Moderate to Severe Glabellar Lines
Conditions
Keywords
Moderate to Severe
Brief summary
The purpose of this study was to demonstrate the safety and the efficacy of a single treatment of an injectable liquid form of Clostridium botulinum toxin type A haemagglutinin complex (BTX-A-HAC; hereafter referred to as BTX-A-HAC Next Generation (BTX-A-HAC NG)), used for the improvement in the appearance of moderate to severe glabellar lines (the lines between the eyebrows).
Detailed description
At the Baseline Visit (Day 1), subjects were randomised in a ratio of 2:1 to receive either BTX-A-HAC NG solution (50 U) or placebo. Randomisation was stratified according to gender and severity of glabellar lines at maximum frown (moderate to severe) at Baseline. A single dose of BTX-A-HAC NG solution 50 U or placebo was injected on Day 1. Subjects were then monitored at the study centre for 30 minutes. On Day 4, subjects were contacted by telephone for adverse event monitoring and to record concomitant medications and treatments. Subjects attended follow-up visits at the study centre on Days 8, 15, 29, 57, 85, 113, 148 and 183. The Day 183 follow-up visit was the end of study visit; all subjects who had completed the Day 183 Visit were considered to have completed the study.
Interventions
BIOLOGICALBotulinum toxin type A
A solution containing 50 U in 0.25 mL (200 U/mL). Each vial contained 0.625 mL of deliverable volume of solution. A volume of 0.25 mL, containing 50 U of BTX-A-HAC NG (i.e. 10 U/0.05 mL) was withdrawn from the vial into a syringe for administration. The total treatment volume (0.25 mL) was divided into five injections (0.05 mL per injection), each of which was to be administered into predefined sites across the glabellar region (two injections into each corrugator muscle and one injection into the procerus muscle).
DRUGPlacebo
A solution containing only the excipients of BTX-A-HAC NG (identical in appearance to the active product). Each vial contained 0.625 mL of deliverable volume of solution. A volume of 0.25 mL was withdrawn from the vial into a syringe for administration. The total treatment volume (0.25 mL) was divided into five injections (0.05 mL per injection), each of which was to be administered into predefined sites across the glabellar region (two injections into each corrugator muscle and one injection into the procerus muscle).
Sponsors
Ipsen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Provision of written informed consent prior to any study related procedures. 2. Male or female between 18 and 65 years of age, inclusive. 3. Had moderate or severe (Grade 2 or 3) vertical glabellar lines at maximum frown at baseline (Day 1), as assessed by the ILA using a validated 4-point photographic scale. 4. Had moderate or severe (Grade 2 or 3) vertical glabellar lines at maximum frown at baseline (Day 1), as assessed by the SSA using a validated 4-point categorical scale. 5. Were dissatisfied or very dissatisfied (Grade 2 or 3) with their glabellar lines at baseline (Day 1), as assessed by the subject's level of satisfaction. 6. Had a negative pregnancy test (for females of childbearing potential only). Nonchildbearing potential was defined as post menopausal for at least 1 year, surgical sterilisation at least 3 months before entering the study, or hysterectomy. 7. Had both the time and the ability to complete the study and comply with study instructions.
Exclusion criteria
1. Previous treatment with any serotype of botulinum toxin (BTX). 2. Any prior treatment with permanent fillers in the upper face including the glabellar lines area. 3. Any prior treatment with long lasting dermal fillers in the upper face including the glabellar lines area within the past 3 years and/or skin abrasions/resurfacing (whatever the interventional technic used) within the past 5 years, or photorejuvenation or skin/vascular laser intervention within the past 12 months. 4. Any planned facial cosmetic surgery during the study. 5. A history of eyelid blepharoplasty or brow lift within the past 5 years. 6. An inability to substantially reduce glabellar lines by physically spreading them apart or lack of capacity to frown. 7. An active infection or other skin problems in the upper face including the glabellar lines area (e.g. acute acne lesions or ulcers). 8. Use of concomitant therapy which, in the Investigator's opinion, would have interfered with the evaluation of the safety or efficacy of the study treatment, including medications affecting bleeding disorders (antiplatelet agents and/or anticoagulants given for treatment or prevention of cardiovascular/cerebrovascular diseases). 9. Pregnant women, nursing mothers, or women who were planning a pregnancy during the study, or believed they may be pregnant at the start of the study. Throughout the course of the study, women of childbearing potential had to use a reliable form of contraception (e.g. oral contraceptives for more than 12 consecutive weeks, or spermicide and condoms). 10. A history of drug or alcohol abuse. 11. Treatment with an experimental drug or use of any experimental device within 30 days prior to the start of the study and during the conduct of the study. 12. Known allergy or hypersensitivity to any serotype of BTX or any component of BTX-A-HAC NG. 13. Clinically diagnosed significant anxiety disorder, or any other significant psychiatric disorder (e.g. depression) that might interfere with the subject's participation in the study. 