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The aim of this study is to assess the efficacy and safety of BoNT/a-DP in the treatment of glabellar lines in comparison with placebo, including efficacy after repeat treatments and long term safety.
This multicenter Phase 3 study is comprised of two parts. The first part of the study is a randomized, double blind, placebo-controlled, phase which aims to demonstrate efficacy and safety of BoNT/A-DP compared with placebo. The second part is an open label extension phase to evaluate efficacy after repeat treatments and long term safety. Subjects can receive a maximum of four treatment cycles over the duration of the study, a single treatment in the first cycle compared with placebo, and up to three subsequent treatments in the open label extension study.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Botulinum toxin A | Experimental | Botulinum Toxin A will be administered in double blind fashion in cycle 1. 20 Units will be administered (divided in five 0.1 mL i.m. injections) into glabellar area. |
|
| Placebo | Placebo Comparator | Placebo will be administered in double blind fashion in cycle 1 divided in five 0.1 mL injections into the glabellar area. |
|
| Botulinum toxin A open label extension phase | Experimental | Open Label Extension Phase for all Subjects of Arm 1 and 2 for up to 3 treatment cycles |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Botulinum Toxin A | Drug | Injection, 20 Units divided in five 0.1 mL i.m injections into the glabellar area |
|
| Measure | Description | Time Frame |
|---|---|---|
| Facial Wrinkle Scale (FWS) Score of 0 or 1 and an Improvement of ≥ 2 Points in FWS Score (at Maximum Frown) at Week 4 Visit Relative to Baseline, Based on Both the Investigators' and the Subjects' In-clinic Assessments | The primary endpoint is the percentage of subjects among BoNT/A-DP and placebo groups with a Facial Wrinkle Scale (FWS) score of 0 or 1 and an improvement of ≥ 2 points in FWS score (at maximum frown) at week 4 visit (of the first treatment cycle) relative to baseline (responders), based on both the investigators' and the subjects' in-clinic assessments. Thus, the primary endpoint is a composite endpoint comprising investigator and subject assessments of treatment effectiveness. FWS scores are a four-point rating scale as follows: 0 = no facial wrinkles; 1 = mild facial wrinkles; 2 = moderate facial wrinkles; and 3 = severe facial wrinkles. | Week 4 |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Responders at Maximum Frown at Week 12 | Percentage of subjects among BoNT/A-DP and placebo groups with a Facial Wrinkle Scale (FWS) score of 0 or 1 and an improvement of ≥ 2 points in FWS score (at maximum frown) at week 12 visit (of the first treatment cycle) relative to baseline (responders), based on both the investigators' and the subjects' in-clinic assessments. FWS scores are a four-point rating scale as follows: 0 = no facial wrinkles; 1 = mild facial wrinkles; 2 = moderate facial wrinkles; and 3 = severe facial wrinkles. |
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Inclusion Criteria:
Exclusion Criteria:
Eligibility Criteria for re-treatment: The following criteria MUST be met for re-treatment:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| California Dermatology & Clinical Research Institute | Encinitas | California | 92024 | United States | ||
| Center for Clinical and Cosmetic Research |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38470985 | Derived | Cox SE, Kaufman-Janette J, Cohen JL, Gold M, Joseph J, Nestor MS, Rzany B, Taylor S, Zhou J, Cecerle M, Pueraro E, Irvine R, Dayan S. LetibotulinumtoxinA Attenuates the Psychological Burden of Glabellar Lines and Is Associated With High Subject Satisfaction in Phase 3 Clinical Trials. Dermatol Surg. 2024 Jun 1;50(6):535-541. doi: 10.1097/DSS.0000000000004152. Epub 2024 Mar 12. |
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Of 251 enrolled participants, 213 met inclusion criteria and were randomized to treatment.
