Safety and Efficacy Study of the Simultaneous Treatment of Upper Facial Lines (Horizontal Forehead Lines, Glabellar Frown Lines and Crows Feet) in Subjects With Moderate to Severe Upper Facial Lines (ULTRA II)

A Prospective, Randomized, Double-blind, Placebo-controlled, Multicenter Study With an Open-label Extension Period to Investigate the Efficacy and Safety of NT 201 in the Simultaneous Treatment of Upper Facial Lines (Horizontal Forehead Lines, Glabellar Frown Lines, and Lateral Canthal Lines)

The purpose of this study is to investigate the safety and efficacy of NT 201 (active ingredient: Botulinum (neuro)toxin type A, free from complexing proteins) in the combined treatment of wrinkles in the upper face (Upper Facial Lines [UFL]): Horizontal Forehead Lines [HFL], Glabellar Frown Lines [GFL], and Lateral Canthal Lines [LCL]). It is a prospective, randomized, double-blind, placebo-controlled, multicenter study with a placebo-control main period (MP) followed by an open-label extension (OLEX) period.

Study Overview

• Status: Completed
• Conditions: Moderate to Severe Upper Facial Lines (Horizontal Forehead Lines, Glabellar Frown Lines, and Lateral Canthal Lines)
• Intervention / Treatment: Drug: NT 201; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 368
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Bad Soden, Germany, 65182
    • Merz Investigational Site
  • Berlin, Germany, 10707
    • Merz Investigational Site
  • Bochum, Germany, 44793
    • Merz Investigational Site
  • Drensteinfurt, Germany, 48317
    • Merz Investigational Site
  • Düsseldorf, Germany, 40212
    • Merz Investigational Site
  • Hamburg, Germany, 20146
    • Merz Investigational Site
  • Hamburg, Germany, 22609
    • Merz Investigational Site
  • Mannheim, Germany, 68161
    • Merz Investigational Site
  • München, Germany, 80539
    • Merz Investigational Site
  • München, Germany, 80636
    • Merz Investigational Site
  • Potsdam, Germany, 14467
    • Merz Investigational Site
  • Wuppertal, Germany, 42287
    • Merz Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Outpatients (male or female) 18 years of age or older.
• Horizontal forehead lines (HFL), glabellar frown lines (GFL), and symmetrical lateral canthal lines (LCL) of moderate to severe intensity at maximum contraction as assessed by the investigator and subject according to Merz Aesthetics Scales (MAS).

Exclusion Criteria:

• Previous treatment with botulinum neurotoxin (BoNT) of any serotype in the face within the last 12 months before injection.
• Any facial cosmetic procedure within the last 12 months before baseline injection.
• Previous treatment with any biodegradable filler in the face within the last 12 months before injection.
• Any previous insertion of permanent material in the face (regardless of the time between previous treatment and this study).
• Any medical condition that may put the subject at increased risk with exposure to NT201.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Main Period: Placebo (Group P); Subjects will receive placebo injection in all three UFL (GFL, HFL and LCL) on Day 1 of main period.	Drug: Placebo; Solution for injection prepared by reconstitution of powder with percent (%) Sodium Chloride (NaCl).
Experimental: Main Period: NT 201 (Group U); Subjects will receive a total of 64 Units (U) of NT 201: 20 U of NT 201 injection both in the GFL area and in the HFL area, and 24 U of NT 201 injection in the LCL area (12 U per side) on Day 1 of main period.	Drug: NT 201; Clostridium Botulinum neurotoxin Type A free from complexing proteins. Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl).; Other Names: Xeomin; IncobotulinumtoxinA; Botulinum toxin type A (150 kiloDalton), free from complexing protein
Experimental: OLEX: NT 201 (Main Period: Group P); Subjects will receive a total of 64 U of NT 201: 20 U of NT 201 injection both in the GFL and in the HFL area, and 24 U of NT 201 injection in the LCL area (12 U per side) on Day 1 (Visit 8) and Visit 13 of OLEX period.	Drug: NT 201; Clostridium Botulinum neurotoxin Type A free from complexing proteins. Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl).; Other Names: Xeomin; IncobotulinumtoxinA; Botulinum toxin type A (150 kiloDalton), free from complexing protein
Experimental: OLEX: NT 201 (Main Period: Group U); Subjects will receive a total of 64 U of NT 201: 20 U of NT 201 injection both in the GFL and in the HFL area, and 24 U of NT 201 injection in the LCL area (12 U per side) on Day 1 (Visit 8) and Visit 13 of OLEX period.	Drug: NT 201; Clostridium Botulinum neurotoxin Type A free from complexing proteins. Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl).; Other Names: Xeomin; IncobotulinumtoxinA; Botulinum toxin type A (150 kiloDalton), free from complexing protein
Experimental: Main Period: NT 201 and Placebo (Group L); Subjects will receive a total of 24 U NT 201: placebo injection both in the GFL and HFL area, and 24 U NT 201 injection in the LCL area (12 U per side) on Day 1 of main period.	Drug: NT 201; Clostridium Botulinum neurotoxin Type A free from complexing proteins. Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl).; Other Names: Xeomin; IncobotulinumtoxinA; Botulinum toxin type A (150 kiloDalton), free from complexing protein; Drug: Placebo; Solution for injection prepared by reconstitution of powder with percent (%) Sodium Chloride (NaCl).
Experimental: OLEX: NT 201 (Main Period: Group L); Subjects will receive a total of 64 U of NT 201: 20 U of NT 201 injection both in the GFL and in the HFL area, and 24 U of NT 201 injection in the LCL area (12 U per side) on Day 1 (Visit 8) and Visit 13 of OLEX period.	Drug: NT 201; Clostridium Botulinum neurotoxin Type A free from complexing proteins. Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl).; Other Names: Xeomin; IncobotulinumtoxinA; Botulinum toxin type A (150 kiloDalton), free from complexing protein

