Findings for Efficacy and Safety of Botulinum Toxin Type A Haemagglutinin Complex Next Generation (BTX-A-HAC NG) in Glabellar Lines (NCT NCT02493946)

Last Updated: 2022-09-28

Results Overview

The appearance of glabellar lines at maximum frown was assessed in the DB period at the Day 29 follow-up visit using the ILA, a validated 4-point photographic scale of glabellar line severity. A responder was defined as having a severity grade of none (Grade 0) or mild (Grade 1) at a given visit and a severity grade of moderate (Grade 2) or severe (Grade 3) at baseline (Day 1 Cycle 1). The adjusted percentage of responders (determined by multivariate logistic regression analysis) at Day 29 of Cycle 1 is presented.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

600 participants

Primary outcome timeframe

Day 29 (Cycle 1)

Results posted on

2022-09-28

Participant Flow

Subjects with moderate or severe glabellar lines were enrolled in 24 sites in France, Germany and the United Kingdom from 23 April 2015. The study was completed in December 2016.

605 subjects were screened. 192 were screened for the double blind (DB) period; 2 were screen failures and 190 were randomised to treatment or placebo. 413 additional subjects were screened for the open label (OL) period referred to as de novo subjects; 3 were screen failures and 410 received at least one treatment cycle.

Participant milestones

Participant milestones
Measure	BTX-A-HAC Solution 50 U - DB Period During the DB period, subjects were randomised to receive a single treatment of Clostridium botulinum toxin type A haemagglutinin complex (BTX-A-HAC) solution 50 Units (U). 50 U (0.25 millilitres \[mL\]) BTX-A-HAC was administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive further BTX-A-HAC treatment.	Placebo - DB Period During the DB period, subjects were randomised to receive a single treatment of placebo. 0.25 mL placebo was administered as five injections of 0.05 mL each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive BTX-A-HAC treatment.	BTX-A-HAC Solution 50 U - Long Term (LT) Analyses Eligible subjects who completed the DB Cycle 1 treatment were able to receive further treatment in the OL period (OL Cycles 2 to 5). Additional BTX-naïve (de novo) subjects were enrolled into the OL period to receive treatment with BTX-A-HAC during OL Cycle 1, and if eligible for retreatment de novo subjects received retreatment in OL Cycles 2 to 5. Each treatment cycle included a single treatment with 50 U (0.25 mL) BTX-A-HAC administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region, and treatments were separated by at least 12 weeks.
DB Period STARTED	126	64	0
DB Period COMPLETED	118	59	0
DB Period NOT COMPLETED	8	5	0
Open Label Period STARTED	0	0	595
Open Label Period COMPLETED	0	0	509
Open Label Period NOT COMPLETED	0	0	86

Reasons for withdrawal

Reasons for withdrawal
Measure	BTX-A-HAC Solution 50 U - DB Period During the DB period, subjects were randomised to receive a single treatment of Clostridium botulinum toxin type A haemagglutinin complex (BTX-A-HAC) solution 50 Units (U). 50 U (0.25 millilitres \[mL\]) BTX-A-HAC was administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive further BTX-A-HAC treatment.	Placebo - DB Period During the DB period, subjects were randomised to receive a single treatment of placebo. 0.25 mL placebo was administered as five injections of 0.05 mL each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive BTX-A-HAC treatment.	BTX-A-HAC Solution 50 U - Long Term (LT) Analyses Eligible subjects who completed the DB Cycle 1 treatment were able to receive further treatment in the OL period (OL Cycles 2 to 5). Additional BTX-naïve (de novo) subjects were enrolled into the OL period to receive treatment with BTX-A-HAC during OL Cycle 1, and if eligible for retreatment de novo subjects received retreatment in OL Cycles 2 to 5. Each treatment cycle included a single treatment with 50 U (0.25 mL) BTX-A-HAC administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region, and treatments were separated by at least 12 weeks.
DB Period Withdrawal by Subject	8	5	0
Open Label Period Withdrawal by Subject	0	0	74
Open Label Period Adverse Event	0	0	4
Open Label Period Lost to Follow-up	0	0	1
Open Label Period Investigator decision, non-compliance	0	0	2
Open Label Period Investigator decision, non-availability	0	0	1
Open Label Period Pregnancy	0	0	3
Open Label Period Site error	0	0	1

Baseline Characteristics

Efficacy and Safety of Botulinum Toxin Type A Haemagglutinin Complex Next Generation (BTX-A-HAC NG) in Glabellar Lines

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	BTX-A-HAC Solution 50 U - DB Period n=126 Participants During the DB period, subjects were randomised to receive a single treatment of BTX-A-HAC solution 50 U. 50 U (0.25 mL) BTX-A-HAC was administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive further BTX-A-HAC treatment.	Placebo -DB Period n=64 Participants During the DB period, subjects were randomised to receive a single treatment of placebo. 0.25 mL placebo was administered as five injections of 0.05 mL each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive BTX-A-HAC treatment.	BTX-A-HAC Solution 50 U - LT Analyses de Novo Subjects n=410 Participants Additional BTX-naïve (de novo) subjects were enrolled into the OL period to receive treatment with BTX-A-HAC during OL Cycle 1, and if eligible for retreatment de novo subjects received retreatment in OL Cycles 2 to 5. Each treatment cycle included a single treatment with 50 U (0.25 mL) BTX-A-HAC administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region, and treatments were separated by at least 12 weeks.	Total n=600 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	123 Participants n=5 Participants	64 Participants n=7 Participants	401 Participants n=5 Participants	588 Participants n=4 Participants
Age, Categorical >=65 years	3 Participants n=5 Participants	0 Participants n=7 Participants	9 Participants n=5 Participants	12 Participants n=4 Participants
Sex: Female, Male Female	115 Participants n=5 Participants	58 Participants n=7 Participants	360 Participants n=5 Participants	533 Participants n=4 Participants
Sex: Female, Male Male	11 Participants n=5 Participants	6 Participants n=7 Participants	50 Participants n=5 Participants	67 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) White	125 Participants n=5 Participants	64 Participants n=7 Participants	405 Participants n=5 Participants	594 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants	3 Participants n=4 Participants

PRIMARY outcome

Timeframe: Day 29 (Cycle 1)

Population: The modified intent-to-treat (mITT) population which consisted of all subjects who were randomised, received study treatment (BTX-A-HAC solution or placebo) and completed one post-treatment assessment of the ILA of glabellar lines at maximum frown.

Outcome measures

Outcome measures
Measure	BTX-A-HAC Solution 50 U - DB Period n=124 Participants During the DB period, subjects were randomised to receive a single treatment of BTX-A-HAC solution 50 U. 50 U (0.25 mL) BTX-A-HAC was administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive further BTX-A-HAC treatment.	Placebo - DB Period n=61 Participants During the DB period, subjects were randomised to receive a single treatment of placebo. 0.25 mL placebo was administered as five injections of 0.05 mL each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive BTX-A-HAC treatment.
The Percentage of Responders at Day 29 Cycle 1 as Measured by Investigator's Live Assessment (ILA) of Glabellar Lines at Maximum Frown: DB Period	81.6 Adjusted Percentage of Responders Interval 61.3 to 92.5	0.8 Adjusted Percentage of Responders Interval 0.1 to 4.8

SECONDARY outcome

Timeframe: Days 8, 57 and 85 (Cycle 1).

Population: The mITT population which consisted of all subjects who were randomised, received study treatment (BTX-A-HAC solution or placebo) and completed one post-treatment assessment of the ILA of glabellar lines at maximum frown. Only subjects with data available at the timepoints of testing are presented.