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| ID | Title | Description |
|---|---|---|
| FG000 | Botulinum Toxin A | Botulinum Toxin A (Clostridium botulinum toxin type A) will be administered in double blind fashion in cycle 1. 20 Units will be administered (divided in five 0.1 mL i.m. injections) into the glabellar area. Botulinum Toxin A: Injection, 20 Units divided in five 0.1 mL i.m. injections into the glabellar area |
| FG001 | Placebo | Placebo will be administered in double blind fashion in cycle 1. divided in five 0.1 mL i.m. injections into the glabellar area. Placebo: Injection, sodium chloride 0.9 % divided in five 0.1 mL i.m. injections into glabellar area |
| FG002 | Botulinum Toxin A Open Label Extension Arm | Open Label Extension Arm where all Subjects from Arm 1 and 2 can receive Experimental Treatment in up to 3 treatment cycles. 20 Units will be administered (divided in five 0.1 mL i.m. injections) into the glabellar area. Botulinum Toxin A: Injection, 20 Units divided in five 0.1 mL i.m. injections into the glabellar area in up to 3 treatment cycles |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Double Blind Phase |
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| Open Label Phase |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Botulinum Toxin A | Botulinum Toxin A (Clostridium botulinum toxin type A) will be administered in double blind fashion in cycle 1. 20 Units will be administered (divided in five 0.1 mL i.m. injections) into the glabellar area. Botulinum Toxin A: Injection, 20 Units divided in five 0.1 mL i.m. injections into the glabellar area |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Facial Wrinkle Scale (FWS) Score of 0 or 1 and an Improvement of ≥ 2 Points in FWS Score (at Maximum Frown) at Week 4 Visit Relative to Baseline, Based on Both the Investigators' and the Subjects' In-clinic Assessments | The primary endpoint is the percentage of subjects among BoNT/A-DP and placebo groups with a Facial Wrinkle Scale (FWS) score of 0 or 1 and an improvement of ≥ 2 points in FWS score (at maximum frown) at week 4 visit (of the first treatment cycle) relative to baseline (responders), based on both the investigators' and the subjects' in-clinic assessments. Thus, the primary endpoint is a composite endpoint comprising investigator and subject assessments of treatment effectiveness. FWS scores are a four-point rating scale as follows: 0 = no facial wrinkles; 1 = mild facial wrinkles; 2 = moderate facial wrinkles; and 3 = severe facial wrinkles. | The population used consists of all randomized subjects who received at least one injection with study medication. Participants were analyzed as randomized. Participants with missing investigator or subject in-clinic assessments with the Facial Wrinkle Scale (FWS) at baseline or week 4 were assigned as being non-responders. | Posted | Count of Participants | Participants | Week 4 |
Up to 60 weeks post first treatment
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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 | Botulinum Toxin A | Botulinum Toxin A (Clostridium botulinum toxin type A) will be administered in double blind fashion in cycle 1. 20 Units will be administered (divided in five 0.1 mL i.m. injections) into the glabellar area. Botulinum Toxin A: Injection, 20 Units divided in five 0.1 mL i.m. injections into the glabellar area |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vitreous detachment | Eye disorders | MedDRA 20.0 | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Upper respiratory tract infection | Infections and infestations | MedDRA 20.0 | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Clinical Development - Head of Clinical Operations | Croma Pharma GmbH | +432262684680 | clinical.studies@croma.at |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Aug 25, 2016 | Dec 11, 2024 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Aug 15, 2017 | Dec 11, 2024 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D019274 | Botulinum Toxins, Type A |
| D012965 | Sodium Chloride |
| ID | Term |
|---|---|
| D001905 | Botulinum Toxins |
| D008666 | Metalloendopeptidases |
| D010450 | Endopeptidases |
| D010447 | Peptide Hydrolases |
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| Placebo | Drug | injection, sodium chloride 0.9% divided in five 0.1 mL i.m. injections into the glabellar area |
|
|
| Botulinum Toxin A - Open Label | Drug | Open Label Extension Phase with Experimental Drug; Injection, 20 Units divided in five 0.1 mL i.m injections into the glabellar area |
|
|
| Week 12 |
| Percentage of Responders at Maximum Frown at Week 16 | Percentage of subjects among BoNT/A-DP and placebo groups with a Facial Wrinkle Scale (FWS) score of 0 or 1 and an improvement of ≥ 2 points in FWS score (at maximum frown) at week 16 visit (of the first treatment cycle) relative to baseline (responders), based on both the investigators' and the subjects' in-clinic assessments. FWS scores are a four-point rating scale as follows: 0 = no facial wrinkles; 1 = mild facial wrinkles; 2 = moderate facial wrinkles; and 3 = severe facial wrinkles. | Week 16 |
| The Percentage of Subjects With a ≥ 1 Point Reduction in Facial Wrinkle Scale (FWS) Score at Rest at Week 4 Based Separately on the Investigators' and the Subjects' In-clinic Assessments | The Percentage of subjects with a ≥ 1 point reduction in Facial Wrinkle Scale (FWS) score at rest at week 4 in the first treatment cycle, based separately on the investigators' and the subjects' in-clinic assessments (applicable only for subjects who have a FWS score at rest ≥ 1 at baseline). FWS scores are a four-point rating scale as follows: 0 = no facial wrinkles; 1 = mild facial wrinkles; 2 = moderate facial wrinkles; and 3 = severe facial wrinkles. | Week 4 |
| Percentage of Responders at Maximum Frown at Weeks 20, 24, 28 and 32 | Percentage of subjects among BoNT/A-DP and placebo groups with a Facial Wrinkle Scale (FWS) score of 0 or 1 and an improvement of ≥ 2 points in FWS score (at maximum frown) at the respective visit (of the first treatment cycle) relative to baseline (responders), based on both the investigators' and the subjects' in-clinic assessments. FWS scores are a four-point rating scale as follows: 0 = no facial wrinkles; 1 = mild facial wrinkles; 2 = moderate facial wrinkles; and 3 = severe facial wrinkles. | Week 20, Week 24, Week 28, Week 32 |