14. Use of medications that affect neuromuscular transmission, such as curare like nondepolarising agents, lincosamides, polymyxins, anticholinesterases and aminoglycoside antibiotics, within the past 30 days. 15. A history of facial nerve palsy. 16. Marked facial asymmetry, ptosis, excessive dermatochalasis, deep dermal scarring, or thick sebaceous skin. 17. The presence of any other condition (e.g. neuromuscular disorder or other disorder that could interfere with neuromuscular function), laboratory finding or circumstance that, in the judgement of the Investigator, might increase the risk to the subject or decrease the chance of obtaining satisfactory data to achieve the objectives of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Proportion of Responders at Day 29 in the ILA of Glabellar Lines at Maximum Frown. | Day 29 | ILA 4-point photographic scale: None - Grade 0; mild - Grade 1; moderate - Grade 2; severe - Grade 3. A responder at maximum frown was defined as having a severity grade of none (Grade 0) or mild (Grade 1) at maximum frown on Day 29 and a severity grade of moderate (Grade 2) or severe (Grade 3) at Baseline (Day 1). The adjusted proportion of responders in each treatment group was provided using a multivariate logistic regression model. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Proportion of Responders on Day 29 Who Remained Responders on Days 57, 85, 113, 148 and 183 as Measured by the ILA at Maximum Frown. | Day 57, 85, 113, 148 and 183 | ILA 4-point photographic scale: None - Grade 0; mild - Grade 1; moderate - Grade 2; severe - Grade 3. A responder at maximum frown was defined as having a severity grade of none (Grade 0) or mild (Grade 1) at maximum frown at a given visit and a severity grade of moderate (Grade 2) or severe (Grade 3) at Baseline (Day 1). Subjects who were not responders at Day 29 were excluded from the analysis. The adjusted proportion of responders in each treatment group was provided using a multivariate logistic regression model. |
| The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Rest. | Day 8, 15, 29, 57, 85, 113, 148 and 183 | ILA 4-point photographic scale: None - Grade 0; mild - Grade 1; moderate - Grade 2; severe - Grade 3. A responder at rest was defined as having a severity grade of none (Grade 0) or mild (Grade 1) at rest at a given visit and a severity grade of moderate (Grade 2) or severe (Grade 3) at Baseline (Day 1). The adjusted proportion of responders in each treatment group was provided using a multivariate logistic regression model. |
| The Proportion of Subjects With a Reduction of Two or More Grades in the Severity of Glabellar Lines at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Maximum Frown. | Day 8, 15, 29, 57, 85, 113, 148 and 183 | ILA 4-point photographic scale: None - Grade 0; mild - Grade 1; moderate - Grade 2; severe - Grade 3. Adjusted proportion of subjects with a reduction of two or more grades in the severity of glabellar lines at each post-treatment visit compared with Baseline. The adjusted proportion of responders in each treatment group was provided using a multivariate logistic regression model. |
| The Proportion of Responders at Each Post-treatment Visit to the Study Centre (Except Day 29) as Measured by the ILA at Maximum Frown. | Day 8, 15, 57, 85, 113, 148 and 183 | ILA 4-point photographic scale: None - Grade 0; mild - Grade 1; moderate - Grade 2; severe - Grade 3. A responder at maximum frown was defined as having a severity grade of none (Grade 0) or mild (Grade 1) at maximum frown at a given visit and a severity grade of moderate (Grade 2) or severe (Grade 3) at Baseline (Day 1). The adjusted proportion of responders in each treatment group was provided using a multivariate logistic regression model. |
| The Proportion 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. | Day 8, 15, 29, 57, 85, 113, 148 and 183 | Adjusted proportion of responders at each post-treatment visit (measured by the subject's level of satisfaction with the appearance of their glabellar lines). 4-point categorical scale: Grade 0 - very satisfied; Grade 1 - satisfied; Grade 2 - dissatisfied; Grade 3 - very dissatisfied. 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). The adjusted proportion of responders in each treatment group was provided using a multivariate logistic regression model. |
| The Time to Onset of Treatment Response Based on the Subject's Diary Card. | Day 1 to 7 | Median time to onset of treatment response: subjects asked to record their assessment of study treatment response in a diary card on Days 1 to 7. They responded '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 Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Self-assessment (SSA) at Maximum Frown. | Day 8, 15, 29, 57, 85, 113, 148 and 183 | SSA 4-point photographic scale: No wrinkles - 0; Mild wrinkles - 1; Moderate wrinkles - 2; Severe wrinkles - 3. A responder at maximum frown 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 wrinkles (Grade 2) or severe wrinkles (Grade 3) at Baseline (Day 1). The adjusted proportion of responders in each treatment group was provided using a multivariate logistic regression model. |
Countries
France, Germany
Participant flow
Recruitment details
Subjects were recruited from nine active sites in France and Germany from January 2015. The study was completed in August 2015.
