Moderate to Severe Glabellar Frown Lines
Conditions
Brief summary
The study objective is to show the superior efficacy of IncobotulinumtoxinA (Xeomin) over placebo by evaluation of treatment success analyzing the investigator's rating on the Facial Wrinkle Scale and the patient's assessment on a 4-point scale. 255 female and male patients with moderate to severe glabellar frown lines will be randomized in a 2:1 ratio to receive one injection of IncobotulinumtoxinA (Xeomin) or placebo and will be followed up until day 120.
Detailed description
The study was a prospective, randomized, double-blind, placebo-controlled, parallel-group, multicenter phase 3 clinical trial. Approximately 285 females and males with moderate to severe glabellar frown lines at maximum frown were to be screened during a screening period of four months in order to randomize approximately 255 subjects into one treatment and one placebo group at a ratio of 2 : 1. After the single injection treatment with a total dose of 20 Units IncobotulinumtoxinA (Xeomin) or corresponding placebo, the subjects were observed over 120 days. During the study participation the subjects performed seven visits. Eight (8) sites in the United States participated in this trial. The study was led by one Lead PI and a Co-Lead PI who was assisting the Lead PI. The role of the Lead PI and the Co-Lead PI was executed by one of the PIs of this study, respectively. The PI at each site was a medical doctor who was experienced in aesthetic dermatology, i.e. who had several years (\>= 2 years) of experience in treatment of glabellar frown lines with BTX-A preparations. The PI was the person who led the team at one trial site and who was responsible for the conduct of the clinical trial at the site. The sub-investigator was a member of the team designated by the PI to perform important trial-related decisions. A maximum number of two sub-investigators could be authorized for injection and rating if necessary. At each site, ideally one investigator was to inject and rate all subjects. Injecting and rating sub-investigators had to be medical doctors with several years of experience in treatment of glabellar frown lines with BTX-A preparations. A subject had to be rated by the same investigator at all visits. Another phase 3 trial MRZ 60201-0724/1 (NCT00770029) with design and endpoints identical to those in this trial was performed in order to compare efficacy and safety results with a second study population.
Interventions
The treatment will be administered only once at day 0 at five injection sites in the glabellar area. The total dose of 20 Units IncobotulinumtoxinA (Xeomin) is reconstituted in a total injection volume of 0.5 mL that is to be injected to the five sites in equal aliquots of 0.1 mL.
DRUGPlacebo
The treatment will be administered only once at day 0 at five injection sites in the glabellar area. Volume of Placebo equivalent to IncobotulinumtoxinA (Xeomin).
Sponsors
Merz Pharmaceuticals GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age 18 or over * Moderate to severe glabellar frown lines at maximum frown (severity score of 2 or 3 on Facial Wrinkle Scale as assessed by investigator's rating: 0= 'none', 1= 'mild', 2= 'moderate', 3= 'severe') * Moderate to severe glabellar frown lines at maximum frown (severity score of 2 or 3 on Facial Wrinkle Scale as assessed by patient's assessment: 0= 'none', 1= 'mild', 2= 'moderate', 3= 'severe') * Stable medical condition
Exclusion criteria
* Previous treatment with Botulinum toxin of any serotype in the glabellar area within the last 8 month * Previous treatment with any facial aesthetic procedure (e.g. injection with biodegradable fillers, chemical peeling, photo rejuvenation) in the glabellar area within the last 12 month * Previous insertion of permanent material in the glabellar area (regardless of the time between previous treatment and this study) * Planned treatment with Botulinum toxin of any serotype in any other body region during the study period * Any surgery in the glabellar area including surgical removal of the corrugator, procerus, or depressor supercilii muscles or a combination of these, or scars in the glabellar area and the surrounding areas (including eye brow) * Any other planned facial aesthetic procedure during the trial period * Inability to substantially lessen glabellar frown lines even by physically spreading them apart * Marked facial asymmetry or ptosis of eyelid and/or eyebrow * History of facial nerve palsy * Any infection in the area of the injection sites
