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.
The study is a parallel-group, randomized, double blind, placebo-controlled study followed by an open label extension. An interim Analysis will be performed when all subjects finalized the re-evaluation for retreatment visit at week 16 of the first treatment cycle or completed the double blind phase (whichever occurs earlier). The first treatment cycle of the study will comprise two treatment groups as follows: * Group A (active): BoNT/A-DP (20 units, 0.5 mL) * Group B (placebo control): sterile, 0.9% sodium chloride, (0.5 mL). Eligible subjects will be randomized at baseline (day 0) to Group A or B to receive the first treatment in a 3:1 randomization scheme, respectively. Investigators and subjects will be blinded to the treatment administered and will evaluate the severity of glabellar lines independently. The subject should perform their assessment independently and ideally before the investigator, to ensure they are not biased by the investigator. The same investigator should assess the subject at baseline and at the visits at weeks 1, 2 and 4 in the first treatment cycle. After a screening period of up to14 calendar days, subjects will receive the first treatment (BoNT/A-DP or placebo) and attend for visits at 1, 2 and 4 weeks after treatment and at 4 weekly intervals thereafter for evaluation of efficacy and safety (primary and key secondary efficacy endpoints are evaluated in the first treatment cycle in comparison with placebo). The first treatment cycle will last at least 12 weeks and will end when the subjects qualify for re-treatment (in accordance with the "eligibility for re-treatment criteria"). After the first treatment cycle is completed, all subjects may enter the open label extension phase and will be dosed with BoNT/A-DP (20 U) for subsequent re-treatments. Evaluation for re-treatment takes place at the earliest at 12 weeks after the first/previous treatment. Subjects who do not qualify for re-treatment at week 12 will have the option (pending eligibility) of re-treatment at a later visit (at 4 weekly intervals thereafter) until they are eligible for re-treatment or until a total of 48 weeks has elapsed since study start. Subjects will attend for visits at 1 and 4 weeks after any re-treatment and at 4 weekly intervals thereafter. At week 2 and week 8 of each open label cycle a telephone call visit will take place. According to the study schedule (Section 2.1 and Section 2.2), a maximum of 4 treatments per subject (4 treatment cycles) is permitted during the study time frame, with treatments separated by a minimum of 12 weeks. The number of treatments administered per subject will depend on the subject's qualification for re-treatment; however, the last opportunity for re-treatment is at week 48.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
410
Injection, 20 Units divided in five 0.1 mL i.m injections into the glabellar area
injection, sodium chloride 0.9 % divided in five 0.1 mL i.m injections into the glabellar area
Injection, 20 Units divided in five 0.1 mL i.m injections into the glabellar area in up to 3 treatment cycles
Tennessee Clinical Research Center
Nashville, Tennessee, United States
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.
Time frame: Week 4
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 * modified Skindex-16 (Glabellar Line Quality of Life Scale, \[GL-QoL\]): Each of 7 items rated on 5-point scale: 0/Never, 1/Rarely, 2/Sometimes, 3/Often, 4/Always bothered, than rescaled to a 0 to 100 standardized score; Emotional Domain is the mean of 4 of the items; Social Functioning Domain is the mean of 3 of the items; Overall score is the mean of all 7 items. All reported scores ranging from 0 (best outcome) to 100 (worst outcome). * validated FACE-Q Appraisal of Lines Between Eyebrows scale: Each of 7 items rated on 4-point scale: 1/Not at all, 2/a little, 3/moderately, 4/extremely. Reported score is the sum of the 7 items, standardized on a scale from 0 (worst outcome) to 100 (best outcome). * Age Appraisal visual analog scale \[VAS\]: Perception of Age compared to actual age, in years ranging from -15 years (best outcome) to +15 years (worst outcome).
Time frame: Week 4
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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Time frame: Week 12
Percentage of Responders 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.
Time frame: Week 16
Percentage of Responders at Week 20
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 20 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.
Time frame: Week 20
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.
Time frame: Week 4
Responder Rate 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.
Time frame: Week 1, Week 2 and Week 8
The Percentage of Subjects With ≥ 2-point and ≥ 1 Reduction in Facial Wrinkle Scale (FWS) Score (at Maximum Frown)
The percentage of subjects with ≥ 2-point and ≥ 1 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 rater's 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.