Pre-assignment details
Overall, 190 subjects were screened, five of whom were screening failures. A total of 185 subjects were randomised to receive treatment. One of the subjects who was randomised to placebo did not receive study treatment due to violation of inclusion criterion 3.
Participants by arm
| Arm | Count |
|---|---|
| BTX-A-HAC NG Solution (50 U) Clostridium Botulinum Toxin Type A (BTX-A-HAC NG) 50 U solution, single dose (intramuscular injection). The total treatment volume (0.25 mL) was divided into five injections (0.05 mL per injection) injected in five predefined sites across the glabellar region. A total of 50 U was injected. | 125 |
| Placebo Placebo single dose (intramuscular injection). The total placebo volume (0.25 mL) was divided into five injections (0.05 mL per injection) injected in five predefined sites across the glabellar region. | 60 |
| Total | 185 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Consent withdrawn | 1 | 8 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Protocol deviation | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | BTX-A-HAC NG Solution (50 U) |
|---|---|---|---|
| Age, Continuous | 48.0 Years STANDARD_DEVIATION 9.09 | 47.8 Years STANDARD_DEVIATION 9.52 | 47.7 Years STANDARD_DEVIATION 9.75 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 60 Participants | 185 Participants | 125 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black/African American | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Caucasian/White | 59 Participants | 183 Participants | 124 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Female | 52 Participants | 160 Participants | 108 Participants |
| Sex: Female, Male Male | 8 Participants | 25 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 49 / 125 | 17 / 59 |
| serious Total, serious adverse events | 2 / 125 | 1 / 59 |
Outcome results
Primary
The Proportion of Responders at Day 29 in the ILA of Glabellar Lines at Maximum Frown.
ILA 4-point photographic scale: None - Grade 0; mild - Grade 1; moderate - Grade 2; severe - Grade 3. A responder at maximum frown was defined as having a severity grade of none (Grade 0) or mild (Grade 1) at maximum frown on Day 29 and a severity grade of moderate (Grade 2) or severe (Grade 3) at Baseline (Day 1). The adjusted proportion of responders in each treatment group was provided using a multivariate logistic regression model.
Time frame: Day 29
Population: Modified intent-to-treat (mITT) population included all randomised subjects who received at least one injection of study treatment into one injection site and who had both Baseline and at least one postbaseline value for the ILA of glabellar lines at maximum frown. Subjects who did not have available data at Day 29 were excluded from the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders at Day 29 in the ILA of Glabellar Lines at Maximum Frown. | 88.3 Adjusted percentage of responders |
| Placebo | The Proportion of Responders at Day 29 in the ILA of Glabellar Lines at Maximum Frown. | 1.4 Adjusted percentage of responders |
Comparison: Comparison of ILA - BTX-A-HAC NG solution (50 U) versus Placebo at Day 29p-value: <0.0001Regression, Logistic
Secondary
The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Rest.
ILA 4-point photographic scale: None - Grade 0; mild - Grade 1; moderate - Grade 2; severe - Grade 3. A responder at rest was defined as having a severity grade of none (Grade 0) or mild (Grade 1) at rest at a given visit and a severity grade of moderate (Grade 2) or severe (Grade 3) at Baseline (Day 1). The adjusted proportion of responders in each treatment group was provided using a multivariate logistic regression model.
