Clinical trial NCT02677298: Botulinum Toxin Treatment of Glabellar Lines: Efficacy and Safety Study I
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Glabellar Frown Lines
Lead sponsor: Croma-Pharma GmbH
Sponsor class: INDUSTRY
First posted: 2016-02-09
Enrollment: 784
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

* Aged ≥ 18 years or older at the 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 has a stable medical condition with no uncontrolled systemic disease.
* Female subjects of childbearing potential must test negative for pregnancy and agree to use highly effective birth control during the course of the study. Such methods include for example: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion or vasectomized partner.
* 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 Functioning subscales 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.

Primary outcomes:
measure: 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.
timeFrame: Week 4
Secondary outcomes:
measure: Percentage of Responders at Maximum Frown at Week 12
timeFrame: Week 12
measure: Percentage of Responders at Week 16
timeFrame: Week 16
measure: 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
timeFrame: Week 4
measure: Percentage of Responders at Week 20 or Later (After the First Treatment).
timeFrame: Week 20, 24, 28, 32 of Treatment Cycle 1
measure: Extent of Change in Psychological Impact
timeFrame: Week 4
measure: Responder Rate at Weeks 1, 2 and 8
timeFrame: Week 1, Week 2, and Week 8
measure: The Percentage of Subjects With ≥ 2-point Reduction in Facial Wrinkle Scale (FWS) Score (at Maximum Frown)
timeFrame: Week 2, 4, 12, 16 and 20
measure: Time to Onset of Effect in the BoNT/A-DP and Placebo Groups in the First Treatment Cycle
timeFrame: From treatment at Day 0 to Week 4 in Treatment Cycle 1
measure: Satisfaction With Treatment, During Each Treatment Cycle, as Assessed by the Validated FACE-Q Satisfaction With Outcome Scale.
timeFrame: Week 4 of Treatment Cycles 1, 2, 3 and 4
measure: 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.
timeFrame: Week 2, 4, 12, 16, 20, 24 and 28 of Treatment Cycle 1
measure: 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.
timeFrame: Week 4 of Treatment Cycles 2, 3 and 4
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious AEs (SAEs) and Adverse Events of Special Interest (AESIs) Events of Special Interest (AESIs)
timeFrame: Through study completion (60 weeks)
measure: Number of Participants With Neutralizing Anti-Drug Antibodies
timeFrame: Through study completion (60 weeks)
measure: Change From Baseline of Alanine Aminotransferase, Alkaline Phosphatase, Aspartate Aminotransferase, Gamma Glutamyl Transferase
timeFrame: Week 4 after treatment in treatment cycle 1, 2, 3 and 4
measure: Change From Baseline of Bilirubin and Creatinine
timeFrame: Week 4 after treatment in treatment cycle 1, 2, 3 and 4
measure: Change From Baseline of Blood Urea Nitrogen, Cholesterol, Glucose, Potassium, Sodium
timeFrame: Week 4 after treatment in treatment cycle 1, 2, 3 and 4
measure: Change From Baseline of Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils, Platelets
timeFrame: Week 4 after treatment in treatment cycle 1, 2, 3 and 4
measure: Change From Baseline of Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/Leukocytes, Neutrophils/Leukocytes
timeFrame: Week 4 after treatment in treatment cycle 1, 2, 3 and 4
measure: Change From Baseline of Erythrocytes
timeFrame: Week 4 after treatment in treatment cycle 1, 2, 3 and 4
measure: Change From Baseline of Erythrocytes MCHC, Hemoglobin
timeFrame: Week 4 after treatment in treatment cycle 1, 2, 3 and 4
measure: Change From Baseline of Erythrocyte MCV
timeFrame: Week 4 after treatment in treatment cycle 1, 2, 3 and 4
measure: Change From Baseline of Systolic and Diastolic Blood Pressure
timeFrame: Week 4 after treatment in treatment cycle 1, 2, 3 and 4
measure: Change From Baseline of Pulse Rate
timeFrame: Week 4 after treatment in treatment cycle 1, 2, 3 and 4
measure: Number of Participants With Normal and Abnormal Electrocardiogram
timeFrame: 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.
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Total Skin And Beauty Dermatology Center, Pc
state: Alabama
city: Encino
country: United States
facility: Clinical Testing of Beverly Hills
state: California
city: San Francisco
country: United States
facility: Maas Clinic
state: California
city: Greenwood Village
country: United States
facility: About Skin
state: Colorado
city: Chicago
country: United States
facility: DeNova Research
state: Illinois
city: Omaha
country: United States
facility: Skin Specialists
state: Nebraska
city: Chapel Hill
country: United States
facility: Aesthetic Solutions
state: North Carolina
city: Philadelphia
country: United States
facility: Society Hill Dermatology
state: Pennsylvania
city: Nashville
country: United States
facility: Tennessee Clinical Research Center
state: Tennessee
city: Starnberg
country: Germany
facility: Praxisklinik Fur Dermatologie, Hautzentrum am Starnberger See
state: Bavaria
city: Darmstadt
country: Germany
facility: Rosenpark Research
state: Hessen
city: Berlin
country: Germany
facility: RZANY & HUND, Privatpraxis
city: Hamburg
country: Germany
facility: S-thetic Clinic Hamburg
city: Muenster
country: Germany
facility: Praxis Klinik Dr. Med. Anita Ruetter
city: Warsaw
country: Poland
facility: Carpe Diem, Centre for Aesthetic Medicine
city: Warsaw
country: Poland
facility: Clinical Research Group Sp. z o.o.
city: Warsaw
country: Poland
facility: Estederm Dr Marcin Ambroziak
city: Warsaw
country: Poland
facility: High-Med. Przychodnia Specjalistyczna
Study officials:
References: