Botulinum Toxin Treatment of Glabellar Lines: Efficacy and Safety Study II

Croma-Pharma GmbH251 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

251

Conditions

Glabellar Frown Lines

Interventions

Botulinum Toxin ADRUG

Injection, 20 Units divided in five 0.1 mL i.m injections into the glabellar area

PlaceboDRUG

injection, sodium chloride 0.9% divided in five 0.1 mL i.m. injections into the glabellar area

Botulinum Toxin A - Open LabelDRUG

Open Label Extension Phase with Experimental Drug; Injection, 20 Units divided in five 0.1 mL i.m injections into the glabellar area

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Aged ≥ 18 years or older at time of screening on FWS) as determined by in-clinic assessments by both the investigator and the subject(where: 0= 'none', 1= 'mild', 2= 'moderate', 3= 'severe'). * Subject has a stable medical condition with no uncontrolled systemic disease. * Female subjects of childbearing potential must test negative for pregnancy and agree to use effective birth control during the course of the study. * Subjects who wear glasses must be able to adequately self-assess the severity of their glabellar lines (according to the FWS), without glasses obstructing the forehead area. * The moderate to severe glabellar lines have an important psychological impact on the subject, as indicated by scores \>0 on either the Emotional or the Social Functioning subscale of the modified Skindex-16 (GL-QoL). Exclusion Criteria: * Previous treatment with any serotype of botulinum toxin for any indication within the 12 months prior to screening, or any planned treatment with botulinum toxin of any serotype for any reason during the trial (other than the investigational treatment). * Known hypersensitivity to the study medication or its excipients. * Any medical condition that may place the subject at increased risk due to exposure to botulinum toxin, including diagnosed myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, profound atrophy or weakness in the target muscles, or any other condition (at the investigator's discretion) that might interfere with neuromuscular function or contraindicate botulinum toxin therapy. * Facial laser or light treatment, microdermabrasion, superficial peels or retinoid therapy within the 3 months prior to screening or planned during the study. * Apart from the procedures specified above, previous treatment with any facial aesthetic procedure in the glabellar area (including chemical peeling, injection with biodegradable fillers,) within 12 months prior to screening or planned during the study. * Previous insertion of permanent material in the glabellar area or planned during the study. * Any surgery, or history of surgery, in the glabellar area including surgical removal of the corrugator, procerus or depressor supercili muscles or a combination of these, or scars in the glabellar area, or such surgery planned during the study. * Active skin disease/infection or irritation at the treatment area. * Inability to substantially lessen glabellar frown lines even by physically spreading them apart. * Use of a muscle relaxant, , within 2 weeks prior to screening or planned during the study. * Marked facial asymmetry or ptosis of eyelid and/or eyebrow, or current facial palsy or neuromuscular junction disorders as judged by the investigator. * Pregnant, breastfeeding or planning to become pregnant during the trial. * Use of prohibited medication including anticholinergic drugs, or drugs which could interfere with neuromuscular function, including aminoglycoside antibiotics and curare-like compounds within 2 weeks prior to screening or planned during the study. * Planned surgery with general anaesthetic (use of local anaesthetic outside the glabellar area is permitted). * Participation in another clinical study within one month of screening and throughout the trial. * Previous participation in another botulinum toxin aesthetic study which involved the treatment of glabellar lines in combination with canthal lines and/or forehead lines in the previous 18 months. * Chronic drug or alcohol abuse (as per investigator discretion). Eligibility Criteria for re-treatment: The following criteria MUST be met for re-treatment: * At time of re-treatment subject does not have relevant changes to their health status from enrollment, which would have prevented subject's entry into the study according to the inclusion and exclusion criteria * The subject must have been randomized to receive treatment and must have received at least one treatment (BoNT/A-DP or placebo). * A minimum of 12 weeks must have elapsed since the previous study treatment. * The subject's glabellar lines at maximum frown must have relapsed to a FWS score of 2 or 3 as determined by the investigator and the subject. * No relevant infection or inflammation in the planned injection area. * Negative urine pregnancy test, in women of child-bearing potential. * The subject must have received fewer than four study treatments. * The subject must agree and consent to re-treatment. * Re-treatment will be performed at the latest by week 48.

Locations (7)

California Dermatology & Clinical Research Institute

Encinitas, California, United States

Center for Clinical and Cosmetic Research

Aventura, Florida, 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

Outcomes

Primary Outcomes

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

Secondary Outcomes

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.

Time frame: 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.

Time frame: 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

Data from ClinicalTrials.gov

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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, United States

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.

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.

Time frame: 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 * 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 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, 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.

Time frame: 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.

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: 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.

Time frame: 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.

Time frame: 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.

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 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