Time frame: Day 8, 15, 29, 57, 85, 113, 148 and 183
Population: mITT: all randomised subjects who received at least one injection of study treatment into one injection site and who had both Baseline and at least one postbaseline value for the ILA of glabellar lines at maximum frown. N'=number of subjects with available data at the given visit.; P=placebo.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Rest. | Day 8 | 73.2 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Rest. | Day 15 | 74.5 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Rest. | Day 29 | 81.1 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Rest. | Day 57 | 77.2 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Rest. | Day 85 | 58.5 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Rest. | Day 113 | 74.7 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Rest. | Day 148 | NA Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Rest. | Day 183 | 56.0 Adjusted percentage of responders |
| Placebo | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Rest. | Day 183 | 10.4 Adjusted percentage of responders |
| Placebo | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Rest. | Day 8 | 2.0 Adjusted percentage of responders |
| Placebo | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Rest. | Day 85 | 0.5 Adjusted percentage of responders |
| Placebo | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Rest. | Day 15 | 1.3 Adjusted percentage of responders |
| Placebo | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Rest. | Day 148 | NA Adjusted percentage of responders |
| Placebo | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Rest. | Day 29 | 1.5 Adjusted percentage of responders |
| Placebo | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Rest. | Day 113 | 4.8 Adjusted percentage of responders |
| Placebo | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Rest. | Day 57 | 0.5 Adjusted percentage of responders |
Comparison: Comparison of ILA - BTX-A-HAC NG solution (50 U) versus Placebo at Day 8p-value: <0.0001Regression, Logistic
Comparison: Comparison of ILA - BTX-A-HAC NG solution (50 U) versus Placebo at Day 15p-value: <0.0001Regression, Logistic
Comparison: Comparison of ILA - BTX-A-HAC NG solution (50 U) versus Placebo at Day 29p-value: <0.0001Regression, Logistic
Comparison: Comparison of ILA - BTX-A-HAC NG solution (50 U) versus Placebo at Day 57p-value: <0.0001Regression, Logistic
Comparison: Comparison of ILA - BTX-A-HAC NG solution (50 U) versus Placebo at Day 85p-value: <0.0001Regression, Logistic
Comparison: Comparison of ILA - BTX-A-HAC NG solution (50 U) versus Placebo at Day 113p-value: <0.0001Regression, Logistic
Comparison: Comparison of ILA - BTX-A-HAC NG solution (50 U) versus Placebo at Day 183p-value: 0.0015Regression, Logistic
Secondary
The Proportion 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.
Adjusted proportion of responders at each post-treatment visit (measured by the subject's level of satisfaction with the appearance of their glabellar lines). 4-point categorical scale: Grade 0 - very satisfied; Grade 1 - satisfied; Grade 2 - dissatisfied; Grade 3 - very dissatisfied. 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). The adjusted proportion of responders in each treatment group was provided using a multivariate logistic regression model.
Time frame: Day 8, 15, 29, 57, 85, 113, 148 and 183
Population: mITT: All randomised subjects who received at least one injection of study treatment into one injection site and who had both Baseline and at least one postbaseline value for the ILA of glabellar lines at maximum frown. N'=number of subjects with available data at the given visit; P=placebo.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BTX-A-HAC NG Solution (50 U) | The Proportion 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. | Day 8 | 72.7 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion 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. | Day 15 | 80.6 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion 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. | Day 29 | 80.9 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion 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. | Day 57 | 74.7 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion 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. | Day 85 | 70.9 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion 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. | Day 113 | 61.9 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion 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. | Day 148 | 58.9 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion 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. | Day 183 | 49.8 Adjusted percentage of responders |
| Placebo | The Proportion 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. | Day 183 | 11.3 Adjusted percentage of responders |
| Placebo | The Proportion 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. | Day 8 | 4.9 Adjusted percentage of responders |
| Placebo | The Proportion 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. | Day 85 | 7.3 Adjusted percentage of responders |
| Placebo | The Proportion 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. | Day 15 | 7.9 Adjusted percentage of responders |
| Placebo | The Proportion 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. | Day 148 | 12.3 Adjusted percentage of responders |
| Placebo | The Proportion 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. | Day 29 | 8.3 Adjusted percentage of responders |
| Placebo | The Proportion 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. | Day 113 | 9.8 Adjusted percentage of responders |
| Placebo | The Proportion 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. | Day 57 | 5.9 Adjusted percentage of responders |
Comparison: Comparison of subject's level of satisfaction - BTX-A-HAC NG solution (50 U) versus Placebo at Day 8p-value: <0.0001Regression, Logistic
Comparison: Comparison of subject's level of satisfaction - BTX-A-HAC NG solution (50 U) versus Placebo at Day 15p-value: <0.0001Regression, Logistic
Comparison: Comparison of subject's level of satisfaction - BTX-A-HAC NG solution (50 U) versus Placebo at Day 29p-value: <0.0001Regression, Logistic
Comparison: Comparison of subject's level of satisfaction - BTX-A-HAC NG solution (50 U) versus Placebo at Day 57p-value: <0.0001Regression, Logistic
Comparison: Comparison of subject's level of satisfaction - BTX-A-HAC NG solution (50 U) versus Placebo at Day 85p-value: <0.0001Regression, Logistic
Comparison: Comparison of subject's level of satisfaction - BTX-A-HAC NG solution (50 U) versus Placebo at Day 113p-value: <0.0001Regression, Logistic
Comparison: Comparison of subject's level of satisfaction - BTX-A-HAC NG solution (50 U) versus Placebo at Day 148p-value: <0.0001Regression, Logistic
Comparison: Comparison of subject's level of satisfaction - BTX-A-HAC NG solution (50 U) versus Placebo at Day 183p-value: <0.0001Regression, Logistic
Secondary
The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Self-assessment (SSA) at Maximum Frown.