The appearance of glabellar lines at maximum frown was assessed in the DB period at post treatment follow-up visits using the ILA, a validated 4-point photographic scale of glabellar line severity. A responder was defined as having a severity grade of none (Grade 0) or mild (Grade 1) at a given visit and a severity grade of moderate (Grade 2) or severe (Grade 3) at baseline (Day 1 Cycle 1). The adjusted percentage of responders (determined by multivariate logistic regression analysis) at Days 8, 57 and 85 of Cycle 1 is presented.

Outcome measures

Outcome measures
Measure	BTX-A-HAC Solution 50 U - DB Period n=125 Participants During the DB period, subjects were randomised to receive a single treatment of BTX-A-HAC solution 50 U. 50 U (0.25 mL) BTX-A-HAC was administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive further BTX-A-HAC treatment.	Placebo - DB Period n=63 Participants During the DB period, subjects were randomised to receive a single treatment of placebo. 0.25 mL placebo was administered as five injections of 0.05 mL each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive BTX-A-HAC treatment.
The Percentage of Responders at Each Post-treatment Visit (Except Day 29 Cycle 1) as Measured by the ILA at Maximum Frown: DB Period Day 8	75.9 Adjusted Percentage of Responders Interval 56.7 to 88.3	0.9 Adjusted Percentage of Responders Interval 0.1 to 5.5
The Percentage of Responders at Each Post-treatment Visit (Except Day 29 Cycle 1) as Measured by the ILA at Maximum Frown: DB Period Day 57	74.7 Adjusted Percentage of Responders Interval 51.4 to 89.2	0.6 Adjusted Percentage of Responders Interval 0.1 to 4.0
The Percentage of Responders at Each Post-treatment Visit (Except Day 29 Cycle 1) as Measured by the ILA at Maximum Frown: DB Period Day 85	55.5 Adjusted Percentage of Responders Interval 35.8 to 73.5	1.8 Adjusted Percentage of Responders Interval 0.4 to 8.9

SECONDARY outcome

Timeframe: Days 29, 57 and 85 (Cycle 1).

Population: The mITT population which consisted of all subjects who were randomised, received study treatment (BTX-A-HAC solution or placebo) and completed one post-treatment assessment of the ILA of glabellar lines at maximum frown. Only responders on Day 29 (n=107,1) and those with data available at the timepoints of testing were included in the analysis.

The appearance of glabellar lines at maximum frown was assessed in the DB period at post treatment follow-up visits using the ILA, a validated 4-point photographic scale of glabellar line severity. A responder was defined as having a severity grade of none (Grade 0) or mild (Grade 1) at a given visit and a severity grade of moderate (Grade 2) or severe (Grade 3) at baseline (Day 1 Cycle 1). The percentage of responders (unadjusted) at Day 29 of Cycle 1 who still fulfilled the criteria for a responder at Days 57 and 85 is presented.

Outcome measures

Outcome measures
Measure	BTX-A-HAC Solution 50 U - DB Period n=107 Participants During the DB period, subjects were randomised to receive a single treatment of BTX-A-HAC solution 50 U. 50 U (0.25 mL) BTX-A-HAC was administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive further BTX-A-HAC treatment.	Placebo - DB Period n=1 Participants During the DB period, subjects were randomised to receive a single treatment of placebo. 0.25 mL placebo was administered as five injections of 0.05 mL each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive BTX-A-HAC treatment.
The Percentage of Responders on Day 29 Cycle 1 Who Remained Responders on Days 57 and 85 as Measured by the ILA at Maximum Frown: DB Period Day 57	87.7 Percentage of Responders Interval 81.5 to 94.0	100.0 Percentage of Responders Interval 100.0 to 100.0
The Percentage of Responders on Day 29 Cycle 1 Who Remained Responders on Days 57 and 85 as Measured by the ILA at Maximum Frown: DB Period Day 85	63.2 Percentage of Responders Interval 54.0 to 72.4	0 Percentage of Responders Interval 0.0 to 0.0

SECONDARY outcome

Timeframe: Days 8, 29, 57 and 85 (Cycle 1).

The appearance of glabellar lines at rest was assessed in the DB period at post treatment follow-up visits using the ILA, a validated 4-point photographic scale of glabellar line severity. A responder was defined as having a severity grade of none (Grade 0) or mild (Grade 1) at a given visit and a severity grade of moderate (Grade 2) or severe (Grade 3) at baseline (Day 1 Cycle 1). The adjusted percentage of responders (determined by multivariate logistic regression analysis) at Days 8, 29, 57 and 85 of Cycle 1 is presented.

Outcome measures

Outcome measures
Measure	BTX-A-HAC Solution 50 U - DB Period n=125 Participants During the DB period, subjects were randomised to receive a single treatment of BTX-A-HAC solution 50 U. 50 U (0.25 mL) BTX-A-HAC was administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive further BTX-A-HAC treatment.	Placebo - DB Period n=63 Participants During the DB period, subjects were randomised to receive a single treatment of placebo. 0.25 mL placebo was administered as five injections of 0.05 mL each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive BTX-A-HAC treatment.
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Rest: DB Period Day 8	69.4 Adjusted Percentage of Responders Interval 49.2 to 84.2	11.4 Adjusted Percentage of Responders Interval 3.9 to 29.0
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Rest: DB Period Day 29	62.2 Adjusted Percentage of Responders Interval 39.0 to 80.9	5.4 Adjusted Percentage of Responders Interval 1.4 to 18.5
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Rest: DB Period Day 57	63.1 Adjusted Percentage of Responders Interval 35.2 to 84.4	0.6 Adjusted Percentage of Responders Interval 0.0 to 8.2
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Rest: DB Period Day 85	49.5 Adjusted Percentage of Responders Interval 29.0 to 70.1	6.8 Adjusted Percentage of Responders Interval 1.9 to 22.0

SECONDARY outcome

Timeframe: Days 8, 29, 57 and 85 (Cycle 1).

The appearance of glabellar lines at maximum frown was assessed using the SSA, a validated 4-point categorical scale of glabellar line severity, in the DB period at post-treatment follow-up visits. A responder was defined as having a severity grade of no wrinkles (Grade 0) or mild wrinkles (Grade 1) at maximum frown at a given visit and a severity grade of moderate (Grade 2) or severe (Grade 3) wrinkles at baseline (Day 1 Cycle 1). The adjusted percentage of responders (determined by multivariate logistic regression analysis) at Days 8, 29, 57 and 85 of Cycle 1 is presented.

Outcome measures

Outcome measures
Measure	BTX-A-HAC Solution 50 U - DB Period n=125 Participants During the DB period, subjects were randomised to receive a single treatment of BTX-A-HAC solution 50 U. 50 U (0.25 mL) BTX-A-HAC was administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive further BTX-A-HAC treatment.	Placebo - DB Period n=63 Participants During the DB period, subjects were randomised to receive a single treatment of placebo. 0.25 mL placebo was administered as five injections of 0.05 mL each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive BTX-A-HAC treatment.
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Self-Assessment (SSA) at Maximum Frown: DB Period Day 8	63.5 Adjusted Percentage of Responders Interval 44.0 to 79.3	2.3 Adjusted Percentage of Responders Interval 0.6 to 9.1
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Self-Assessment (SSA) at Maximum Frown: DB Period Day 29	68.1 Adjusted Percentage of Responders Interval 48.4 to 82.9	2.3 Adjusted Percentage of Responders Interval 0.6 to 8.5
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Self-Assessment (SSA) at Maximum Frown: DB Period Day 57	71.2 Adjusted Percentage of Responders Interval 51.2 to 85.3	0.7 Adjusted Percentage of Responders Interval 0.1 to 6.8
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Self-Assessment (SSA) at Maximum Frown: DB Period Day 85	34.7 Adjusted Percentage of Responders Interval 18.5 to 55.4	1.7 Adjusted Percentage of Responders Interval 0.3 to 8.0

SECONDARY outcome

Timeframe: Days 8, 29, 57 and 85 (Cycle 1).