Time frame: Week 2, 4, 12, 16 and 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.
Time frame: 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."
Time frame: Week4 Cycle1(on average 4 Weeks from Baseline, up to Week 7), Week4 Cycle2 (on average 20 Weeks from Baseline, up to Week 52), Week4 Cycle3 (on average 37 Weeks from Baseline, up to Week 53), Week4 Cycle4 (on average 46 Weeks from Baseline, up to Week 56)
The Percentage of Subjects With a ≥ 1 Point Reduction in Facial Wrinkle Scale (FWS) Score at Rest Based on the Independent Rater's Assessment of Photos.
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 rater's assessment of photos. 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.
Time frame: Week 2, Week 4, Week 12, Week 16, Week 20 of Treatment Cycle 1
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 investigator's and the subject's 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.
Time frame: Week4 Cycle1(on average 4 Weeks from Baseline, up to Week 7), Week4 Cycle2 (on average 20 Weeks from Baseline, up to Week 52), Week4 Cycle3 (on average 37 Weeks from Baseline, up to Week 53), Week4 Cycle4 (on average 46 Weeks from Baseline, up to Week 56)
The Percentage of Subjects With ≥ 1-point Reduction in Facial Wrinkle Scale (FWS) Score (at Maximum Frown) During the First Treatment Cycle at Week 1, 2, 4, 8, 12, 16 and 20 Relative to Baseline
The percentage of subjects with ≥ 1-point reduction in Facial Wrinkle Scale (FWS) score (at maximum frown) in the BoNT/A-DP and placebo groups during the first treatment cycle at week 1, 2, 4, 8, 12, 16 and 20 relative to baseline, based on both the investigators' and the subjects' in-clinic assessments (composite endpoint). For week 16 and 20 subjects who were re-treated before the respective visits were counted as non-responders. 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.
Time frame: Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20 of Treatment Cycle 1
The Percentage of Subjects With ≥ 1-point Reduction in Facial Wrinkle Scale (FWS) Score (at Maximum Frown) During Each Re-treatment Cycle at Week 4 Relative to Re-treatment-baseline.
The percentage of subjects with ≥ 1-point reduction in Facial Wrinkle Scale (FWS) score (at maximum frown) in the BoNT/A-DP during each re-treatment cycle at week 4 relative to re-treatment baseline, 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.
Time frame: Week4 Cycle1(on average 4 Weeks from Baseline, up to Week 7), Week4 Cycle2 (on average 20 Weeks from Baseline, up to Week 52), Week4 Cycle3 (on average 37 Weeks from Baseline, up to Week 53), Week4 Cycle4 (on average 46 Weeks from Baseline, up to Week 56)
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious AEs (SAEs) and AEs of Special Interest (AESIs)
Number of Participants with treatment-emergent adverse events (TEAEs), serious AEs (SAEs) and AEs of special interest (AESIs)
Time frame: 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.