SSA 4-point photographic scale: No wrinkles - 0; Mild wrinkles - 1; Moderate wrinkles - 2; Severe wrinkles - 3. A responder at maximum frown 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 wrinkles (Grade 2) or severe wrinkles (Grade 3) at Baseline (Day 1). The adjusted proportion of responders in each treatment group was provided using a multivariate logistic regression model.
Time frame: Day 8, 15, 29, 57, 85, 113, 148 and 183
Population: mITT: all randomised subjects who received at least one injection of study treatment into one injection site and who had both Baseline and at least one postbaseline value for the ILA of glabellar lines at maximum frown. N'=number of subjects with available data at the given visit; P=placebo.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Self-assessment (SSA) at Maximum Frown. | Day 8 | 62.0 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Self-assessment (SSA) at Maximum Frown. | Day 15 | 75.6 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Self-assessment (SSA) at Maximum Frown. | Day 29 | 76.0 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Self-assessment (SSA) at Maximum Frown. | Day 57 | 67.5 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Self-assessment (SSA) at Maximum Frown. | Day 85 | 61.8 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Self-assessment (SSA) at Maximum Frown. | Day 113 | 46.2 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Self-assessment (SSA) at Maximum Frown. | Day 148 | 44.1 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Self-assessment (SSA) at Maximum Frown. | Day 183 | 27.0 Adjusted percentage of responders |
| Placebo | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Self-assessment (SSA) at Maximum Frown. | Day 183 | 6.0 Adjusted percentage of responders |
| Placebo | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Self-assessment (SSA) at Maximum Frown. | Day 8 | 5.1 Adjusted percentage of responders |
| Placebo | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Self-assessment (SSA) at Maximum Frown. | Day 85 | 3.9 Adjusted percentage of responders |
| Placebo | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Self-assessment (SSA) at Maximum Frown. | Day 15 | 4.4 Adjusted percentage of responders |
| Placebo | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Self-assessment (SSA) at Maximum Frown. | Day 148 | 13.1 Adjusted percentage of responders |
| Placebo | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Self-assessment (SSA) at Maximum Frown. | Day 29 | 5.2 Adjusted percentage of responders |
| Placebo | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Self-assessment (SSA) at Maximum Frown. | Day 113 | 9.8 Adjusted percentage of responders |
| Placebo | The Proportion of Responders at Each Post-treatment Visit to the Study Centre as Measured by the Subject's Self-assessment (SSA) at Maximum Frown. | Day 57 | 2.2 Adjusted percentage of responders |
Comparison: Comparison of SSA - BTX-A-HAC NG solution (50 U) versus Placebo at Day 8p-value: <0.0001Regression, Logistic
Comparison: Comparison of SSA - BTX-A-HAC NG solution (50 U) versus Placebo at Day 15p-value: <0.0001Regression, Logistic
Comparison: Comparison of SSA - BTX-A-HAC NG solution (50 U) versus Placebo at Day 29p-value: <0.0001Regression, Logistic
Comparison: Comparison of SSA - BTX-A-HAC NG solution (50 U) versus Placebo at Day 57p-value: <0.0001Regression, Logistic
Comparison: Comparison of SSA - Dysport 50 U versus Placebo at Day 85p-value: <0.0001Regression, Logistic
Comparison: Comparison of SSA - BTX-A-HAC NG solution (50 U) versus Placebo at Day 113p-value: <0.0001Regression, Logistic
Comparison: Comparison of SSA - BTX-A-HAC NG solution (50 U) versus Placebo at Day 148p-value: 0.0011Regression, Logistic
Comparison: Comparison of SSA - BTX-A-HAC NG solution (50 U) versus Placebo at Day 183p-value: 0.0036Regression, Logistic
Secondary
The Proportion of Responders at Each Post-treatment Visit to the Study Centre (Except Day 29) as Measured by the ILA at Maximum Frown.
ILA 4-point photographic scale: None - Grade 0; mild - Grade 1; moderate - Grade 2; severe - Grade 3. A responder at maximum frown was defined as having a severity grade of none (Grade 0) or mild (Grade 1) at maximum frown at a given visit and a severity grade of moderate (Grade 2) or severe (Grade 3) at Baseline (Day 1). The adjusted proportion of responders in each treatment group was provided using a multivariate logistic regression model.
