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

Phase 3

Completed

Conditions: Glabellar Frown Lines

Interventions: Drug: Botulinum Toxin A
Drug: Placebo
Drug: Botulinum Toxin A - Open Label

Registration Number: NCT02677805

Lead Sponsor: Croma-Pharma GmbH

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 251

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Botulinum toxin A	Botulinum Toxin A	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	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	Botulinum Toxin A - Open Label	Open Label Extension Phase for all Subjects of Arm 1 and 2 for up to 3 treatment cycles

Primary Outcome Measures

Name	Time	Method
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	Week 4	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.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline of Erythrocyte MCHC, Hemoglobin	Week 4 of each treatment cycle	Safety assessments by evaluating change from baseline of Erythrocyte MCHC, Hemoglobin as per the study schedule
Change From Baseline of of Erythrocyte MCV	Week 4 of each treatment cycle	Safety assessments by evaluating change from baseline of Erythrocyte MCV as per the study schedule
Change From Baseline of Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/Leukocytes, Neutrophils/Leukocytes	Week 4 of each treatment cycle	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
Change From Baseline of Systolic and Diastolic Blood Pressure	Week 4 of Treatment Cycles 1, 2, 3 and 4	Safety assessments by evaluating change from baseline of Systolic and Diastolic Blood Pressure as per the study schedule
Change From Baseline of Pulse Rate	Week 4 of Treatment Cycles 1, 2, 3 and 4	Safety assessments by evaluating change from baseline of Pulse rate as per the study schedule
Number of Participants With Normal and Abnormal Electrocardiogram	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.	Safety assessments by evaluating Electrocardiogram as per the study schedule
Change From Baseline of Cholesterol, Glucose, Potassium, Sodium, Urea Nitrogen	Week 4 of each treatment cycle	Safety assessments by evaluating change from baseline of Cholesterol, Glucose, Potassium, Sodium, Urea Nitrogen as per the study schedule
Change From Baseline of Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils, Platelets	Week 4 of each treatment cycle	Safety assessments by evaluating change from baseline of Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils, Platelets as per the study schedule
Change From Baseline of Erythrocytes	Week 4 of each treatment cycle	Safety assessments by evaluating change from baseline of Erythrocytes as per the study schedule
Change From Baseline of Alanine Aminotransferase, Alkaline Phosphatase, Aspartate Aminotransferase, Gamma Glutamyl Transferase	Week 4 of each treatment cycle	Safety assessments by evaluating change from baseline of Alanine Aminotransferase, Alkaline Phosphatase, Aspartate Aminotransferase, Gamma Glutamyl Transferase as per the study schedule
Change From Baseline of Bilirubin, Creatinine	Week 4 of each treatment cycle	Safety assessments by evaluating change from baseline of Bilirubin, Creatinine as per the study schedule as change from baseline
Percentage of Responders at Maximum Frown at Week 12	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.
Percentage of Responders at Maximum Frown at Week 16	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 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	Week 4	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	Week 20, Week 24, Week 28, Week 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.
Extent of Change in Psychological Impact (Emotional and Social Functioning and Concerns Relating to Glabellar Lines)	Week 4	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).
Percentage of Responders at Maximum Frown at Weeks 1, 2 and 8	Week 1, Week 2, Week 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.
Percentage of Subjects With ≥ 2-point Reduction in Facial Wrinkle Scale (FWS) Score (at Maximum Frown) Based on Independent Raters' Assessment of of Photographs	Week 2, Week 4, Week 12, Week 16, Week 20	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 to Onset of Effect in the BoNT/A-DP and Placebo Groups in the First Treatment Cycle	From treatment at Day 0 to Week 4 in Treatment Cycle 1	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.
Satisfaction With Treatment, During Each Treatment Cycle, as Assessed by the Validated FACE-Q Satisfaction With Outcome Scale	Week 4 of Treatment Cycles 1, 2, 3 and 4	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".
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	Week 2, Week 4, Week 12, Week 16, Week 20, Week 24, Week 28	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.
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	Week 4 of Treatment Cycles 2, 3 and 4	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.
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious AEs (SAEs) and AEs of Special Interest (AESIs)	Through study completion (60 weeks)	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.
Number of Participants With Neutralizing Anti-Drug Antibodies	Through study completion (60 weeks)	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.

Trial Locations

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
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