Time frame: Through study completion (60 weeks)
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
Time frame: Week4 Cycle1(on average 4 Weeks from Baseline, up to Week 7), Week4 Cycle2 (on average 20 Weeks from Baseline, up to Week 52), Week4 Cycle3 (on average 37 Weeks from Baseline, up to Week 53), Week4 Cycle4 (on average 46 Weeks from Baseline, up to Week 56)
Change From Baseline of Alanine Aminotransferase, Alkaline Phosphatase , Aspartate Aminotransferase, Gamma Glutamyl Transpeptidase
Safety assessments by evaluating change from baseline of Alanine Aminotransferase, Alkaline Phosphatase , Aspartate Aminotransferase, Gamma Glutamyl Transpeptidase as per the study schedule
Time frame: Week4 Cycle1(on average 4 Weeks from Baseline, up to Week 7), Week4 Cycle2 (on average 20 Weeks from Baseline, up to Week 52), Week4 Cycle3 (on average 37 Weeks from Baseline, up to Week 53), Week4 Cycle4 (on average 46 Weeks from Baseline, up to Week 56)
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
Time frame: Week4 Cycle1(on average 4 Weeks from Baseline, up to Week 7), Week4 Cycle2 (on average 20 Weeks from Baseline, up to Week 52), Week4 Cycle3 (on average 37 Weeks from Baseline, up to Week 53), Week4 Cycle4 (on average 46 Weeks from Baseline, up to Week 56)
Change From to Baseline of Bilirubin, Creatinin
Safety assessments by evaluating change from baseline of Bilirubin, Creatinin as per the study schedule
Time frame: Week4 Cycle1(on average 4 Weeks from Baseline, up to Week 7), Week4 Cycle2 (on average 20 Weeks from Baseline, up to Week 52), Week4 Cycle3 (on average 37 Weeks from Baseline, up to Week 53), Week4 Cycle4 (on average 46 Weeks from Baseline, up to Week 56)
Change From Baseline of Erythrocytes
Safety assessments by evaluating change from baseline of Erythrocytes as per the study schedule
Time frame: Week4 Cycle1(on average 4 Weeks from Baseline, up to Week 7), Week4 Cycle2 (on average 20 Weeks from Baseline, up to Week 52), Week4 Cycle3 (on average 37 Weeks from Baseline, up to Week 53), Week4 Cycle4 (on average 46 Weeks from Baseline, up to Week 56)
Change From Baseline of Erythrocytes MCV
Safety assessments by evaluating change from baseline of Erythrocytes MCV as per the study schedule
Time frame: Week4 Cycle1(on average 4 Weeks from Baseline, up to Week 7), Week4 Cycle2 (on average 20 Weeks from Baseline, up to Week 52), Week4 Cycle3 (on average 37 Weeks from Baseline, up to Week 53), Week4 Cycle4 (on average 46 Weeks from Baseline, up to Week 56)
Change From Baseline of Erythrocyte MCHC, Hemoglobin
Safety assessments by evaluating change from baseline of Erythrocyte MCHC, Hemoglobin as per the study schedule
Time frame: Week4 Cycle1(on average 4 Weeks from Baseline, up to Week 7), Week4 Cycle2 (on average 20 Weeks from Baseline, up to Week 52), Week4 Cycle3 (on average 37 Weeks from Baseline, up to Week 53), Week4 Cycle4 (on average 46 Weeks from Baseline, up to Week 56)
Change From Baseline of Lymphocytes/Leukocytes, Monocytes/Leukocytes, Neutrophils/Leukocytes, Basophiles/Leukocytes, Eosinophils/Leukocytes
Safety assessments by evaluating change from baseline of Lymphocytes/leukocytes, Monocytes/leukocytes, Neutrophils/leukocytes, Basophiles/leukocytes, Eosinophils/leukocytes as per the study schedule
Time frame: Week4 Cycle1(on average 4 Weeks from Baseline, up to Week 7), Week4 Cycle2 (on average 20 Weeks from Baseline, up to Week 52), Week4 Cycle3 (on average 37 Weeks from Baseline, up to Week 53), Week4 Cycle4 (on average 46 Weeks from Baseline, up to Week 56)
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
Time frame: Week4 Cycle1(on average 4 Weeks from Baseline, up to Week 7), Week4 Cycle2 (on average 20 Weeks from Baseline, up to Week 52), Week4 Cycle3 (on average 37 Weeks from Baseline, up to Week 53), Week4 Cycle4 (on average 46 Weeks from Baseline, up to Week 56)
Change From Baseline of Pulse Rate
Safety assessments by evaluating change from baseline of Pulse rate as per the study schedule
Time frame: Week4 Cycle1(on average 4 Weeks from Baseline, up to Week 7), Week4 Cycle2 (on average 20 Weeks from Baseline, up to Week 52), Week4 Cycle3 (on average 37 Weeks from Baseline, up to Week 53), Week4 Cycle4 (on average 46 Weeks from Baseline, up to Week 56)
Number of Participants With Normal and Abnormal Electrocardiogram
Safety assessments by evaluating Electrocardiogram as per the study schedule
Time frame: Week 4 and last visit of Treatment Cycle 1 (End of Cycle procedures), conducted upon confirmation of eligibility for retreatment, assessed starting 12 weeks post-treatment with 4-weekly evaluations up to a max. of 48 weeks post treatment.