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Main Period: Percentage of Glabellar Frown Line (GFL) Responders at Day 30	The Merz aesthetics scales (MAS) are 5-point scales used to identify responders in a clinical context. They are validated photograph-based outcome instruments designed specifically for assessment of each upper facial area. GFL-response was defined as a score of 0 (no) or 1 (mild) and at least two-grade improvement from baseline to Day 30 of main period on MAS for GFL at maximum contraction as assessed by both the investigator and the subject. The MAS for GFL ranged as 0 to 4 where 0 is "No glabellar lines", 1 is "Mild glabellar lines", 2 is "Moderate glabellar lines", 3 is "Severe glabellar lines" and 4 is "Very severe glabellar lines".	Day 30
Main Period: Percentage of Horizontal Forehead Lines (HFL) Responders at Day 30	The MAS are 5-point scales used to identify responders in a clinical context. They are validated photograph-based outcome instruments designed specifically for assessment of each upper facial area. HFL-response was defined as a score of 0 (no) or 1 (mild) and at least two-grade improvement from baseline to Day 30 of main period on MAS for HFL at maximum contraction as assessed by both the investigator and the subject. The MAS for HFL ranged as 0 to 4 where 0 is "No lines", 1 is "Mild lines", 2 is "Moderate lines", 3 is "Severe lines" and 4 is "Very severe lines".	Day 30
Main Period: Percentage of Lateral Canthal Lines (LCL) Responders at Day 30	The MAS are 5-point scales used to identify responders in a clinical context. They are validated photograph-based outcome instruments designed specifically for assessment of each upper facial area. LCL-response was defined as a score of 0 (no) or 1 (mild) and at least two-grade improvement from baseline to Day 30 of main period on MAS for both left and right LCL at maximum contraction as assessed by both the investigator and the subject. The MAS for LCL ranged as 0 to 4 where 0 is "No lines", 1 is "Mild lines", 2 is "Moderate lines", 3 is "Severe lines" and 4 is "Very severe lines".	Day 30