Time frame: Day 8, 15, 57, 85, 113, 148 and 183
Population: mITT: all randomised subjects who received at least one injection of study treatment into one injection site and who had both Baseline and at least one postbaseline value for the ILA of glabellar lines at maximum frown. N'=number of subjects with available data at the given visit; P=placebo.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders at Each Post-treatment Visit to the Study Centre (Except Day 29) as Measured by the ILA at Maximum Frown. | Day 57 | 77.4 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders at Each Post-treatment Visit to the Study Centre (Except Day 29) as Measured by the ILA at Maximum Frown. | Day 113 | 34.0 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders at Each Post-treatment Visit to the Study Centre (Except Day 29) as Measured by the ILA at Maximum Frown. | Day 15 | 87.0 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders at Each Post-treatment Visit to the Study Centre (Except Day 29) as Measured by the ILA at Maximum Frown. | Day 148 | 17.1 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders at Each Post-treatment Visit to the Study Centre (Except Day 29) as Measured by the ILA at Maximum Frown. | Day 85 | 51.3 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders at Each Post-treatment Visit to the Study Centre (Except Day 29) as Measured by the ILA at Maximum Frown. | Day 183 | 4.9 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders at Each Post-treatment Visit to the Study Centre (Except Day 29) as Measured by the ILA at Maximum Frown. | Day 8 | 80.5 Adjusted percentage of responders |
| Placebo | The Proportion of Responders at Each Post-treatment Visit to the Study Centre (Except Day 29) as Measured by the ILA at Maximum Frown. | Day 183 | 0.9 Adjusted percentage of responders |
| Placebo | The Proportion of Responders at Each Post-treatment Visit to the Study Centre (Except Day 29) as Measured by the ILA at Maximum Frown. | Day 8 | 1.3 Adjusted percentage of responders |
| Placebo | The Proportion of Responders at Each Post-treatment Visit to the Study Centre (Except Day 29) as Measured by the ILA at Maximum Frown. | Day 15 | 1.5 Adjusted percentage of responders |
| Placebo | The Proportion of Responders at Each Post-treatment Visit to the Study Centre (Except Day 29) as Measured by the ILA at Maximum Frown. | Day 57 | 1.0 Adjusted percentage of responders |
| Placebo | The Proportion of Responders at Each Post-treatment Visit to the Study Centre (Except Day 29) as Measured by the ILA at Maximum Frown. | Day 85 | 1.0 Adjusted percentage of responders |
| Placebo | The Proportion of Responders at Each Post-treatment Visit to the Study Centre (Except Day 29) as Measured by the ILA at Maximum Frown. | Day 113 | 0.8 Adjusted percentage of responders |
| Placebo | The Proportion of Responders at Each Post-treatment Visit to the Study Centre (Except Day 29) as Measured by the ILA at Maximum Frown. | Day 148 | 1.8 Adjusted percentage of responders |
Comparison: Comparison of ILA at Day 8 - BTX-A-HAC NG solution (50 U) versus placebop-value: <0.0001Regression, Logistic
Comparison: Comparison of ILA at Day 15 - BTX-A-HAC NG solution (50 U) versus placebop-value: <0.0001Regression, Logistic
Comparison: Comparison of ILA at Day 57 - BTX-A-HAC NG solution (50 U) versus placebop-value: <0.0001Regression, Logistic
Comparison: Comparison of ILA at Day 85 - BTX-A-HAC NG solution (50 U) versus placebop-value: <0.0001Regression, Logistic
Comparison: Comparison of ILA at Day 113 - BTX-A-HAC NG solution (50 U) versus placebop-value: <0.0001Regression, Logistic
Comparison: Comparison of ILA at Day 148 - BTX-A-HAC NG solution (50 U) versus placebop-value: 0.0035Regression, Logistic
Comparison: Comparison of ILA at Day 183 (End of Study) - BTX-A-HAC NG solution (50 U) versus placebop-value: 0.0441Regression, Logistic
Secondary
The Proportion of Responders on Day 29 Who Remained Responders on Days 57, 85, 113, 148 and 183 as Measured by the ILA at Maximum Frown.
ILA 4-point photographic scale: None - Grade 0; mild - Grade 1; moderate - Grade 2; severe - Grade 3. A responder at maximum frown was defined as having a severity grade of none (Grade 0) or mild (Grade 1) at maximum frown at a given visit and a severity grade of moderate (Grade 2) or severe (Grade 3) at Baseline (Day 1). Subjects who were not responders at Day 29 were excluded from the analysis. The adjusted proportion of responders in each treatment group was provided using a multivariate logistic regression model.
