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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| IncobotulinumtoxinA (Xeomin) (20 Units) | Experimental | 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; dose: one injection session of solution, prepared by reconstitution of powder with 0.9% sodium chloride (NaCl), 20 units, total volume 0.5 mL, mode of administration: intramuscular injection |
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| Placebo | Placebo Comparator | Placebo to IncobotulinumtoxinA (Xeomin) powder for solution for injection; dose: one injection session of solution, prepared by reconstitution of powder with 0.9% NaCl, corresponding to total placebo volume 0.5 mL; mode of administration: intramuscular injection |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| IncobotulinumtoxinA (Xeomin) (20 Units) | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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:
A subject was a responder only if a 2-point improvement compared to baseline occurred simultaneously for both variables. | Baseline to Day 30 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Baseline to Day 30 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| William Hanke, MD | Principal Investigator | |
| Rhoda Narins, MD | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| About Skin Dermatoloy | Englewood | Colorado | 80113 | United States | ||
| Center for Cosmetic Enhancement |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Placebo | Drug | 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). |
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| 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. |
| Baseline to Day 30 |
| 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. | Baseline to Day 30 |
| 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. | Baseline to Day 30 |
| Aventura |
| Florida |
| 33180 |
| United States |
| Frederic Brandt | Coral Gables | Florida | 33146 | United States |
| Advanced Dermatology Research Institute | Lincolnshire | Illinois | 60069 | United States |
| Laser & Skin Surgery Center of Indiana | Carmel | Indiana | 46032 | United States |
| Joel Schlessinger | Omaha | Nebraska | 68144 | United States |
| Image Dermatology P.C. | Montclair | New Jersey | 07042 | United States |
| Rhoda Narins | White Plains | New York | 10604-2926 | United States |
| FG001 |
| 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) |
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| BG001 | 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) |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| 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:
A subject was a responder only if a 2-point improvement compared to baseline occurred simultaneously for both variables. | 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'. | Posted | Number | Particpants | Baseline to Day 30 |
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| 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. | 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 | Posted | Number | Participants | Baseline to Day 30 |
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| 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. | The number and percentage of responses by treatment group will be provided for all secondary endpoints on the FAS observed cases. | Posted | Number | Participants | Baseline to Day 30 |
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| 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. | 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 | Posted | Number | Participants | Baseline to Day 30 |
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| 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. | The number and percentage of responses by treatment group will be provided for all secondary endpoints on the FAS observed cases. | Posted | Number | Participants | Baseline to Day 30 |
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All SAEs/AEs after injection were reported. All subjects experiencing SAEs/AEs were to be monitored until AE was resolved or stabilized or until a plausible explanation for the cause of the event had been found.
Data pertaining to AEs were collected during each study visit either based on the subject's spontaneous description or by investigator's inquiry or discovered in the course of examinations done during the visit. The table of Adverse Events includes all non-serious AEs.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 | 0 | 182 | 35 | 182 | ||
| EG001 | 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) | 1 | 89 | 18 | 89 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Renal cell carcinoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 12.1 | Systematic Assessment | Start date: 06JAN2009 Stop date: 10JAN2009 Moderate intensity Not related to study treatment Recovered/resolved |
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| Nephrectomy | Surgical and medical procedures | MedDRA 12.1 | Systematic Assessment | Start date: 06JAN2009 Stop date: 06JAN2009 Moderate intensity Not related to study treatment Recovered/resolved |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | Nervous system disorders | MedDRA 12.1 | Systematic Assessment |
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| Nasopharyngitis | Infections and infestations | MedDRA 12.1 | Systematic Assessment |
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| Sinus headache | Nervous system disorders | MedDRA 12.1 | Systematic Assessment |
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| Sinusitis | Infections and infestations | MedDRA 12.1 | Systematic Assessment |
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| Upper respiratory tract infection | Infections and infestations | MedDRA 12.1 | Systematic Assessment |
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| Pharyngitis streptococcal | Infections and infestations | MedDRA 12.1 | Systematic Assessment |
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| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA 12.1 | Systematic Assessment |
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| Musculoskeletal stiffness | Musculoskeletal and connective tissue disorders | MedDRA 12.1 | Systematic Assessment |
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| Actinic keratosis | Skin and subcutaneous tissue disorders | MedDRA 12.1 | Systematic Assessment |
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No results to be published without written agreement by sponsor; manuscripts to be sent to sponsor at least 6 wks before submission. Sponsor to give written opinion within 30 d. Sponsor is entitled to exert influence on the contents of publications, to postpone publications up to 36 months after end of the study, and to name co-authors. In case of justified doubts of sponsor, the INVESTIGATOR will consider these doubts in the publication as long as the scientific neutrality is not affected.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Matthias Zerm | Merz Pharmaceuticals GmbH | 0049-69-1503 | 865 | matthias.zerm@merz.de |
| ID | Term |
|---|---|
| C545476 | incobotulinumtoxinA |
| D019274 | Botulinum Toxins, Type A |
| ID | Term |
|---|---|
| D001905 | Botulinum Toxins |
| D008666 | Metalloendopeptidases |
| D010450 | Endopeptidases |
| D010447 | Peptide Hydrolases |
| D006867 | Hydrolases |
| D004798 | Enzymes |
| D045762 | Enzymes and Coenzymes |
| D045726 | Metalloproteases |
| D001426 | Bacterial Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D001427 | Bacterial Toxins |
| D014118 | Toxins, Biological |
| D001685 | Biological Factors |
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