| Extent of Change in Psychological Impact (Emotional and Social Functioning and Concerns Relating to Glabellar Lines) | Extent of change in psychological impact at week 4 after first treatment, relative to baseline, assessed by
| Week 4 |
| Percentage of Responders at Maximum Frown at Weeks 1, 2 and 8 | The Percentage of responders among BoNT/A-DP and placebo groups with a Facial Wrinkle Scale (FWS) score at maximum frown of 0 or 1 and an improvement ≥ 2 points in FWS score (at maximum frown) during the first treatment cycle visit relative to baseline, based on both the investigators' and the subjects' in-clinic assessments (composite endpoint, at weeks 1, 2 and 8). FWS scores are a four-point rating scale as follows: 0 = no facial wrinkles; 1 = mild facial wrinkles; 2 = moderate facial wrinkles; and 3 = severe facial wrinkles. | Week 1, Week 2, Week 8 |
| Percentage of Subjects With ≥ 2-point Reduction in Facial Wrinkle Scale (FWS) Score (at Maximum Frown) Based on Independent Raters' Assessment of of Photographs | The percentage of subjects with ≥ 2-point reduction in Facial Wrinkle Scale (FWS) score (at maximum frown) in the BoNT/A-DP and placebo groups during the first treatment cycle visit relative to baseline, based on the independent raters' assessment of photographs (at baseline and visits 2, 4, 12, 16 and 20 weeks after treatment, within the first treatment cycle). The median value of all assessments of the same photography was considered for analysis. FWS scores are a four-point rating scale as follows: 0 = no facial wrinkles; 1 = mild facial wrinkles; 2 = moderate facial wrinkles; and 3 = severe facial wrinkles. | Week 2, Week 4, Week 12, Week 16, Week 20 |
| Time to Onset of Effect in the BoNT/A-DP and Placebo Groups in the First Treatment Cycle | Time to onset of effect in the BoNT/A-DP and placebo groups in the first treatment cycle, as measured at weeks 1, 2 and 4 based separately on subject and investigator assessment. Onset of effect defined as at least a 1 point improvement in Facial Wrinkle Scale (FWS) score from baseline (at maximum frown). FWS scores are a four-point rating scale as follows: 0 = no facial wrinkles; 1 = mild facial wrinkles; 2 = moderate facial wrinkles; and 3 = severe facial wrinkles. | From treatment at Day 0 to Week 4 in Treatment Cycle 1 |
| Satisfaction With Treatment, During Each Treatment Cycle, as Assessed by the Validated FACE-Q Satisfaction With Outcome Scale | The extent of subject perceptions of effect of, and satisfaction with, treatment in the BoNT/A-DP and placebo groups, during each treatment cycle, as assessed by the validated FACE-Q Satisfaction with Outcome Scale. The FACE-Q Satisfaction with Outcome scale is a patient-reported outcome measure designed to assess a patient's satisfaction with the results of a facial aesthetic procedure. This scale comprises six items, each with four response options: "definitely agree", "somewhat agree", "somewhat disagree", and "definitely disagree". | Week 4 of Treatment Cycles 1, 2, 3 and 4 |
| Percentage of Subjects With a ≥ 1 Point Reduction in Facial Wrinkle Scale (FWS) Score at Rest Based on the Independent Rater's Assessment of Photographs | The Percentage of subjects with a ≥ 1 point reduction in Facial Wrinkle Scale (FWS) score at rest in the BoNT/A-DP and placebo groups, relative to baseline, during the first treatment cycle, based on the independent raters' assessment of photographs. The median value of all assessments of the same photography was considered for analysis. FWS scores are a four-point rating scale as follows: 0 = no facial wrinkles; 1 = mild facial wrinkles; 2 = moderate facial wrinkles; and 3 = severe facial wrinkles. | Week 2, Week 4, Week 12, Week 16, Week 20, Week 24, Week 28 |
| Percentage of Subjects With a Facial Wrinkle Scale (FWS) Score of 0 or 1 and an Improvement of ≥ 2 Points in FWS Score (at Maximum Frown) at 4 Weeks After Re-treatment Relative to the Rating at the Preceding End-of-Cycle Visit | The percentage of subjects with a Facial Wrinkle Scale (FWS) score of 0 or 1 and an improvement of ≥ 2 points in FWS score (at maximum frown) at 4 weeks after re-treatment relative to the rating at the preceding end-of-cycle visit, based on both the investigators' and the subjects' in-clinic assessments (composite endpoint). FWS scores are a four-point rating scale as follows: 0 = no facial wrinkles; 1 = mild facial wrinkles; 2 = moderate facial wrinkles; and 3 = severe facial wrinkles. | Week 4 of Treatment Cycles 2, 3 and 4 |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious AEs (SAEs) and AEs of Special Interest (AESIs) | Frequency, severity and causal relationship of adverse events (AEs), serious adverse events (SAEs) and adverse events of special interest (AESIs) during the entire study period. | Through study completion (60 weeks) |
| Number of Participants With Neutralizing Anti-Drug Antibodies | Number of Participants with Neutralizing Anti-Drug Antibodies Antibody formation, evaluation pre-dose before each treatment, at 4 weeks after each treatment and at the final study visit. | Through study completion (60 weeks) |
| Change From Baseline of Alanine Aminotransferase, Alkaline Phosphatase, Aspartate Aminotransferase, Gamma Glutamyl Transferase | Safety assessments by evaluating change from baseline of Alanine Aminotransferase, Alkaline Phosphatase, Aspartate Aminotransferase, Gamma Glutamyl Transferase as per the study schedule | Week 4 of each treatment cycle |
| Change From Baseline of Bilirubin, Creatinine | Safety assessments by evaluating change from baseline of Bilirubin, Creatinine as per the study schedule as change from baseline | Week 4 of each treatment cycle |
| Change From Baseline of Cholesterol, Glucose, Potassium, Sodium, Urea Nitrogen | Safety assessments by evaluating change from baseline of Cholesterol, Glucose, Potassium, Sodium, Urea Nitrogen as per the study schedule | Week 4 of each treatment cycle |
| Change From Baseline of Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils, Platelets | Safety assessments by evaluating change from baseline of Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils, Platelets as per the study schedule | Week 4 of each treatment cycle |
| Change From Baseline of Erythrocytes | Safety assessments by evaluating change from baseline of Erythrocytes as per the study schedule | Week 4 of each treatment cycle |
