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

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

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.

Inclusion Criteria:

• Ages ≥ 18 years or older at time of screening (upper limit 75 years, inclusive).
• Has moderate to severe glabellar frown lines at maximum frown (severity score of 2 or 3 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 had a stable medical condition with no uncontrolled systemic disease.

• Female subjects of childbearing potential had to test negative for pregnancy and agree to use effective birth control during the course of the study.
• Subjects who wear glasses had to be able to adequately self-assess the severity of their glabellar lines (according to the FWS), without glasses obstructing the forehead area.
• Moderate to severe glabellar lines indicating 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 scale.

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 study (other than the investigational treatment).
• Known hypersensitivity to the study drug 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 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).
• 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 supercilii 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.2
• 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 study.
• Use of prohibited medication including anticholinergic drugs, or drugs that could interfere with neuromuscular function, including aminoglycoside antibiotics and curare-like compounds within 2 weeks prior to screening or planned during the study.2
• Planned surgery with general anesthetic (use of local anesthetic outside the glabellar area was permitted).
• Participation in another clinical study within 1 month of screening and throughout the study.
• Previous participation in another botulinum toxin aesthetic study which involved the treatment of glabellar lines in combination with canthal lines and/or forehead lines, within the previous 18 months.
• Chronic drug or alcohol abuse (as per investigator discretion).

Eligibility Criteria for Retreatment

The following criteria had to be met for retreatment:

• At time of retreatment, the subject did not have relevant changes to their health status from enrolment, which could have prevented the subject's entry into the study according to the inclusion and exclusion criteria.
• The subject had to have been randomized to receive treatment and must have received ≥ 1 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 both the investigator and the subject.
• No relevant infection or inflammation in the planned injection area.
• Negative urine pregnancy test, in women of childbearing potential.
• The subject had to have received fewer than 4 study treatments.
• The subject had to have agreed and consented to retreatment.
• Retreatment was to be performed at the latest by Week 48.