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Main Period: Global Aesthetic Improvement Scale (GAIS) at Day 30 as Assessed by the Subjects	The GAIS is a 7-point Likert scale capturing the global aesthetic improvement ranging from +3 (very much improved); +2 (much improved); +1 (improved); 0 (no change); -1 (worse); -2 (much worse); -3 (very much worse), as assessed by the subject. GAIS as assessed by the subject at Day 30 was analyzed using an analysis of covariance (ANCOVA) model.	Day 30
Main Period: Global Aesthetic Improvement Scale (GAIS) at Day 30 as Assessed by the Investigator	The GAIS is a 7-point Likert scale capturing the global aesthetic improvement ranging from +3 (very much improved); +2 (much improved); +1 (improved); 0 (no change); -1 (worse); -2 (much worse); -3 (very much worse), as assessed by the investigator. GAIS as assessed by the investigator at Day 30 was analyzed using an ANCOVA model.	Day 30
Main Period: Percentage of Subjects With a Score of 0 (no) or 1 (Mild) on MAS for GFL at Maximum Contraction as Assessed by the Investigator at Day 30	The MAS are 5-point scales used to identify responders in clinical context. They are validated photograph-based outcome instruments designed specifically for assessment of each upper facial area. MAS for GFL ranged as 0 to 4, where 0 is "No glabellar lines", 1 is "Mild glabellar lines", 2 is "Moderate glabellar lines", 3 is "Severe glabellar lines" and 4 is "Very severe glabellar lines".	Day 30
Main Period: Percentage of Subjects With a Score of 0 (no) or 1 (Mild) on MAS for HFL at Maximum Contraction as Assessed by the Investigator at Day 30	The MAS are 5-point scales used to identify responders in clinical context. They are validated photograph-based outcome instruments designed specifically for assessment of each upper facial area. The MAS for HFL ranged as 0 to 4 where 0 is "No lines", 1 is "Mild lines", 2 is "Moderate lines", 3 is "Severe lines" and 4 is "Very severe lines".	Day 30
Main Period: Percentage of Subjects With a Score of 0 (no) or 1 (Mild) on MAS for Both Left and Right LCL at Maximum Contraction as Assessed by the Investigator at Day 30	The MAS are 5-point scales used to identify responders in clinical context. They are validated photograph-based outcome instruments designed specifically for assessment of each upper facial area. The MAS for LCL ranged as 0 to 4 where 0 is "No lines", 1 is "Mild lines", 2 is "Moderate lines", 3 is "Severe lines" and 4 is "Very severe lines".	Day 30
Main Period: Percentage of Subjects With a Score of 0 (no) or 1 (Mild) on MAS for GFL at Maximum Contraction as Assessed by the Subject at Day 30	The MAS are 5-point scales used to identify responders in clinical context. They are validated photograph-based outcome instruments designed specifically for assessment of each upper facial area. The MAS for GFL ranged as 0 to 4, where 0 is "No glabellar lines", 1 is "Mild glabellar lines", 2 is "Moderate glabellar lines", 3 is "Severe glabellar lines" and 4 is "Very severe glabellar lines".	Day 30
Main Period: Percentage of Subjects With a Score of 0 (no) or 1 (Mild) on MAS for HFL at Maximum Contraction as Assessed by the Subject at Day 30	The MAS are 5-point scales used to identify responders in clinical context. They are validated photograph-based outcome instruments designed specifically for assessment of each upper facial area. The MAS for HFL ranged as 0 to 4 where 0 is "No lines", 1 is "Mild lines", 2 is "Moderate lines", 3 is "Severe lines" and 4 is "Very severe lines".	Day 30
Main Period: Percentage of Subjects With a Score of 0 (no) or 1 (Mild) on MAS for Both Left and Right LCL at Maximum Contraction as Assessed by the Subject at Day 30	The MAS are 5-point scales used to identify responders in clinical context. They are validated photograph-based outcome instruments designed specifically for assessment of each upper facial area. The MAS for LCL ranged as 0 to 4 where 0 is "No lines", 1 is "Mild lines", 2 is "Moderate lines", 3 is "Severe lines" and 4 is "Very severe lines".	Day 30
Main Period: Percentage of Subjects With at Least One-grade Improvement From Baseline to Day 30 of Main Period on MAS for GFL at Maximum Contraction as Assessed by the Investigator	The MAS are 5-point scales used to identify responders in a clinical context. They are validated photograph- based outcome instruments designed specifically for assessment of each upper facial area. The MAS for GFL ranged as 0 to 4 where 0 is "No glabellar lines", 1 is "Mild glabellar lines", 2 is "Moderate glabellar lines", 3 is "Severe glabellar lines" and 4 is "Very severe glabellar lines".	Day 30
Main Period: Percentage of Subjects With at Least One-grade Improvement From Baseline to Day 30 of Main Period on MAS for HFL at Maximum Contraction as Assessed by the Investigator	The MAS are 5-point scales used to identify responders in a clinical context. They are validated photograph-based outcome instruments designed specifically for assessment of each upper facial area. The MAS for HFL ranged as 0 to 4 where 0 is "No lines", 1 is "Mild lines", 2 is "Moderate lines", 3 is "Severe lines" and 4 is "Very severe lines".	Day 30
Main Period: Percentage of Subjects With at Least One-grade Improvement From Baseline to Day 30 of Main Period on MAS for Both Left and Right LCL at Maximum Contraction as Assessed by the Investigator	The MAS are 5-point scales used to identify responders in a clinical context. They are validated photograph-based outcome instruments designed specifically for assessment of each upper facial area. The MAS for LCL ranged as 0 to 4 where 0 is "No lines", 1 is "Mild lines", 2 is "Moderate lines", 3 is "Severe lines" and 4 is "Very severe lines".	Day 30
Main Period: Number of Subjects With Related Treatment-Emergent Adverse Events (TEAEs)	TEAEs during the Main Period are defined as adverse events (AEs) with onset or worsening on or after date and time of first dose of study treatment and before date and time of first administration of study treatment in the OLEX period or the final study visit, if subject was not treated in the OLEX period. An AE is considered to be related if a causal relationship between study treatment and the AE is at least reasonably possible.	Up to 22 weeks
OLEX: Number of Subjects With Related TEAEs	TEAEs of the OLEX period are defined as adverse events (AEs) with onset or worsening on or after date and time of first dose of study treatment in the OLEX period up to and including the final study visit. An AE is considered to be related if a causal relationship between study treatment and the AE is at least reasonably possible.	Up to 39 weeks

Collaborators and Investigators

• Sponsor: Merz North America, Inc.
• Collaborators: Merz Pharmaceuticals GmbH
• Investigators: Study Director: Merz Medical Expert, Merz North America, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): November 12, 2020
• Primary Completion (Actual): June 16, 2021
• Study Completion (Actual): July 8, 2022

Study Registration Dates

• First Submitted: November 4, 2020
• First Submitted That Met QC Criteria: November 4, 2020
• First Posted (Actual): November 9, 2020

Study Record Updates

• Last Update Posted (Actual): August 6, 2024
• Last Update Submitted That Met QC Criteria: July 11, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Facies; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Cholinergic Agents; Membrane Transport Modulators; Acetylcholine Release Inhibitors; Neuromuscular Agents; Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA; incobotulinumtoxinA
• Other Study ID Numbers: M602011070; 2019-004113-13 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No