| Change From Baseline of Erythrocyte MCHC, Hemoglobin | Safety assessments by evaluating change from baseline of Erythrocyte MCHC, Hemoglobin as per the study schedule | Week 4 of each treatment cycle |
| Change From Baseline of of Erythrocyte MCV | Safety assessments by evaluating change from baseline of Erythrocyte MCV as per the study schedule | Week 4 of each treatment cycle |
| Change From Baseline of Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/Leukocytes, Neutrophils/Leukocytes | Safety assessments by evaluating change from baseline of Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/Leukocytes, Neutrophils/Leukocytes as per the study schedule as change from baseline | Week 4 of each treatment cycle |
| Change From Baseline of Systolic and Diastolic Blood Pressure | Safety assessments by evaluating change from baseline of Systolic and Diastolic Blood Pressure as per the study schedule | Week 4 of Treatment Cycles 1, 2, 3 and 4 |
| Change From Baseline of Pulse Rate | Safety assessments by evaluating change from baseline of Pulse rate as per the study schedule | Week 4 of Treatment Cycles 1, 2, 3 and 4 |
| Number of Participants With Normal and Abnormal Electrocardiogram | Safety assessments by evaluating Electrocardiogram as per the study schedule | Last visit of Treatment Cycle 1 (End of Cycle procedures) conducted upon confirmation of eligibility for retreatment, which was assessed starting 12 weeks post-treatment with 4-weekly evaluations up to a maximum of 48 weeks post treatment. |
| Aventura |
| Florida |
| 33180 |
| United States |
| Holcomb Kreithen Plastic Surgery | Sarasota | Florida | United States |
| Skin Laser And Surgery Specialists Of New York & New Jersey | Hillsborough | New Jersey | United States |
| The Center for Dermatology, Cosmetic & Laser Surger | Mount Kisco | New York | United States |
| Lorenc Aesthetic Plastic Surgery Center | New York | New York | United States |
| Skintastic Medical | Plano | Texas | 75093 | United States |
| NOT COMPLETED |
|
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| Placebo |
Placebo will be administered in double blind fashion in cycle 1. divided in five 0.1 mL i.m. injections into the glabellar area. Placebo: Injection, sodium chloride 0.9 % divided in five 0.1 mL i.m. injections into glabellar area |
| BG002 | Total | Total of all reporting groups |
| Participants |
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Count of Participants | Participants |
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| Facial Wrinkle Scale at Maximum Frown by Investigator and Subject In-clinic Assessment | Facial Wrinkle Scale scores are a four-point rating scale as follows: 0 = no facial wrinkles; 1 = mild facial wrinkles; 2 = moderate facial wrinkles; and 3 = severe facial wrinkles. | Count of Participants | Participants |
|
| ID | Title | Description |
|---|---|---|
| OG000 | Botulinum Toxin A | Botulinum Toxin A (Clostridium botulinum toxin type A) will be administered in double blind fashion in cycle 1. 20 Units will be administered (divided in five 0.1 mL i.m. injections) into the glabellar area. Botulinum Toxin A: Injection, 20 Units divided in five 0.1 mL i.m. injections into the glabellar area |
| OG001 | Placebo | Placebo will be administered in double blind fashion in cycle 1. divided in five 0.1 mL i.m. injections into the glabellar area. Placebo: Injection, sodium chloride 0.9 % divided in five 0.1 mL i.m. injections into glabellar area |
|
|
|
| Secondary | Percentage of Responders at Maximum Frown at Week 12 | Percentage of subjects among BoNT/A-DP and placebo groups with a Facial Wrinkle Scale (FWS) score of 0 or 1 and an improvement of ≥ 2 points in FWS score (at maximum frown) at week 12 visit (of the first treatment cycle) relative to baseline (responders), based on both the investigators' and the subjects' in-clinic assessments. FWS scores are a four-point rating scale as follows: 0 = no facial wrinkles; 1 = mild facial wrinkles; 2 = moderate facial wrinkles; and 3 = severe facial wrinkles. | The population used consists of all randomized subjects who received at least one injection with study medication. Participants were analyzed as randomized. Participants with missing investigator or subject in-clinic assessments with the Facial Wrinkle Scale (FWS) at baseline or week 12 were assigned as being non-responders. | Posted | Count of Participants | Participants | Week 12 |
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| Secondary | Percentage of Responders at Maximum Frown at Week 16 | Percentage of subjects among BoNT/A-DP and placebo groups with a Facial Wrinkle Scale (FWS) score of 0 or 1 and an improvement of ≥ 2 points in FWS score (at maximum frown) at week 16 visit (of the first treatment cycle) relative to baseline (responders), based on both the investigators' and the subjects' in-clinic assessments. FWS scores are a four-point rating scale as follows: 0 = no facial wrinkles; 1 = mild facial wrinkles; 2 = moderate facial wrinkles; and 3 = severe facial wrinkles. | The population used consists of all randomized subjects who received at least one injection with study medication and for whom data are available for week 16 or who were re-treated before week 16. They were analyzed as randomized and participants who were re-treated before week 16 were counted as non-responders. | Posted | Count of Participants | Participants | Week 16 |
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| Secondary | The Percentage of Subjects With a ≥ 1 Point Reduction in Facial Wrinkle Scale (FWS) Score at Rest at Week 4 Based Separately on the Investigators' and the Subjects' In-clinic Assessments | The Percentage of subjects with a ≥ 1 point reduction in Facial Wrinkle Scale (FWS) score at rest at week 4 in the first treatment cycle, based separately on the investigators' and the subjects' in-clinic assessments (applicable only for subjects who have a FWS score at rest ≥ 1 at baseline). FWS scores are a four-point rating scale as follows: 0 = no facial wrinkles; 1 = mild facial wrinkles; 2 = moderate facial wrinkles; and 3 = severe facial wrinkles. | The population used consists of all randomized subjects who received at least one injection with study medication and who had a Facial Wrinkle Scale (FWS) score at rest ≥1 at baseline. Participants were analyzed as randomized. Participants with missing investigator or subject in-clinic assessments with the Facial Wrinkle Scale at week 4 were assigned as being non-responders. | Posted | Count of Participants | Participants | Week 4 |