The subject's level of satisfaction with the appearance of their glabellar lines was assessed in the DB period at post-treatment follow-up visits using a 4-point categorical scale. A responder was defined as having a satisfaction rating of very satisfied (Grade 0) or satisfied (Grade 1) at a given visit and a satisfaction rating of dissatisfied (Grade 2) or very dissatisfied (Grade 3) at baseline (Day 1 Cycle 1). The adjusted percentage of responders (determined by multivariate logistic regression analysis) at Days 8, 29, 57 and 85 of Cycle 1 is presented.

Outcome measures

Outcome measures
Measure	BTX-A-HAC Solution 50 U - DB Period n=125 Participants During the DB period, subjects were randomised to receive a single treatment of BTX-A-HAC solution 50 U. 50 U (0.25 mL) BTX-A-HAC was administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive further BTX-A-HAC treatment.	Placebo - DB Period n=63 Participants During the DB period, subjects were randomised to receive a single treatment of placebo. 0.25 mL placebo was administered as five injections of 0.05 mL each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive BTX-A-HAC treatment.
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Level of Satisfaction With the Appearance of Their Glabellar Lines: DB Period Day 8	76.3 Adjusted Percentage of Responders Interval 59.3 to 87.6	8.1 Adjusted Percentage of Responders Interval 3.0 to 19.7
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Level of Satisfaction With the Appearance of Their Glabellar Lines: DB Period Day 29	83.1 Adjusted Percentage of Responders Interval 67.3 to 92.1	5.7 Adjusted Percentage of Responders Interval 1.9 to 15.7
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Level of Satisfaction With the Appearance of Their Glabellar Lines: DB Period Day 57	77.9 Adjusted Percentage of Responders Interval 60.0 to 89.2	3.5 Adjusted Percentage of Responders Interval 1.0 to 11.9
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Level of Satisfaction With the Appearance of Their Glabellar Lines: DB Period Day 85	51.3 Adjusted Percentage of Responders Interval 30.7 to 71.4	0.3 Adjusted Percentage of Responders Interval 0.0 to 4.2

SECONDARY outcome

Timeframe: Days 1 to 7 (Cycle 1).

Subjects were asked to record their assessment of study treatment response on a diary card on Days 1 to 7 at approximately the same time each day. Subjects were asked to respond 'yes' or 'no' to the following question: 'Since being injected have you noticed an improvement in the appearance of your glabellar lines (lines between your eyebrows)?' The time to onset of response was defined as the first day the subject responded 'yes' to this question.

Outcome measures

Outcome measures
Measure	BTX-A-HAC Solution 50 U - DB Period n=125 Participants During the DB period, subjects were randomised to receive a single treatment of BTX-A-HAC solution 50 U. 50 U (0.25 mL) BTX-A-HAC was administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive further BTX-A-HAC treatment.	Placebo - DB Period n=63 Participants During the DB period, subjects were randomised to receive a single treatment of placebo. 0.25 mL placebo was administered as five injections of 0.05 mL each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive BTX-A-HAC treatment.
The Median Time to Onset of Treatment Response Based on the Subject's Diary Card: DB Period	2.0 Days Interval 2.0 to 3.0	NA Days The median was not calculable due to the small number of responders.

SECONDARY outcome

Timeframe: Baseline (Day 1) and Days 8, 29, 57 and 85 (Cycle 1).

FACE-Q is a subject-reported outcome instrument to evaluate the experience and outcomes of aesthetic facial procedures from the subject's perspective. One of three scales that was selected for this study was the satisfaction with facial appearance overall scale. This consisted of 10 items with 4 possible answers for each: 1 (Very Dissatisfied), 2 (Somewhat Dissatisfied), 3 (Somewhat Satisfied) and 4 (Very Satisfied). The least squares mean change from baseline at post-treatment visits of Rasch transformed scores is presented. The Rasch transformed score was calculated by adding the 10 items (scored from 1 to 4) and converting the score to a scale from 0 (most dissatisfied) to 100 (most satisfied) using a conversion table.

Outcome measures

Outcome measures
Measure	BTX-A-HAC Solution 50 U - DB Period n=125 Participants During the DB period, subjects were randomised to receive a single treatment of BTX-A-HAC solution 50 U. 50 U (0.25 mL) BTX-A-HAC was administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive further BTX-A-HAC treatment.	Placebo - DB Period n=63 Participants During the DB period, subjects were randomised to receive a single treatment of placebo. 0.25 mL placebo was administered as five injections of 0.05 mL each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive BTX-A-HAC treatment.
Change From Baseline at All Post-treatment Visits in the FACE-Q Satisfaction With Facial Appearance Overall Scale: DB Period Day 29	8.1 Scores on a Scale Standard Error 1.90	-3.0 Scores on a Scale Standard Error 2.12
Change From Baseline at All Post-treatment Visits in the FACE-Q Satisfaction With Facial Appearance Overall Scale: DB Period Day 8	9.4 Scores on a Scale Standard Error 1.72	0.8 Scores on a Scale Standard Error 1.93
Change From Baseline at All Post-treatment Visits in the FACE-Q Satisfaction With Facial Appearance Overall Scale: DB Period Day 57	11.2 Scores on a Scale Standard Error 1.83	0.7 Scores on a Scale Standard Error 2.03
Change From Baseline at All Post-treatment Visits in the FACE-Q Satisfaction With Facial Appearance Overall Scale: DB Period Day 85	4.7 Scores on a Scale Standard Error 1.91	-5.0 Scores on a Scale Standard Error 2.15

SECONDARY outcome

Timeframe: Baseline (Day 1) and Days 8, 29, 57 and 85 (Cycle 1).

FACE-Q is a subject-reported outcome instrument to evaluate the experience and outcomes of aesthetic facial procedures from the subject's perspective. One of three scales that was selected for this study was the psychological well-being scale. This consisted of 10 items with 4 possible answers for each: 1 (Definitely disagree), 2 (Somewhat disagree), 3 (Somewhat agree) and 4 (Definitely agree). The least squares mean change from baseline at post-treatment visits of Rasch transformed scores is presented. The Rasch transformed score was calculated by adding the 10 items (scored from 1 to 4) and converting the score to a scale from 0 (worst) to 100 (best) using a conversion table.

Outcome measures

Outcome measures
Measure	BTX-A-HAC Solution 50 U - DB Period n=125 Participants During the DB period, subjects were randomised to receive a single treatment of BTX-A-HAC solution 50 U. 50 U (0.25 mL) BTX-A-HAC was administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive further BTX-A-HAC treatment.	Placebo - DB Period n=63 Participants During the DB period, subjects were randomised to receive a single treatment of placebo. 0.25 mL placebo was administered as five injections of 0.05 mL each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive BTX-A-HAC treatment.
Change From Baseline at All Post-treatment Visits in the FACE-Q Psychological Well-being Scale: DB Period Day 8	6.6 Scores on a Scale Standard Error 2.19	-2.7 Scores on a Scale Standard Error 2.46
Change From Baseline at All Post-treatment Visits in the FACE-Q Psychological Well-being Scale: DB Period Day 29	4.5 Scores on a Scale Standard Error 2.39	-6.9 Scores on a Scale Standard Error 2.66
Change From Baseline at All Post-treatment Visits in the FACE-Q Psychological Well-being Scale: DB Period Day 57	6.1 Scores on a Scale Standard Error 2.41	-5.1 Scores on a Scale Standard Error 2.69
Change From Baseline at All Post-treatment Visits in the FACE-Q Psychological Well-being Scale: DB Period Day 85	0.7 Scores on a Scale Standard Error 2.28	-7.5 Scores on a Scale Standard Error 2.57

SECONDARY outcome

Timeframe: Baseline (Day 1) and Days 8, 29, 57 and 85 (Cycle 1).