Time frame: Day 57, 85, 113, 148 and 183
Population: mITT: All randomised subjects who received at least one injection of study treatment into one injection site and who had both Baseline and at least one postbaseline value for the ILA of glabellar lines at maximum frown. N'=number of subjects with available data at the given visit; P=placebo.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders on Day 29 Who Remained Responders on Days 57, 85, 113, 148 and 183 as Measured by the ILA at Maximum Frown. | Day 85 | 61.1 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders on Day 29 Who Remained Responders on Days 57, 85, 113, 148 and 183 as Measured by the ILA at Maximum Frown. | Day 148 | 20.1 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders on Day 29 Who Remained Responders on Days 57, 85, 113, 148 and 183 as Measured by the ILA at Maximum Frown. | Day 113 | 39.6 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders on Day 29 Who Remained Responders on Days 57, 85, 113, 148 and 183 as Measured by the ILA at Maximum Frown. | Day 183 | 5.3 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Responders on Day 29 Who Remained Responders on Days 57, 85, 113, 148 and 183 as Measured by the ILA at Maximum Frown. | Day 57 | 87.3 Adjusted percentage of responders |
| Placebo | The Proportion of Responders on Day 29 Who Remained Responders on Days 57, 85, 113, 148 and 183 as Measured by the ILA at Maximum Frown. | Day 183 | 8.0 Adjusted percentage of responders |
| Placebo | The Proportion of Responders on Day 29 Who Remained Responders on Days 57, 85, 113, 148 and 183 as Measured by the ILA at Maximum Frown. | Day 57 | 47.0 Adjusted percentage of responders |
| Placebo | The Proportion of Responders on Day 29 Who Remained Responders on Days 57, 85, 113, 148 and 183 as Measured by the ILA at Maximum Frown. | Day 85 | 4.9 Adjusted percentage of responders |
| Placebo | The Proportion of Responders on Day 29 Who Remained Responders on Days 57, 85, 113, 148 and 183 as Measured by the ILA at Maximum Frown. | Day 113 | 24.0 Adjusted percentage of responders |
| Placebo | The Proportion of Responders on Day 29 Who Remained Responders on Days 57, 85, 113, 148 and 183 as Measured by the ILA at Maximum Frown. | Day 148 | 32.1 Adjusted percentage of responders |
Comparison: Comparison of the proportion of responders on Day 29 who remained responders at Day 57 - BTX-A-HAC NG solution (50 U) versus Placebop-value: 0.2422Regression, Logistic
Comparison: Comparison of the proportion of responders on Day 29 who remained responders at Day 85 - BTX-A-HAC NG solution (50 U) versus Placebop-value: 0.0917Regression, Logistic
Comparison: Comparison of the proportion of responders on Day 29 who remained responders at Day 113 - BTX-A-HAC NG solution (50 U) versus Placebop-value: 0.7064Regression, Logistic
Comparison: Comparison of the proportion of responders on Day 29 who remained responders at Day 148 - BTX-A-HAC NG solution (50 U) versus Placebop-value: 0.701Regression, Logistic
Comparison: Comparison of the proportion of responders on Day 29 who remained responders at Day 183 - BTX-A-HAC NG solution (50 U) versus Placebop-value: 0.7894Regression, Logistic
Secondary
The Proportion of Subjects With a Reduction of Two or More Grades in the Severity of Glabellar Lines at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Maximum Frown.
ILA 4-point photographic scale: None - Grade 0; mild - Grade 1; moderate - Grade 2; severe - Grade 3. Adjusted proportion of subjects with a reduction of two or more grades in the severity of glabellar lines at each post-treatment visit compared with Baseline. The adjusted proportion of responders in each treatment group was provided using a multivariate logistic regression model.