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| Secondary | Percentage of Responders at Maximum Frown at Weeks 20, 24, 28 and 32 | Percentage of subjects among BoNT/A-DP and placebo groups with a Facial Wrinkle Scale (FWS) score of 0 or 1 and an improvement of ≥ 2 points in FWS score (at maximum frown) at the respective visit (of the first treatment cycle) relative to baseline (responders), based on both the investigators' and the subjects' in-clinic assessments. FWS scores are a four-point rating scale as follows: 0 = no facial wrinkles; 1 = mild facial wrinkles; 2 = moderate facial wrinkles; and 3 = severe facial wrinkles. | The population used consists of all randomized subjects who received at least one injection with study medication and for whom data are available for the respective visit. They were analyzed as randomized. In addition, only for Week 20 visit participants who were re-treated before week 20 were counted as non-responders in the analysis. | Posted | Count of Participants | Participants | Week 20, Week 24, Week 28, Week 32 |
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| Secondary | Extent of Change in Psychological Impact (Emotional and Social Functioning and Concerns Relating to Glabellar Lines) | Extent of change in psychological impact at week 4 after first treatment, relative to baseline, assessed by
| The population used consists of all randomized subjects who received at least one injection with study medication and for whom data are available for the respective timepoint. They were analyzed as randomized. | Posted | Mean | Standard Deviation | score on a scale | Week 4 |
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| Secondary | Percentage of Responders at Maximum Frown at Weeks 1, 2 and 8 | The Percentage of responders among BoNT/A-DP and placebo groups with a Facial Wrinkle Scale (FWS) score at maximum frown of 0 or 1 and an improvement ≥ 2 points in FWS score (at maximum frown) during the first treatment cycle visit relative to baseline, based on both the investigators' and the subjects' in-clinic assessments (composite endpoint, at weeks 1, 2 and 8). FWS scores are a four-point rating scale as follows: 0 = no facial wrinkles; 1 = mild facial wrinkles; 2 = moderate facial wrinkles; and 3 = severe facial wrinkles. | The population used consists of all randomized subjects who received at least one injection with study medication. Participants were analyzed as randomized. Participants with missing investigator or subject in-clinic assessments with the Facial Wrinkle Scale (FWS) at baseline or at the respective visit were assigned as being non-responders. | Posted | Count of Participants | Participants | Week 1, Week 2, Week 8 |
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| Secondary | Percentage of Subjects With ≥ 2-point Reduction in Facial Wrinkle Scale (FWS) Score (at Maximum Frown) Based on Independent Raters' Assessment of of Photographs | The percentage of subjects with ≥ 2-point reduction in Facial Wrinkle Scale (FWS) score (at maximum frown) in the BoNT/A-DP and placebo groups during the first treatment cycle visit relative to baseline, based on the independent raters' assessment of photographs (at baseline and visits 2, 4, 12, 16 and 20 weeks after treatment, within the first treatment cycle). The median value of all assessments of the same photography was considered for analysis. FWS scores are a four-point rating scale as follows: 0 = no facial wrinkles; 1 = mild facial wrinkles; 2 = moderate facial wrinkles; and 3 = severe facial wrinkles. | The population used consists of all randomized subjects who received at least one injection with study medication and for whom data are available for the respective timepoint. Participants were analyzed as randomized. | Posted | Count of Participants | Participants | Week 2, Week 4, Week 12, Week 16, Week 20 |
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| Secondary | Time to Onset of Effect in the BoNT/A-DP and Placebo Groups in the First Treatment Cycle | Time to onset of effect in the BoNT/A-DP and placebo groups in the first treatment cycle, as measured at weeks 1, 2 and 4 based separately on subject and investigator assessment. Onset of effect defined as at least a 1 point improvement in Facial Wrinkle Scale (FWS) score from baseline (at maximum frown). FWS scores are a four-point rating scale as follows: 0 = no facial wrinkles; 1 = mild facial wrinkles; 2 = moderate facial wrinkles; and 3 = severe facial wrinkles. | The population used consists of all randomized subjects who received at least one injection with study medication and for whom data are available for the respective timepoint. Participants were analyzed as randomized. | Posted | Median | Inter-Quartile Range | Days | From treatment at Day 0 to Week 4 in Treatment Cycle 1 |
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| Secondary | Satisfaction With Treatment, During Each Treatment Cycle, as Assessed by the Validated FACE-Q Satisfaction With Outcome Scale | The extent of subject perceptions of effect of, and satisfaction with, treatment in the BoNT/A-DP and placebo groups, during each treatment cycle, as assessed by the validated FACE-Q Satisfaction with Outcome Scale. The FACE-Q Satisfaction with Outcome scale is a patient-reported outcome measure designed to assess a patient's satisfaction with the results of a facial aesthetic procedure. This scale comprises six items, each with four response options: "definitely agree", "somewhat agree", "somewhat disagree", and "definitely disagree". | The population used consists of all randomized subjects who received at least one injection with study medication in the respective treatment cycle. Participants were analyzed as randomized. | Posted | Count of Participants | Participants | Week 4 of Treatment Cycles 1, 2, 3 and 4 |