FACE-Q is a subject-reported outcome instrument to evaluate the experience and outcomes of aesthetic facial procedures from the subject's perspective. One of three scales that was selected for this study was the aging appearance appraisal VAS. The VAS ranged from -15 ('I look 15 years younger') to +15 ('I look 15 years older'), with 0 indicating 'I look my age'. Subjects were asked to circle one number on the VAS indicating how many years younger or older they thought they looked compared to their actual age, with lower scores indicating a better outcome and higher scores a worse outcome. The least squares mean change from baseline at post-treatment visits is presented.

Outcome measures

Outcome measures
Measure	BTX-A-HAC Solution 50 U - DB Period n=125 Participants During the DB period, subjects were randomised to receive a single treatment of BTX-A-HAC solution 50 U. 50 U (0.25 mL) BTX-A-HAC was administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive further BTX-A-HAC treatment.	Placebo - DB Period n=63 Participants During the DB period, subjects were randomised to receive a single treatment of placebo. 0.25 mL placebo was administered as five injections of 0.05 mL each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive BTX-A-HAC treatment.
Change From Baseline at All Post-treatment Visits in the FACE-Q Aging Appearance Appraisal Visual Analogue Scale (VAS): DB Period Day 85	-0.4 Scores on a Scale Standard Error 0.31	1.1 Scores on a Scale Standard Error 0.36
Change From Baseline at All Post-treatment Visits in the FACE-Q Aging Appearance Appraisal Visual Analogue Scale (VAS): DB Period Day 8	-0.8 Scores on a Scale Standard Error 0.25	-0.2 Scores on a Scale Standard Error 0.28
Change From Baseline at All Post-treatment Visits in the FACE-Q Aging Appearance Appraisal Visual Analogue Scale (VAS): DB Period Day 29	-0.8 Scores on a Scale Standard Error 0.28	0.3 Scores on a Scale Standard Error 0.32
Change From Baseline at All Post-treatment Visits in the FACE-Q Aging Appearance Appraisal Visual Analogue Scale (VAS): DB Period Day 57	-0.6 Scores on a Scale Standard Error 0.34	0.7 Scores on a Scale Standard Error 0.39

SECONDARY outcome

Timeframe: Days 8, 29, 57 and 85 of Cycles 1 - 5 (up to 15 months).

Population: The LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period. Only subjects with data available at the timepoints of testing are presented.

The appearance of glabellar lines at maximum frown was assessed in the OL period at post-treatment follow-up visits using the ILA, a validated 4-point photographic scale of glabellar line severity. A responder was defined as having a severity grade of none (Grade 0) or mild (Grade 1) at a given visit and a severity grade of moderate (Grade 2) or severe (Grade 3) at baseline. The cycle baseline was defined as the last measurement collected prior to the study treatment injection of the corresponding cycle. The percentage of responders (unadjusted) at each post-treatment visit for Cycles 1 to 5 is presented. Cycle 1 corresponds to the first administration of BTX-A-HAC solution and includes the DB Cycle 1 of subjects who were treated with BTX-A-HAC solution, the Cycle 1 of de novo subjects and Cycle 2 of subjects who were randomised to receive placebo in the DB period.

Outcome measures

Outcome measures
Measure	BTX-A-HAC Solution 50 U - DB Period n=595 Participants During the DB period, subjects were randomised to receive a single treatment of BTX-A-HAC solution 50 U. 50 U (0.25 mL) BTX-A-HAC was administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive further BTX-A-HAC treatment.	Placebo - DB Period During the DB period, subjects were randomised to receive a single treatment of placebo. 0.25 mL placebo was administered as five injections of 0.05 mL each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive BTX-A-HAC treatment.
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Maximum Frown: LT Analyses Cycle 1: Day 8	75.7 Percentage of Responders Interval 72.3 to 79.2	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Maximum Frown: LT Analyses Cycle 1: Day 29	82.2 Percentage of Responders Interval 79.1 to 85.3	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Maximum Frown: LT Analyses Cycle 1: Day 57	69.9 Percentage of Responders Interval 66.2 to 73.7	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Maximum Frown: LT Analyses Cycle 1: Day 85	53.0 Percentage of Responders Interval 49.0 to 57.1	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Maximum Frown: LT Analyses Cycle 2: Day 8	80.8 Percentage of Responders Interval 77.6 to 84.1	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Maximum Frown: LT Analyses Cycle 2: Day 29	84.5 Percentage of Responders Interval 81.4 to 87.5	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Maximum Frown: LT Analyses Cycle 2: Day 57	74.3 Percentage of Responders Interval 70.6 to 77.9	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Maximum Frown: LT Analyses Cycle 2: Day 85	53.7 Percentage of Responders Interval 49.5 to 57.9	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Maximum Frown: LT Analyses Cycle 3: Day 8	86.5 Percentage of Responders Interval 83.5 to 89.6	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Maximum Frown: LT Analyses Cycle 3: Day 29	87.8 Percentage of Responders Interval 84.9 to 90.8	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Maximum Frown: LT Analyses Cycle 3: Day 57	78.6 Percentage of Responders Interval 74.9 to 82.3	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Maximum Frown: LT Analyses Cycle 3: Day 85	56.8 Percentage of Responders Interval 52.3 to 61.2	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Maximum Frown: LT Analyses Cycle 4: Day 8	84.3 Percentage of Responders Interval 80.3 to 88.3	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Maximum Frown: LT Analyses Cycle 4: Day 29	86.1 Percentage of Responders Interval 82.3 to 90.0	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Maximum Frown: LT Analyses Cycle 4: Day 57	76.1 Percentage of Responders Interval 71.4 to 80.9	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Maximum Frown: LT Analyses Cycle 4: Day 85	50.7 Percentage of Responders Interval 45.0 to 56.3	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Maximum Frown: LT Analyses Cycle 5: Day 8	84.1 Percentage of Responders Interval 76.4 to 91.7	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Maximum Frown: LT Analyses Cycle 5: Day 29	82.8 Percentage of Responders Interval 74.8 to 90.7	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Maximum Frown: LT Analyses Cycle 5: Day 57	55.8 Percentage of Responders Interval 45.3 to 66.3	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Maximum Frown: LT Analyses Cycle 5: Day 85	45.3 Percentage of Responders Interval 34.8 to 55.9	—

SECONDARY outcome

Timeframe: Days 8, 29, 57 and 85 of Cycles 1 - 5 (up to 15 months).

The appearance of glabellar lines at rest was assessed in the OL period at post-treatment follow-up visits using the ILA, a validated 4-point photographic scale of glabellar line severity. A responder was defined as having a severity grade of none (Grade 0) or mild (Grade 1) at a given visit and a severity grade of moderate (Grade 2) or severe (Grade 3) at baseline. The cycle baseline was defined as the last measurement collected prior to the study treatment injection of the corresponding cycle. The percentage of responders (unadjusted) at each post-treatment visit for Cycles 1 to 5 is presented. Cycle 1 corresponds to the first administration of BTX-A-HAC solution and includes the DB Cycle 1 of subjects who were treated with BTX-A-HAC solution, the Cycle 1 of de novo subjects and Cycle 2 of subjects who were randomised to receive placebo in the DB period.

