Botulinum Toxin Treatment of Glabellar Lines: Efficacy and Safety Study III (BLESSIII)

Study Overview
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Brief Summary
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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.

Detailed Description
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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 visist 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.

Official Title
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Randomized Double Blind Phase 3 Study to Assess the Efficacy and Safety of BoNT/A-DP in the Treatment of Glabellar Lines in Comparison With Placebo Followed by an Open Label Extension Study

Conditions
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Glabellar Frown Lines

Intervention / Treatment
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* Drug: Botulinum Toxin A
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ages ≥ 18 years or older at time of screening Has moderate to severe glabellar fown lines at maximum frown (severity score of 2 or 3 on FWS) as determinated by in-clinic assessments by both the investigator and the subject (where: 0 =´none´, 1= ´mild´, 2= ´moderate´, 3= ´severe´). Exclusion Criteria: 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 inivestigator´s discretion) that might interfere with neuromuscular function or contraindicate botulinum toxin therapy. 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 trail (other than the investigational treatment). Active skin disease/ infection or irritation at the treatment area Pregnant, breastfeeding or planning to become pregnant during the trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Botulinum toxin A<br>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. | Drug: Botulinum Toxin A<br>* Injection, 20 Units divided in five 0.1 mL i.m injections into the glabellar area<br>* Other names: BoNT/A-DP;|
| Placebo Comparator: Placebo<br>Placebo will be administered in double blind fashion in cycle 1 divided in five 0.1 mL injections into the glabellar area. | Drug: Placebo<br>* injection, sodium chloride 0.9 % divided in five 0.1 mL i.m injections into the glabellar area<br>* Other names: sodium chloride 0,9 %;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 proportion 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. | week 4 relative to baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of responders at maximum frown at week 12 | The percentage of responders at maximum frown at week 12 (after the first treatment with BoNT/A-DP or placebo). | week 12 | 
| Percentage of responders at week 16 | The percentage of responders at week 16 (after the first treatment). | week 16 | 
| The proportion of subjects with a ≥ 1 point reduction in FWS score at rest at week 4 based separately on the investogators´and the subjects´ in-clinic assessments | 3. The proportion of subjects with a ≥ 1 point reduction in 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). | week 4 | 
| Percentage of responders at week 20 or up to week 48 | The percentage of responders at week 20 or up to week 48 (after the first treatment) | week 20 | 
| Frequency, severity and causal relationship of AEs, SAes and 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) |