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| Secondary | Percentage of Subjects With a ≥ 1 Point Reduction in Facial Wrinkle Scale (FWS) Score at Rest Based on the Independent Rater's Assessment of Photographs | The Percentage of subjects with a ≥ 1 point reduction in Facial Wrinkle Scale (FWS) score at rest in the BoNT/A-DP and placebo groups, relative to baseline, during the first treatment cycle, based on the independent raters' assessment of photographs. The median value of all assessments of the same photography was considered for analysis. FWS scores are a four-point rating scale as follows: 0 = no facial wrinkles; 1 = mild facial wrinkles; 2 = moderate facial wrinkles; and 3 = severe facial wrinkles. | The population used consists of all randomized subjects who received at least one injection with study medication and for whom data are available for the respective timepoint. Participants were analyzed as randomized. | Posted | Count of Participants | Participants | Week 2, Week 4, Week 12, Week 16, Week 20, Week 24, Week 28 |
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| Secondary | Percentage of Subjects With a Facial Wrinkle Scale (FWS) Score of 0 or 1 and an Improvement of ≥ 2 Points in FWS Score (at Maximum Frown) at 4 Weeks After Re-treatment Relative to the Rating at the Preceding End-of-Cycle Visit | The percentage of subjects with a Facial Wrinkle Scale (FWS) score of 0 or 1 and an improvement of ≥ 2 points in FWS score (at maximum frown) at 4 weeks after re-treatment relative to the rating at the preceding end-of-cycle visit, based on both the investigators' and the subjects' in-clinic assessments (composite endpoint). FWS scores are a four-point rating scale as follows: 0 = no facial wrinkles; 1 = mild facial wrinkles; 2 = moderate facial wrinkles; and 3 = severe facial wrinkles. | The population used consists of all randomized subjects who received at least one injection with study medication in the respective treatment cycle and for whom data are available for the respective timepoint. Participants were analyzed as randomized. | Posted | Count of Participants | Participants | Week 4 of Treatment Cycles 2, 3 and 4 |
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| Secondary | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious AEs (SAEs) and AEs of Special Interest (AESIs) | Frequency, severity and causal relationship of adverse events (AEs), serious adverse events (SAEs) and adverse events of special interest (AESIs) during the entire study period. | The population used consists of all subjects who received at least one injection with study medication. Participants were analyzed as treated. | Posted | Count of Participants | Participants | Through study completion (60 weeks) |
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| Secondary | Number of Participants With Neutralizing Anti-Drug Antibodies | Number of Participants with Neutralizing Anti-Drug Antibodies Antibody formation, evaluation pre-dose before each treatment, at 4 weeks after each treatment and at the final study visit. | The population used consists of all subjects who received at least one injection with study medication. Participants were analyzed as treated. Confirmation assays have only been performed for subjects with a reactive Screening Assay result. | Posted | Count of Participants | Participants | Through study completion (60 weeks) |
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| Secondary | Change From Baseline of Alanine Aminotransferase, Alkaline Phosphatase, Aspartate Aminotransferase, Gamma Glutamyl Transferase | Safety assessments by evaluating change from baseline of Alanine Aminotransferase, Alkaline Phosphatase, Aspartate Aminotransferase, Gamma Glutamyl Transferase as per the study schedule | The population used consists of all subjects who received at least one injection with study medication and have data available for the respective visit. Participants were analyzed as treated. | Posted | Mean | Standard Deviation | U/L | Week 4 of each treatment cycle |
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| Secondary | Change From Baseline of Bilirubin, Creatinine | Safety assessments by evaluating change from baseline of Bilirubin, Creatinine as per the study schedule as change from baseline | The population used consists of all subjects who received at least one injection with study medication and have data available for the respective visit. Participants were analyzed as treated. | Posted | Mean | Standard Deviation | μmol/L | Week 4 of each treatment cycle |
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| Secondary | Change From Baseline of Cholesterol, Glucose, Potassium, Sodium, Urea Nitrogen | Safety assessments by evaluating change from baseline of Cholesterol, Glucose, Potassium, Sodium, Urea Nitrogen as per the study schedule | The population used consists of all subjects who received at least one injection with study medication and have data available for the respective visit. Participants were analyzed as treated. | Posted | Mean | Standard Deviation | mmol/L | Week 4 of each treatment cycle |
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| Secondary | Change From Baseline of Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils, Platelets | Safety assessments by evaluating change from baseline of Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils, Platelets as per the study schedule | The population used consists of all subjects who received at least one injection with study medication and have data available for the respective visit. Participants were analyzed as treated. | Posted | Mean | Standard Deviation | x10^9 cells/L | Week 4 of each treatment cycle |
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| Secondary | Change From Baseline of Erythrocytes | Safety assessments by evaluating change from baseline of Erythrocytes as per the study schedule | The population used consists of all subjects who received at least one injection with study medication and have data available for the respective visit. Participants were analyzed as treated. | Posted | Mean | Standard Deviation | x10^12 cells/L | Week 4 of each treatment cycle |
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| Secondary | Change From Baseline of Erythrocyte MCHC, Hemoglobin | Safety assessments by evaluating change from baseline of Erythrocyte MCHC, Hemoglobin as per the study schedule | The population used consists of all subjects who received at least one injection with study medication and have data available for the respective visit. Participants were analyzed as treated. | Posted | Mean | Standard Deviation | g/dL | Week 4 of each treatment cycle |