Outcome measures

Outcome measures
Measure	BTX-A-HAC Solution 50 U - DB Period n=595 Participants During the DB period, subjects were randomised to receive a single treatment of BTX-A-HAC solution 50 U. 50 U (0.25 mL) BTX-A-HAC was administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive further BTX-A-HAC treatment.	Placebo - DB Period During the DB period, subjects were randomised to receive a single treatment of placebo. 0.25 mL placebo was administered as five injections of 0.05 mL each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive BTX-A-HAC treatment.
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Rest: LT Analyses Cycle 1: Day 8	74.1 Percentage of Responders Interval 69.7 to 78.6	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Rest: LT Analyses Cycle 1: Day 29	81.7 Percentage of Responders Interval 77.8 to 85.6	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Rest: LT Analyses Cycle 1: Day 57	77.3 Percentage of Responders Interval 73.0 to 81.6	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Rest: LT Analyses Cycle 1: Day 85	61.1 Percentage of Responders Interval 56.2 to 66.1	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Rest: LT Analyses Cycle 2: Day 8	74.5 Percentage of Responders Interval 68.9 to 80.0	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Rest: LT Analyses Cycle 2: Day 29	78.4 Percentage of Responders Interval 73.1 to 83.6	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Rest: LT Analyses Cycle 2: Day 57	71.4 Percentage of Responders Interval 65.6 to 77.2	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Rest: LT Analyses Cycle 2: Day 85	47.9 Percentage of Responders Interval 41.5 to 54.3	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Rest: LT Analyses Cycle 3: Day 8	82.2 Percentage of Responders Interval 76.9 to 87.5	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Rest: LT Analyses Cycle 3: Day 29	84.2 Percentage of Responders Interval 79.1 to 89.3	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Rest: LT Analyses Cycle 3: Day 57	80.0 Percentage of Responders Interval 74.4 to 85.6	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Rest: LT Analyses Cycle 3: Day 85	58.7 Percentage of Responders Interval 51.8 to 65.6	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Rest: LT Analyses Cycle 4: Day 8	77.6 Percentage of Responders Interval 70.6 to 84.7	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Rest: LT Analyses Cycle 4: Day 29	81.3 Percentage of Responders Interval 74.7 to 87.9	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Rest: LT Analyses Cycle 4: Day 57	78.9 Percentage of Responders Interval 72.0 to 85.9	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Rest: LT Analyses Cycle 4: Day 85	59.5 Percentage of Responders Interval 51.1 to 67.9	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Rest: LT Analyses Cycle 5: Day 8	85.7 Percentage of Responders Interval 75.1 to 96.3	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Rest: LT Analyses Cycle 5: Day 29	78.0 Percentage of Responders Interval 65.4 to 90.7	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Rest: LT Analyses Cycle 5: Day 57	63.4 Percentage of Responders Interval 48.7 to 78.2	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the ILA at Rest: LT Analyses Cycle 5: Day 85	56.1 Percentage of Responders Interval 40.9 to 71.3	—

SECONDARY outcome

Timeframe: Days 8, 29, 57 and 85 of Cycles 1 - 5 (up to 15 months).

The appearance of glabellar lines at maximum frown was assessed using the SSA, a validated 4-point categorical scale of glabellar line severity, in the OL period at post-treatment follow-up visits. A responder was defined as having a severity grade of no wrinkles (Grade 0) or mild wrinkles (Grade 1) at maximum frown at a given visit and a severity grade of moderate (Grade 2) or severe (Grade 3) wrinkles at baseline. The cycle baseline was defined as the last measurement collected prior to the study treatment injection of the corresponding cycle. The percentage of responders (unadjusted) at each post-treatment visit for Cycles 1 to 5 is presented. Cycle 1 corresponds to the first administration of BTX-A-HAC solution and includes the DB Cycle 1 of subjects who were treated with BTX-A-HAC solution, the Cycle 1 of de novo subjects and Cycle 2 of subjects who were randomised to receive placebo in the DB period.

Outcome measures

Outcome measures
Measure	BTX-A-HAC Solution 50 U - DB Period n=595 Participants During the DB period, subjects were randomised to receive a single treatment of BTX-A-HAC solution 50 U. 50 U (0.25 mL) BTX-A-HAC was administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive further BTX-A-HAC treatment.	Placebo - DB Period During the DB period, subjects were randomised to receive a single treatment of placebo. 0.25 mL placebo was administered as five injections of 0.05 mL each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive BTX-A-HAC treatment.
The Percentage of Responders at Each Post-treatment Visit as Measured by the SSA at Maximum Frown: LT Analyses Cycle 1: Day 8	62.8 Percentage of Responders Interval 58.9 to 66.7	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the SSA at Maximum Frown: LT Analyses Cycle 1: Day 29	72.5 Percentage of Responders Interval 68.9 to 76.1	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the SSA at Maximum Frown: LT Analyses Cycle 1: Day 57	64.3 Percentage of Responders Interval 60.4 to 68.3	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the SSA at Maximum Frown: LT Analyses Cycle 1: Day 85	43.6 Percentage of Responders Interval 39.6 to 47.6	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the SSA at Maximum Frown: LT Analyses Cycle 2: Day 8	74.8 Percentage of Responders Interval 71.1 to 78.5	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the SSA at Maximum Frown: LT Analyses Cycle 2: Day 29	75.3 Percentage of Responders Interval 71.6 to 79.0	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the SSA at Maximum Frown: LT Analyses Cycle 2: Day 57	69.3 Percentage of Responders Interval 65.3 to 73.3	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the SSA at Maximum Frown: LT Analyses Cycle 2: Day 85	44.3 Percentage of Responders Interval 40.0 to 48.6	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the SSA at Maximum Frown: LT Analyses Cycle 3: Day 8	78.8 Percentage of Responders Interval 75.1 to 82.5	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the SSA at Maximum Frown: LT Analyses Cycle 3: Day 29	80.6 Percentage of Responders Interval 77.0 to 84.2	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the SSA at Maximum Frown: LT Analyses Cycle 3: Day 57	67.1 Percentage of Responders Interval 62.8 to 71.4	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the SSA at Maximum Frown: LT Analyses Cycle 3: Day 85	44.9 Percentage of Responders Interval 40.4 to 49.5	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the SSA at Maximum Frown: LT Analyses Cycle 4: Day 8	80.3 Percentage of Responders Interval 75.9 to 84.7	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the SSA at Maximum Frown: LT Analyses Cycle 4: Day 29	75.2 Percentage of Responders Interval 70.4 to 80.1	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the SSA at Maximum Frown: LT Analyses Cycle 4: Day 57	66.1 Percentage of Responders Interval 60.8 to 71.4	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the SSA at Maximum Frown: LT Analyses Cycle 4: Day 85	47.3 Percentage of Responders Interval 41.7 to 53.0	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the SSA at Maximum Frown: LT Analyses Cycle 5: Day 8	66.7 Percentage of Responders Interval 56.8 to 76.6	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the SSA at Maximum Frown: LT Analyses Cycle 5: Day 29	62.8 Percentage of Responders Interval 52.6 to 73.0	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the SSA at Maximum Frown: LT Analyses Cycle 5: Day 57	49.4 Percentage of Responders Interval 38.8 to 60.0	—
The Percentage of Responders at Each Post-treatment Visit as Measured by the SSA at Maximum Frown: LT Analyses Cycle 5: Day 85	37.6 Percentage of Responders Interval 27.3 to 47.9	—

SECONDARY outcome

Timeframe: Days 8, 29, 57 and 85 of Cycles 1 - 5 (up to 15 months).