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite Endpoint Treatment Success (CETS) Constituted by 2 Variables: 2-point Responders at Maximum Frown (Frown as Much as Possible) at Day 30 by Investigator's Rating on the Facial Wrinkle Scale and the Patient's Assessment on 4-point Scale | Baseline to Day 30 | Composite endpoint CETS constituted by two efficacy variables: 1. The investigator's assessment on the four-point FWS: none = 0, mild = 1, moderate = 2, severe = 3. 2. Patient's assessment on the 4-point scale in comparison to sample photos: 0 = No muscle action at all; 1 = Some even slight muscle action possible i.e. visible furrows; 2 = Moderately strong muscle action possible i.e. visible muscle bulges; 3 = Strong muscle action possible which may cause local pallor. A subject was a responder only if a 2-point improvement compared to baseline occurred simultaneously for both variables. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Responders at Rest at Day 30 by Investigator's Assessment on Facial Wrinkle Scale (FWS) | Baseline to Day 30 | The investigator's assessment at rest (no muscle action in the face, no frown at all) on the four-point FWS: none = 0, mild = 1, moderate = 2, severe = 3. A responder was defined as a subject with a rating of none = 0 or mild = 1. |
| 1-point Responders at Rest at Day 30 by Patient's Assessment on 4-point Scale | Baseline to Day 30 | Patient's assessment at rest (no muscle action in the face, no frown at all) on the 4-point scale in comparison to sample photos: 0 = No visible vertical line(s) at all (i.e. no visible upright line); 1 = Slightly visible vertical line(s) (i.e. slightly visible upright line); 2 = Moderate vertical line(s) with depression (i.e. upright line with deepening); 3 = Deep vertical line(s) and depression which cannot be effaced by spreading (i.e. cannot be smoothed out). A subject was a responder if a 1-point improvement occurred compared to baseline. |
| Responders at Maximum Frown at Day 30 by Investigator's Rating on FWS | Baseline to Day 30 | The investigator's assessment at maximum frown (frown as much as possible) on the four-point FWS: none = 0, mild = 1, moderate = 2, severe = 3. A responder was defined as a subject with a rating of none = 0 or mild = 1. |
| 1-point Responders at Maximum Frown at Day 30 by Patient's Assessment on 4-point Scale | Baseline to Day 30 | Patient's assessment at maximum frown (frown as much as possible) on the 4-point scale in comparison to sample photos: 0 = No muscle action at all; 1 = Some even slight muscle action possible i.e. visible furrows; 2 = Moderately strong muscle action possible i.e. visible muscle bulges; 3 = Strong muscle action possible which may cause local pallor. A subject was a responder if a 1-point improvement occurred compared to baseline. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| IncobotulinumtoxinA (Xeomin) (20 Units) IncobotulinumtoxinA (Xeomin), also known as 'NT 201' or 'Botulinum toxin type A (150 kD), free from complexing proteins' (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection, 20 units; mode of administration: intramuscular injection | 182 |
| Placebo Placebo to IncobotulinumtoxinA (Xeomin) powder for solution for injection; dose: one injection session of solution, prepared by reconstitution of powder with 0.9% NaCl; mode of administration: same as for IncobotulinumtoxinA (Xeomin) | 89 |
| Total | 271 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | IncobotulinumtoxinA (Xeomin) (20 Units) | Placebo | Total |
|---|---|---|---|
| Age Continuous | 46.9 years STANDARD_DEVIATION 9.32 | 45.7 years STANDARD_DEVIATION 11.41 | 46.5 years STANDARD_DEVIATION 10.05 |
| Sex: Female, Male Female | 170 Participants | 84 Participants | 254 Participants |
| Sex: Female, Male Male | 12 Participants | 5 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 | 35 / 182 | 18 / 89 |
| serious Total, serious adverse events | 0 / 182 | 1 / 89 |
Outcome results
Primary
Composite Endpoint Treatment Success (CETS) Constituted by 2 Variables: 2-point Responders at Maximum Frown (Frown as Much as Possible) at Day 30 by Investigator's Rating on the Facial Wrinkle Scale and the Patient's Assessment on 4-point Scale
Composite endpoint CETS constituted by two efficacy variables: 1. The investigator's assessment on the four-point FWS: none = 0, mild = 1, moderate = 2, severe = 3. 2. Patient's assessment on the 4-point scale in comparison to sample photos: 0 = No muscle action at all; 1 = Some even slight muscle action possible i.e. visible furrows; 2 = Moderately strong muscle action possible i.e. visible muscle bulges; 3 = Strong muscle action possible which may cause local pallor. A subject was a responder only if a 2-point improvement compared to baseline occurred simultaneously for both variables.