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| Secondary | Change From Baseline of of Erythrocyte MCV | Safety assessments by evaluating change from baseline of Erythrocyte MCV as per the study schedule | The population used consists of all subjects who received at least one injection with study medication and have data available for the respective visit. Participants were analyzed as treated. | Posted | Mean | Standard Deviation | fL | Week 4 of each treatment cycle |
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| Secondary | Change From Baseline of Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/Leukocytes, Neutrophils/Leukocytes | Safety assessments by evaluating change from baseline of Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/Leukocytes, Neutrophils/Leukocytes as per the study schedule as change from baseline | The population used consists of all subjects who received at least one injection with study medication and have data available for the respective visit. Participants were analyzed as treated. | Posted | Mean | Standard Deviation | % of leukocytes | Week 4 of each treatment cycle |
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| Secondary | Change From Baseline of Systolic and Diastolic Blood Pressure | Safety assessments by evaluating change from baseline of Systolic and Diastolic Blood Pressure as per the study schedule | The population used consists of all subjects who received at least one injection with study medication and have data available for the respective visit. Participants were analyzed as treated. | Posted | Mean | Standard Deviation | mmHg | Week 4 of Treatment Cycles 1, 2, 3 and 4 |
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| Secondary | Change From Baseline of Pulse Rate | Safety assessments by evaluating change from baseline of Pulse rate as per the study schedule | The population used consists of all subjects who received at least one injection with study medication and have data available for the respective visit. Participants were analyzed as treated. | Posted | Mean | Standard Deviation | bpm | Week 4 of Treatment Cycles 1, 2, 3 and 4 |
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| Secondary | Number of Participants With Normal and Abnormal Electrocardiogram | Safety assessments by evaluating Electrocardiogram as per the study schedule | The population used consists of all subjects who received at least one injection with study medication and who have data available post-baseline and the respective category of baseline electrocardiogram interpretation. Participants were analyzed as treated. | Posted | Count of Participants | Participants | Last visit of Treatment Cycle 1 (End of Cycle procedures) conducted upon confirmation of eligibility for retreatment, which was assessed starting 12 weeks post-treatment with 4-weekly evaluations up to a maximum of 48 weeks post treatment. |
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|
| 0 |
| 160 |
| 0 |
| 160 |
| 12 |
| 160 |
| EG001 | Placebo | Placebo will be administered in double blind fashion in cycle 1. divided in five 0.1 mL i.m. injections into the glabellar area. Placebo: Injection, sodium chloride 0.9 % divided in five 0.1mL i.m. injections into glabellar area | 0 | 53 | 0 | 53 | 2 | 53 |
| EG002 | Botulinum Toxin A Open Label Extension Arm | Open Label Extension Arm where all Subjects from Arm 1 and 2 can receive Experimental Treatment in up to 3 treatment cycles. 20 Units will be administered (divided in five 0.1 mL i.m. injections) into the glabellar area. Botulinum Toxin A: Injection, 20 Units divided in five 0.1 mL i.m. injections into the glabellar area in up to 3 treatment cycles | 0 | 195 | 2 | 195 | 18 | 195 |
| Chest pain | General disorders | MedDRA 20.0 | Non-systematic Assessment |
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| Adenomyosis | Reproductive system and breast disorders | MedDRA 20.0 | Non-systematic Assessment |
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| Vaginal haemorrhage | Reproductive system and breast disorders | MedDRA 20.0 | Non-systematic Assessment |
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| Urinary tract infection | Infections and infestations | MedDRA 20.0 | Non-systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 20.0 | Non-systematic Assessment |
|
Not provided
| 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 |
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017670 | Sodium Compounds |
| Moderate facial wrinkles |
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| Severe facial wrinkles |
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| Subject's In-clinic Assessment |
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|
Test performed for Subject's In-clinic Assessment |
| Cochran-Mantel-Haenszel |
| <0.001 |
For the testing a hierarchical approach has been applied. The result of this test is considered confirmative if the test of the Primary and all previous Secondary Outcome Measures show a confirmatory result at a one-sided significance level of 0.025. |
| Superiority |
| Week 24 |
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| Week 28 |
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| Week 32 |
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| Modified Skindex-16 (GL-QoL) Overall score - Change from Baseline at Week 4 |
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| FACE-Q Appraisal of Lines Between Eyebrows - Change from Baseline at Week 4 |
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| Age Appraisal VAS - Change from Baseline at Week 4 |
|
Test performed for Modified Skindex-16 (GL-QoL) Social Functioning domain - Change from Baseline at Week 4 |
| Wilcoxon (Mann-Whitney) |
| <0.001 |
For the testing a hierarchical approach has been applied. The result of this test is considered confirmative if the test of the Primary and all previous Secondary Outcome Measures show a confirmatory result at a one-sided significance level of 0.025. |
| Superiority |
| Test performed for Modified Skindex-16 (GL-QoL) Overall score - Change from Baseline at Week 4. | Wilcoxon (Mann-Whitney) | <0.001 | For the testing a hierarchical approach has been applied. The result of this test is considered confirmative if the test of the Primary and all previous Secondary Outcome Measures show a confirmatory result at a one-sided significance level of 0.025. | Superiority |