The subject's level of satisfaction with the appearance of their glabellar lines was assessed in the OL period at post-treatment follow-up visits of each treatment cycle using a 4-point categorical scale. A responder was defined as having a satisfaction rating of very satisfied (Grade 0) or satisfied (Grade 1) at a given visit and a satisfaction rating of dissatisfied (Grade 2) or very dissatisfied (Grade 3) at baseline. The cycle baseline was defined as the last measurement collected prior to the study treatment injection of the corresponding cycle. The percentage of responders (unadjusted) at each post-treatment visit for Cycles 1 to 5 is presented. Cycle 1 corresponds to the first administration of BTX-A-HAC solution and includes the DB Cycle 1 of subjects who were treated with BTX-A-HAC solution, the Cycle 1 of de novo subjects and Cycle 2 of subjects who were randomised to receive placebo in the DB period.

Outcome measures

Outcome measures
Measure	BTX-A-HAC Solution 50 U - DB Period n=595 Participants During the DB period, subjects were randomised to receive a single treatment of BTX-A-HAC solution 50 U. 50 U (0.25 mL) BTX-A-HAC was administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive further BTX-A-HAC treatment.	Placebo - DB Period During the DB period, subjects were randomised to receive a single treatment of placebo. 0.25 mL placebo was administered as five injections of 0.05 mL each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive BTX-A-HAC treatment.
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Level of Satisfaction With the Appearance of Their Glabellar Lines: LT Analyses Cycle 1: Day 8	78.8 Percentage of Responders Interval 75.5 to 82.1	—
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Level of Satisfaction With the Appearance of Their Glabellar Lines: LT Analyses Cycle 1: Day 29	86.0 Percentage of Responders Interval 83.2 to 88.8	—
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Level of Satisfaction With the Appearance of Their Glabellar Lines: LT Analyses Cycle 1: Day 57	75.8 Percentage of Responders Interval 72.3 to 79.3	—
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Level of Satisfaction With the Appearance of Their Glabellar Lines: LT Analyses Cycle 1: Day 85	56.3 Percentage of Responders Interval 52.3 to 60.3	—
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Level of Satisfaction With the Appearance of Their Glabellar Lines: LT Analyses Cycle 2: Day 8	80.8 Percentage of Responders Interval 77.2 to 84.5	—
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Level of Satisfaction With the Appearance of Their Glabellar Lines: LT Analyses Cycle 2: Day 29	85.2 Percentage of Responders Interval 81.9 to 88.5	—
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Level of Satisfaction With the Appearance of Their Glabellar Lines: LT Analyses Cycle 2: Day 57	79.0 Percentage of Responders Interval 75.2 to 82.8	—
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Level of Satisfaction With the Appearance of Their Glabellar Lines: LT Analyses Cycle 2: Day 85	51.8 Percentage of Responders Interval 47.2 to 56.4	—
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Level of Satisfaction With the Appearance of Their Glabellar Lines: LT Analyses Cycle 3: Day 8	88.3 Percentage of Responders Interval 85.1 to 91.4	—
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Level of Satisfaction With the Appearance of Their Glabellar Lines: LT Analyses Cycle 3: Day 29	87.8 Percentage of Responders Interval 84.6 to 91.1	—
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Level of Satisfaction With the Appearance of Their Glabellar Lines: LT Analyses Cycle 3: Day 57	80.6 Percentage of Responders Interval 76.6 to 84.5	—
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Level of Satisfaction With the Appearance of Their Glabellar Lines: LT Analyses Cycle 3: Day 85	54.6 Percentage of Responders Interval 49.7 to 59.5	—
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Level of Satisfaction With the Appearance of Their Glabellar Lines: LT Analyses Cycle 4: Day 8	87.1 Percentage of Responders Interval 83.0 to 91.1	—
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Level of Satisfaction With the Appearance of Their Glabellar Lines: LT Analyses Cycle 4: Day 29	87.3 Percentage of Responders Interval 83.3 to 91.4	—
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Level of Satisfaction With the Appearance of Their Glabellar Lines: LT Analyses Cycle 4: Day 57	74.3 Percentage of Responders Interval 69.0 to 79.7	—
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Level of Satisfaction With the Appearance of Their Glabellar Lines: LT Analyses Cycle 4: Day 85	58.3 Percentage of Responders Interval 52.2 to 64.3	—
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Level of Satisfaction With the Appearance of Their Glabellar Lines: LT Analyses Cycle 5: Day 8	74.0 Percentage of Responders Interval 63.9 to 84.0	—
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Level of Satisfaction With the Appearance of Their Glabellar Lines: LT Analyses Cycle 5: Day 29	72.2 Percentage of Responders Interval 61.9 to 82.6	—
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Level of Satisfaction With the Appearance of Their Glabellar Lines: LT Analyses Cycle 5: Day 57	60.6 Percentage of Responders Interval 49.2 to 71.9	—
The Percentage of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Level of Satisfaction With the Appearance of Their Glabellar Lines: LT Analyses Cycle 5: Day 85	44.3 Percentage of Responders Interval 32.6 to 55.9	—

SECONDARY outcome

Timeframe: Cycles 1 - 4 (up to 12 months).

The median time to onset of the next eligible treatment cycle is presented for Cycles 1 to 4. Cycle 1 corresponds to the first administration of BTX-A-HAC solution and includes the DB Cycle 1 of subjects who were treated with BTX-A-HAC solution, the Cycle 1 of de novo subjects and Cycle 2 of subjects who were randomised to receive placebo in the DB period. Subjects who were not subsequently retreated after a given cycle were excluded from the summary of time to retreatment at that cycle.

Outcome measures

Outcome measures
Measure	BTX-A-HAC Solution 50 U - DB Period n=595 Participants During the DB period, subjects were randomised to receive a single treatment of BTX-A-HAC solution 50 U. 50 U (0.25 mL) BTX-A-HAC was administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive further BTX-A-HAC treatment.	Placebo - DB Period During the DB period, subjects were randomised to receive a single treatment of placebo. 0.25 mL placebo was administered as five injections of 0.05 mL each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive BTX-A-HAC treatment.
Median Time to Retreatment in LT Analysis Cycle 1	113.0 Days Interval 113.0 to 116.0	—
Median Time to Retreatment in LT Analysis Cycle 2	114.0 Days Interval 113.0 to 117.0	—
Median Time to Retreatment in LT Analysis Cycle 3	110.0 Days Interval 106.0 to 113.0	—
Median Time to Retreatment in LT Analysis Cycle 4	99.0 Days Interval 92.0 to 110.0	—

SECONDARY outcome

Timeframe: Days 8, 29, 57 and 85 of Cycles 1 to 3; Days 8, 29 and 85 of Cycles 4 and 5.

FACE-Q is a subject-reported outcome instrument to evaluate the experience and outcomes of aesthetic facial procedures from the subject's perspective. One of three scales that was selected for this study was the satisfaction with facial appearance overall scale. This consisted of 10 items with 4 possible answers for each: 1 (Very Dissatisfied), 2 (Somewhat Dissatisfied), 3 (Somewhat Satisfied) and 4 (Very Satisfied). The mean change from baseline at post-treatment visits of Rasch transformed scores is presented. The Rasch transformed score was calculated by adding the 10 items (scored from 1 to 4) and converting the score to a scale from 0 (most dissatisfied) to 100 (most satisfied) using a conversion table.