Time frame: Baseline to Day 30
Population: Full Analysis Set (FAS): All randomized subjects treated with study medication. Missing values were imputed by the evaluations made at Day 7 according to the LOCF (last observation carried forward). If no ratings for Day 7 were available values were set to 'no 2-point responder'.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IncobotulinumtoxinA (Xeomin) (20 Units) | Composite Endpoint Treatment Success (CETS) Constituted by 2 Variables: 2-point Responders at Maximum Frown (Frown as Much as Possible) at Day 30 by Investigator's Rating on the Facial Wrinkle Scale and the Patient's Assessment on 4-point Scale | 87 Particpants |
| Placebo | Composite Endpoint Treatment Success (CETS) Constituted by 2 Variables: 2-point Responders at Maximum Frown (Frown as Much as Possible) at Day 30 by Investigator's Rating on the Facial Wrinkle Scale and the Patient's Assessment on 4-point Scale | 0 Particpants |
Comparison: The efficacy of the treatment was confirmed, if H0 was rejected at a given alpha of 5%, that means if the two sided p-value is ≤ 0.05. Power of 90%p-value: <0.000195% CI: [0.4, 0.56]Fisher Exact
Secondary
1-point Responders at Maximum Frown at Day 30 by Patient's Assessment on 4-point Scale
Patient's assessment at maximum frown (frown as much as possible) on the 4-point scale in comparison to sample photos: 0 = No muscle action at all; 1 = Some even slight muscle action possible i.e. visible furrows; 2 = Moderately strong muscle action possible i.e. visible muscle bulges; 3 = Strong muscle action possible which may cause local pallor. A subject was a responder if a 1-point improvement occurred compared to baseline.
Time frame: Baseline to Day 30
Population: The number and percentage of responses by treatment group will be provided for all secondary endpoints on the FAS observed cases.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IncobotulinumtoxinA (Xeomin) (20 Units) | 1-point Responders at Maximum Frown at Day 30 by Patient's Assessment on 4-point Scale | 152 Participants |
| Placebo | 1-point Responders at Maximum Frown at Day 30 by Patient's Assessment on 4-point Scale | 10 Participants |
Secondary
1-point Responders at Rest at Day 30 by Patient's Assessment on 4-point Scale
Patient's assessment at rest (no muscle action in the face, no frown at all) on the 4-point scale in comparison to sample photos: 0 = No visible vertical line(s) at all (i.e. no visible upright line); 1 = Slightly visible vertical line(s) (i.e. slightly visible upright line); 2 = Moderate vertical line(s) with depression (i.e. upright line with deepening); 3 = Deep vertical line(s) and depression which cannot be effaced by spreading (i.e. cannot be smoothed out). A subject was a responder if a 1-point improvement occurred compared to baseline.
Time frame: Baseline to Day 30
Population: The number and percentage of responses by treatment group will be provided for all secondary endpoints on the FAS observed cases.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IncobotulinumtoxinA (Xeomin) (20 Units) | 1-point Responders at Rest at Day 30 by Patient's Assessment on 4-point Scale | 137 Participants |
| Placebo | 1-point Responders at Rest at Day 30 by Patient's Assessment on 4-point Scale | 13 Participants |
Secondary
Responders at Maximum Frown at Day 30 by Investigator's Rating on FWS
The investigator's assessment at maximum frown (frown as much as possible) on the four-point FWS: none = 0, mild = 1, moderate = 2, severe = 3. A responder was defined as a subject with a rating of none = 0 or mild = 1.
Time frame: Baseline to Day 30
Population: The number and percentage of responses by treatment group will be provided for all secondary endpoints on the FAS observed cases. Responder as having a rating of none or mild
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IncobotulinumtoxinA (Xeomin) (20 Units) | Responders at Maximum Frown at Day 30 by Investigator's Rating on FWS | 139 Participants |
| Placebo | Responders at Maximum Frown at Day 30 by Investigator's Rating on FWS | 0 Participants |
Secondary
Responders at Rest at Day 30 by Investigator's Assessment on Facial Wrinkle Scale (FWS)
The investigator's assessment at rest (no muscle action in the face, no frown at all) on the four-point FWS: none = 0, mild = 1, moderate = 2, severe = 3. A responder was defined as a subject with a rating of none = 0 or mild = 1.
Time frame: Baseline to Day 30
Population: The number and percentage of responses by treatment group will be provided for all secondary endpoints on the FAS observed cases. Responder defined as having a rating of none or mild
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IncobotulinumtoxinA (Xeomin) (20 Units) | Responders at Rest at Day 30 by Investigator's Assessment on Facial Wrinkle Scale (FWS) | 157 Participants |
| Placebo | Responders at Rest at Day 30 by Investigator's Assessment on Facial Wrinkle Scale (FWS) | 50 Participants |