Time frame: Day 8, 15, 29, 57, 85, 113, 148 and 183
Population: mITT: all randomised subjects who received at least one injection of study treatment into one injection site and who had both Baseline and at least one postbaseline value for the ILA of glabellar lines at maximum frown. N'=number of subjects with available data at the given visit; P=placebo.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BTX-A-HAC NG Solution (50 U) | The Proportion of Subjects With a Reduction of Two or More Grades in the Severity of Glabellar Lines at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Maximum Frown. | Day 8 | 56.2 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Subjects With a Reduction of Two or More Grades in the Severity of Glabellar Lines at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Maximum Frown. | Day 15 | 69.7 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Subjects With a Reduction of Two or More Grades in the Severity of Glabellar Lines at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Maximum Frown. | Day 29 | 63.6 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Subjects With a Reduction of Two or More Grades in the Severity of Glabellar Lines at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Maximum Frown. | Day 57 | 48.0 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Subjects With a Reduction of Two or More Grades in the Severity of Glabellar Lines at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Maximum Frown. | Day 85 | 24.3 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Subjects With a Reduction of Two or More Grades in the Severity of Glabellar Lines at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Maximum Frown. | Day 113 | 10.1 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Subjects With a Reduction of Two or More Grades in the Severity of Glabellar Lines at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Maximum Frown. | Day 148 | 3.5 Adjusted percentage of responders |
| BTX-A-HAC NG Solution (50 U) | The Proportion of Subjects With a Reduction of Two or More Grades in the Severity of Glabellar Lines at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Maximum Frown. | Day 183 | 3.4 Adjusted percentage of responders |
| Placebo | The Proportion of Subjects With a Reduction of Two or More Grades in the Severity of Glabellar Lines at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Maximum Frown. | Day 183 | 1.3 Adjusted percentage of responders |
| Placebo | The Proportion of Subjects With a Reduction of Two or More Grades in the Severity of Glabellar Lines at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Maximum Frown. | Day 8 | 0.2 Adjusted percentage of responders |
| Placebo | The Proportion of Subjects With a Reduction of Two or More Grades in the Severity of Glabellar Lines at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Maximum Frown. | Day 85 | 0.3 Adjusted percentage of responders |
| Placebo | The Proportion of Subjects With a Reduction of Two or More Grades in the Severity of Glabellar Lines at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Maximum Frown. | Day 15 | 0.2 Adjusted percentage of responders |
| Placebo | The Proportion of Subjects With a Reduction of Two or More Grades in the Severity of Glabellar Lines at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Maximum Frown. | Day 148 | 0.3 Adjusted percentage of responders |
| Placebo | The Proportion of Subjects With a Reduction of Two or More Grades in the Severity of Glabellar Lines at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Maximum Frown. | Day 29 | 0.1 Adjusted percentage of responders |
| Placebo | The Proportion of Subjects With a Reduction of Two or More Grades in the Severity of Glabellar Lines at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Maximum Frown. | Day 113 | 0.3 Adjusted percentage of responders |
| Placebo | The Proportion of Subjects With a Reduction of Two or More Grades in the Severity of Glabellar Lines at Each Post-treatment Visit to the Study Centre as Measured by the ILA at Maximum Frown. | Day 57 | 0.1 Adjusted percentage of responders |
Comparison: Comparison of ILA - BTX-A-HAC NG solution (50 U) versus Placebo at Day 8p-value: <0.0001Regression, Logistic
Comparison: Comparison of ILA - BTX-A-HAC NG solution (50 U) versus Placebo at Day 15p-value: <0.0001Regression, Logistic
Comparison: Comparison of ILA - BTX-A-HAC NG solution (50 U) versus Placebo at Day 29p-value: <0.0001Regression, Logistic
Comparison: Comparison of ILA - BTX-A-HAC NG solution (50 U) versus Placebo at Day 57p-value: <0.0001Regression, Logistic
Comparison: Comparison of ILA - BTX-A-HAC NG solution (50 U) versus Placebo at Day 85p-value: 0.0008Regression, Logistic
Comparison: Comparison of ILA - BTX-A-HAC NG solution (50 U) versus Placebo at Day 113p-value: 0.0065Regression, Logistic
Comparison: Comparison of ILA - BTX-A-HAC NG solution (50 U) versus Placebo at Day 148p-value: 0.0643Regression, Logistic
Comparison: Comparison of ILA - BTX-A-HAC NG solution (50 U) versus Placebo at Day 183p-value: 0.367Regression, Logistic
Secondary
The Time to Onset of Treatment Response Based on the Subject's Diary Card.
Median time to onset of treatment response: subjects asked to record their assessment of study treatment response in a diary card on Days 1 to 7. They responded '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)?'
Time frame: Day 1 to 7
Population: mITT: All randomised subjects who received at least one injection of study treatment into one injection site and who had both Baseline and at least one postbaseline value for the ILA of glabellar lines at maximum frown. One subject from the placebo group was excluded from the analysis due to missing data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BTX-A-HAC NG Solution (50 U) | The Time to Onset of Treatment Response Based on the Subject's Diary Card. | 3.0 Days |
| Placebo | The Time to Onset of Treatment Response Based on the Subject's Diary Card. | NA Days |
Comparison: Comparison of time to onset of treatment response - BTX-A-HAC NG solution (50 U) versus Placebop-value: <0.0001Log Rank
Comparison: Comparison of time to onset of treatment response - BTX-A-HAC NG solution (50 U) versus placebop-value: <0.0001Cox proportional hazard model