Outcome measures

Outcome measures
Measure	BTX-A-HAC Solution 50 U - DB Period n=595 Participants During the DB period, subjects were randomised to receive a single treatment of BTX-A-HAC solution 50 U. 50 U (0.25 mL) BTX-A-HAC was administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive further BTX-A-HAC treatment.	Placebo - DB Period During the DB period, subjects were randomised to receive a single treatment of placebo. 0.25 mL placebo was administered as five injections of 0.05 mL each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive BTX-A-HAC treatment.
Change From Baseline at All Post-treatment Visits in the FACE-Q Satisfaction With Facial Appearance Overall Scale: LT Analyses Cycle 1: Day 8	9.2 Scores on a Scale Standard Deviation 14.5	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Satisfaction With Facial Appearance Overall Scale: LT Analyses Cycle 1: Day 29	10.9 Scores on a Scale Standard Deviation 15.9	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Satisfaction With Facial Appearance Overall Scale: LT Analyses Cycle 1: Day 57	9.9 Scores on a Scale Standard Deviation 15.4	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Satisfaction With Facial Appearance Overall Scale: LT Analyses Cycle 1: Day 85	6.6 Scores on a Scale Standard Deviation 14.7	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Satisfaction With Facial Appearance Overall Scale: LT Analyses Cycle 2: Day 8	9.5 Scores on a Scale Standard Deviation 14.6	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Satisfaction With Facial Appearance Overall Scale: LT Analyses Cycle 2: Day 29	9.7 Scores on a Scale Standard Deviation 15.1	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Satisfaction With Facial Appearance Overall Scale: LT Analyses Cycle 2: Day 57	0.0 Scores on a Scale Standard Deviation 0.0	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Satisfaction With Facial Appearance Overall Scale: LT Analyses Cycle 2: Day 85	4.8 Scores on a Scale Standard Deviation 12.3	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Satisfaction With Facial Appearance Overall Scale: LT Analyses Cycle 3: Day 8	10.9 Scores on a Scale Standard Deviation 15.0	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Satisfaction With Facial Appearance Overall Scale: LT Analyses Cycle 3: Day 29	9.9 Scores on a Scale Standard Deviation 15.1	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Satisfaction With Facial Appearance Overall Scale: LT Analyses Cycle 3: Day 57	6.0 Scores on a Scale Standard Deviation 4.6	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Satisfaction With Facial Appearance Overall Scale: LT Analyses Cycle 3: Day 85	5.0 Scores on a Scale Standard Deviation 12.7	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Satisfaction With Facial Appearance Overall Scale: LT Analyses Cycle 4: Day 8	11.2 Scores on a Scale Standard Deviation 14.3	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Satisfaction With Facial Appearance Overall Scale: LT Analyses Cycle 4: Day 29	9.9 Scores on a Scale Standard Deviation 13.8	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Satisfaction With Facial Appearance Overall Scale: LT Analyses Cycle 4: Day 85	5.6 Scores on a Scale Standard Deviation 11.8	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Satisfaction With Facial Appearance Overall Scale: LT Analyses Cycle 5: Day 8	12.0 Scores on a Scale Standard Deviation 18.2	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Satisfaction With Facial Appearance Overall Scale: LT Analyses Cycle 5: Day 29	9.4 Scores on a Scale Standard Deviation 17.5	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Satisfaction With Facial Appearance Overall Scale: LT Analyses Cycle 5: Day 85	5.3 Scores on a Scale Standard Deviation 10.6	—

SECONDARY outcome

Timeframe: Days 8, 29, 57 and 85 of Cycles 1 to 3; Days 8, 29 and 85 of Cycles 4 and 5.

FACE-Q is a subject-reported outcome instrument to evaluate the experience and outcomes of aesthetic facial procedures from the subject's perspective. One of three scales that was selected for this study was the psychological well-being scale. This consisted of 10 items with 4 possible answers for each: 1 (Definitely disagree), 2 (Somewhat disagree), 3 (Somewhat agree) and 4 (Definitely agree). The mean change from baseline at post-treatment visits of Rasch transformed scores is presented. The Rasch transformed score was calculated by adding the 10 items (scored from 1 to 4) and converting the score to a scale from 0 (worst) to 100 (best) using a conversion table.

Outcome measures

Outcome measures
Measure	BTX-A-HAC Solution 50 U - DB Period n=595 Participants During the DB period, subjects were randomised to receive a single treatment of BTX-A-HAC solution 50 U. 50 U (0.25 mL) BTX-A-HAC was administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive further BTX-A-HAC treatment.	Placebo - DB Period During the DB period, subjects were randomised to receive a single treatment of placebo. 0.25 mL placebo was administered as five injections of 0.05 mL each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive BTX-A-HAC treatment.
Change From Baseline at All Post-treatment Visits in the FACE-Q Psychological Well-being Scale: LT Analyses Cycle 1: Day 8	6.7 Scores on a Scale Standard Deviation 16.9	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Psychological Well-being Scale: LT Analyses Cycle 1: Day 29	7.2 Scores on a Scale Standard Deviation 19.2	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Psychological Well-being Scale: LT Analyses Cycle 1: Day 57	5.5 Scores on a Scale Standard Deviation 18.7	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Psychological Well-being Scale: LT Analyses Cycle 1: Day 85	2.7 Scores on a Scale Standard Deviation 16.9	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Psychological Well-being Scale: LT Analyses Cycle 2: Day 8	7.8 Scores on a Scale Standard Deviation 14.0	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Psychological Well-being Scale: LT Analyses Cycle 2: Day 29	8.2 Scores on a Scale Standard Deviation 15.6	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Psychological Well-being Scale: LT Analyses Cycle 2: Day 57	0.0 Scores on a Scale Standard Deviation 0.0	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Psychological Well-being Scale: LT Analyses Cycle 2: Day 85	4.6 Scores on a Scale Standard Deviation 13.6	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Psychological Well-being Scale: LT Analyses Cycle 3: Day 8	8.8 Scores on a Scale Standard Deviation 15.5	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Psychological Well-being Scale: LT Analyses Cycle 3: Day 29	9.4 Scores on a Scale Standard Deviation 15.3	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Psychological Well-being Scale: LT Analyses Cycle 3: Day 85	4.4 Scores on a Scale Standard Deviation 13.0	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Psychological Well-being Scale: LT Analyses Cycle 4: Day 8	10.1 Scores on a Scale Standard Deviation 16.0	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Psychological Well-being Scale: LT Analyses Cycle 4: Day 29	8.8 Scores on a Scale Standard Deviation 14.9	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Psychological Well-being Scale: LT Analyses Cycle 4: Day 85	6.3 Scores on a Scale Standard Deviation 13.7	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Psychological Well-being Scale: LT Analyses Cycle 5: Day 8	10.1 Scores on a Scale Standard Deviation 17.0	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Psychological Well-being Scale: LT Analyses Cycle 5: Day 29	8.4 Scores on a Scale Standard Deviation 14.4	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Psychological Well-being Scale: LT Analyses Cycle 5: Day 85	7.0 Scores on a Scale Standard Deviation 12.1	—

SECONDARY outcome

Timeframe: Days 8, 29, 57 and 85 of Cycles 1 to 3; Days 8, 29 and 85 of Cycles 4 and 5.