| Test performed for FACE-Q Appraisal of Lines Between Eyebrows - Change from Baseline at Week 4 | Wilcoxon (Mann-Whitney) | <0.001 | For the testing a hierarchical approach has been applied. The result of this test is considered confirmative if the test of the Primary and all previous Secondary Outcome Measures show a confirmatory result at a one-sided significance level of 0.025. | Superiority |
| Test performed for FACE-Q Age Appraisal VAS score | Wilcoxon (Mann-Whitney) | <0.001 | For the testing a hierarchical approach has been applied. The result of this test is considered confirmative if the test of the Primary and all previous Secondary Outcome Measures show a confirmatory result at a one-sided significance level of 0.025. | Superiority |
| Week 8 |
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| Week 4 |
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| Week 12 |
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| Week 16 |
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| Week 20 |
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| Somewhat disagree |
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| Somewhat agree |
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| Definitely agree |
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| Missing |
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| Cycle 1 Week 4 - expected |
|
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| Cycle 1 Week 4 - great |
|
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| Cycle 1 Week 4 - look in mirror |
|
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| Cycle 1 Week 4 - fantastic |
|
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| Cycle 1 Week 4 - miraculous |
|
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| Cycle 2 Week 4 - pleased |
|
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| Cycle 2 Week 4 - expected |
|
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| Cycle 2 Week 4 - great |
|
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| Cycle 2 Week 4 - look in mirror |
|
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| Cycle 2 Week 4 - fantastic |
|
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| Cycle 2 Week 4 - miraculous |
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| Cycle 3 Week 4 - pleased |
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| Cycle 3 Week 4 - expected |
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| Cycle 3 Week 4 - great |
|
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| Cycle 3 Week 4 - look in mirror |
|
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| Cycle 3 Week 4 - fantastic |
|
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| Cycle 3 Week 4 - miraculous |
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| Cycle 4 Week 4 - pleased |
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| Cycle 4 Week 4 - expected |
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| Cycle 4 Week 4 - great |
|
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| Cycle 4 Week 4 - look in mirror |
|
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| Cycle 4 Week 4 - fantastic |
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| Cycle 4 Week 4 - miraculous |
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| Week 4 |
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| Week 12 |
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| Week 16 |
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| Week 20 |
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| Week 24 |
|
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| Week 28 |
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| Week 4 after 3rd Re-treatment |
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| Subjects with any Injection Procedure Related TEAE |
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| Subjects with any Severe TEAE |
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| Subjects with any Serious TEAE |
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| Subjects with any Adverse Events of Special Interest (AESI) |
|
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| Week 4 of each treatment cycle - Alkaline Phosphatase (U/L) |
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| Week 4 of each treatment cycle - Aspartate Aminotransferase (U/L) |
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| Week 4 of each treatment cycle - Gamma Glutamyl Transferase (U/L) |
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| Week 4 of each treatment cycle - Creatinine (μmol/L) |
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| Week 4 of each treatment cycle - Glucose (mmol/L) |
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| Week 4 of each treatment cycle - Potassium (mmol/L) |
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| Week 4 of each treatment cycle - Sodium (mmol/L) |
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| Week 4 of each treatment cycle - Urea Nitrogen (mmol/L) |
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| Week 4 of each treatment cycle - Eosinophils (x10^9 cells/L) |
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| Week 4 of each treatment cycle - Leukocytes (x10^9 cells/L) |
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| Week 4 of each treatment cycle - Lymphocytes (x10^9 cells/L) |
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| Week 4 of each treatment cycle - Monocytes (x10^9 cells/L) |
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| Week 4 of each treatment cycle - Neutrophils (x10^9 cells/L) |
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| Week 4 of each treatment cycle - Platelets (x10^9 cells/L) |
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| Week 4 of each treatment cycle - Hemoglobin (g/dL) |
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| Week 4 of each treatment cycle - Eosinophils/Leukocytes (%) |
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| Week 4 of each treatment cycle - Lymphocytes/Leukocytes (%) |
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| Week 4 of each treatment cycle - Monocytes/Leukocytes (%) |
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| Week 4 of each treatment cycle - Neutrophils/Leukocytes (%) |
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| Week 4 of each treatment cycle - Diastolic Blood Pressure (mmHg) |
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| Last observation in Cycle 1 - Abnormal |
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