FACE-Q is a subject-reported outcome instrument to evaluate the experience and outcomes of aesthetic facial procedures from the subject's perspective. One of three scales that was selected for this study was the aging appearance appraisal VAS. The VAS ranged from -15 ('I look 15 years younger') to +15 ('I look 15 years older'), with 0 indicating 'I look my age'. Subjects were asked to circle one number on the VAS indicating how many years younger or older they thought they looked compared to their actual age, with lower scores indicating a better outcome and higher scores a worse outcome. The mean change from baseline at post-treatment visits is presented.

Outcome measures

Outcome measures
Measure	BTX-A-HAC Solution 50 U - DB Period n=595 Participants During the DB period, subjects were randomised to receive a single treatment of BTX-A-HAC solution 50 U. 50 U (0.25 mL) BTX-A-HAC was administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive further BTX-A-HAC treatment.	Placebo - DB Period During the DB period, subjects were randomised to receive a single treatment of placebo. 0.25 mL placebo was administered as five injections of 0.05 mL each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive BTX-A-HAC treatment.
Change From Baseline at All Post-treatment Visits in the FACE-Q Aging Appearance Appraisal VAS: LT Analyses Cycle 1: Day 8	-1.0 Scores on a Scale Standard Deviation 2.2	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Aging Appearance Appraisal VAS: LT Analyses Cycle 1: Day 29	-1.3 Scores on a Scale Standard Deviation 2.5	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Aging Appearance Appraisal VAS: LT Analyses Cycle 1: Day 57	-1.2 Scores on a Scale Standard Deviation 2.6	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Aging Appearance Appraisal VAS: LT Analyses Cycle 1: Day 85	-0.8 Scores on a Scale Standard Deviation 2.5	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Aging Appearance Appraisal VAS: LT Analyses Cycle 2: Day 8	-0.9 Scores on a Scale Standard Deviation 1.8	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Aging Appearance Appraisal VAS: LT Analyses Cycle 2: Day 29	-1.0 Scores on a Scale Standard Deviation 1.9	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Aging Appearance Appraisal VAS: LT Analyses Cycle 2: Day 57	0.0 Scores on a Scale Standard Deviation 0.0	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Aging Appearance Appraisal VAS: LT Analyses Cycle 3: Day 8	-1.0 Scores on a Scale Standard Deviation 1.9	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Aging Appearance Appraisal VAS: LT Analyses Cycle 3: Day 29	-1.0 Scores on a Scale Standard Deviation 2.1	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Aging Appearance Appraisal VAS: LT Analyses Cycle 3: Day 57	-0.3 Scores on a Scale Standard Deviation 1.5	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Aging Appearance Appraisal VAS: LT Analyses Cycle 3: Day 85	-0.5 Scores on a Scale Standard Deviation 1.7	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Aging Appearance Appraisal VAS: LT Analyses Cycle 4: Day 8	-1.1 Scores on a Scale Standard Deviation 1.8	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Aging Appearance Appraisal VAS: LT Analyses Cycle 4: Day 29	-0.9 Scores on a Scale Standard Deviation 1.8	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Aging Appearance Appraisal VAS: LT Analyses Cycle 4: Day 85	-0.5 Scores on a Scale Standard Deviation 1.6	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Aging Appearance Appraisal VAS: LT Analyses Cycle 5: Day 8	-1.3 Scores on a Scale Standard Deviation 2.3	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Aging Appearance Appraisal VAS: LT Analyses Cycle 5: Day 29	-1.1 Scores on a Scale Standard Deviation 2.0	—
Change From Baseline at All Post-treatment Visits in the FACE-Q Aging Appearance Appraisal VAS: LT Analyses Cycle 5: Day 85	-0.7 Scores on a Scale Standard Deviation 1.9	—

Adverse Events

BTX-A-HAC Solution 50 U - LT Analyses

Serious events: 34 serious events

Other events: 279 other events

Deaths: 0 deaths

BTX-A-HAC Solution 50 U - DB Period

Serious events: 1 serious events

Other events: 35 other events

Deaths: 0 deaths

Placebo - DB Period

Serious events: 2 serious events

Other events: 13 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	BTX-A-HAC Solution 50 U - LT Analyses n=595 participants at risk Eligible subjects who completed the DB Cycle 1 treatment were able to receive further treatment in the OL period (OL Cycles 2 to 5). Additional BTX-naïve (de novo) subjects were enrolled into the OL period to receive treatment with BTX-A-HAC during OL Cycle 1, and if eligible for retreatment de novo subjects received retreatment in OL Cycles 2 to 5. Each treatment cycle included a single treatment with 50 U (0.25 mL) BTX-A-HAC administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region, and treatments were separated by at least 12 weeks.	BTX-A-HAC Solution 50 U - DB Period n=126 participants at risk During the DB period, subjects were randomised to receive a single treatment of BTX-A-HAC solution 50 U. 50 U (0.25 mL) BTX-A-HAC was administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive further BTX-A-HAC treatment.	Placebo - DB Period n=64 participants at risk During the DB period, subjects were randomised to receive a single treatment of placebo. 0.25 mL placebo was administered as five injections of 0.05 mL each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive BTX-A-HAC treatment.
Infections and infestations Nasopharyngitis	28.2% 168/595 • Number of events 252 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.	10.3% 13/126 • Number of events 14 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.	12.5% 8/64 • Number of events 10 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.
Infections and infestations Pharyngitis	1.2% 7/595 • Number of events 7 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.	2.4% 3/126 • Number of events 3 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.	0.00% 0/64 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.
Nervous system disorders Headache	19.7% 117/595 • Number of events 272 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.	10.3% 13/126 • Number of events 22 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.	6.2% 4/64 • Number of events 4 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.
Vascular disorders Haematoma	2.5% 15/595 • Number of events 16 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.	4.0% 5/126 • Number of events 5 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.	0.00% 0/64 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.
Ear and labyrinth disorders Vertigo	1.0% 6/595 • Number of events 6 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.	2.4% 3/126 • Number of events 3 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.	0.00% 0/64 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.
Infections and infestations Bronchitis	3.4% 20/595 • Number of events 21 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.	0.79% 1/126 • Number of events 1 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.	0.00% 0/64 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.
Infections and infestations Sinusitis	3.2% 19/595 • Number of events 22 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.	0.79% 1/126 • Number of events 1 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.	1.6% 1/64 • Number of events 2 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.
Infections and infestations Gastroenteritis	3.0% 18/595 • Number of events 19 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.	0.79% 1/126 • Number of events 1 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.	0.00% 0/64 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.
Infections and infestations Influenza	2.7% 16/595 • Number of events 17 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.	0.00% 0/126 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.	0.00% 0/64 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.
Infections and infestations Cystitis	2.5% 15/595 • Number of events 20 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.	0.79% 1/126 • Number of events 5 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.	0.00% 0/64 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.
Nervous system disorders Migraine	2.2% 13/595 • Number of events 20 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.	1.6% 2/126 • Number of events 5 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.	0.00% 0/64 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.
Musculoskeletal and connective tissue disorders Back pain	4.2% 25/595 • Number of events 29 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.	1.6% 2/126 • Number of events 2 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.	1.6% 1/64 • Number of events 3 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.
Eye disorders Eyelid ptosis	2.5% 15/595 • Number of events 19 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.	0.00% 0/126 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.	0.00% 0/64 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.
Eye disorders Eyelid oedema	2.4% 14/595 • Number of events 16 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.	1.6% 2/126 • Number of events 3 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.	0.00% 0/64 • Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period or OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months. For the DB period arms, the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. For the LT Analyses arm, the LTA population consisted of all subjects included in the DB period or as de novo subjects in the OL period who received at least one injection of BTX-A-HAC solution in the OL period.

Additional Information

Medical Director, Neurology

Ipsen

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place