In pivotal clinical studies, the duration of effect of 20U INCO for the treatment of GFL was not explored beyond 4 months.7-9 However, a recent randomized, double-blind, investigatorinitiated study showed a strong dose-response relationship with doses of 20, 60, or 100U INCO exhibiting a median duration of effect of 120, 180, and 270 days, respectively. All adverse events (AEs) were mild and consistent with the known safety profile of INCO.10
To investigate the duration of effect further for INCO treatment, a prospective, randomized, controlled trial was initiated for the treatment of GFL. This 2-stage study aimed to assess the safety and duration of escalating INCO doses (20U, 50U, 75U in stage 1 and 20U, 100U in stage 2) for up to 360 days. We investigated dose steps of 25 and 30U as these offer practical application to clinical practice and are readily administered from commercially available 50 and 100U vials; 75U was chosen as a suitable intermediate dose. Results for the primary efficacy and safety endpoints from the first stage of this study (dose groups: 20, 50, and 75U) are reported.
SUBJECTS AND METHODS
This is a prospective, randomized, double-blind, dose-ranging, Phase 2 clinical study with two stages, conducted across 4 sites in Germany and 5 sites in the USA (ClinicalTrials.gov identification number: NCT03806933; EudraCT identification number 2018- 002743-28) as of January 2019. The study was conducted in compliance with the Declaration of Helsinki and Good Clinical Practice principles. All subjects provided written informed consent prior to beginning any study-related procedures.
In Stage 1, 151 subjects were randomized 1:2:2 to receive GFL treatment with 20, 50, or 75U INCO and followed from treatment until return to baseline severity of GFL wrinkle severity according to the blinded investigator assessment on the FWS at maximum frown. Subjects were required to remain in the study for at least 180±7 days and no longer than 360±7 days, depending on return to baseline.
Male and female subjects (≥18 of age) with moderate (score=2) to severe (score=3) GFL at maximum frown according to both subject and investigator assessment on the 4-point FWS were eligible for this study. Key exclusion criteria included: treatment with BoNT (any serotype) in the facial area ≤12 months before injection; treatment with any facial cosmetic procedure in the glabella area ≤12 months before injection; treatment with any biodegradable filler in the glabella area ≤12 months before injection; any previous insertion of permanent material in the glabella area; and planned cosmetic treatment of the face during the study period.
Subjects received a single GFL treatment on day 1, with an optional follow-up treatment (20U INCO) for subjects who had completed the main period (MP) of the study. INCO was reconstituted with unpreserved, sterile 0.9% saline solution. The injection volume was constant across all dose groups. Blinded syringes were loaded with a total injection volume of 0.25 mL and administered by the investigator with a 30 or 32G needle in equal aliquots of 0.05 mL into each of 5 injection sites of the procerus and corrugator muscles (Figure 1).
Primary Efficacy Endpoint
The primary efficacy endpoint was duration of effect, assessed as the time between treatment and return to baseline severity. Effect was defined as ≥1-point improvement compared to baseline at maximum frown by investigator’s live assessment at maximum frown using the FWS, a widely used 4-point standardized photonumeric assessment scale for glabellar line severity (0=no muscle action at all; 1=some even slight muscle action possible; 2=moderately strong muscle action possible; 3=strong muscle action possible that may cause local pallor).
Primary Safety Endpoints
Primary safety endpoints were the occurrence of treatmentemergent AEs (TEAEs), treatment-emergent serious AEs (TESAEs), treatment-emergent AEs of special interest (TEAESIs), related TEAEs, and related TESAEs by dose group as reported by patient and/or investigator. TEAE was defined as an AE emergent with onset or worsening on or after date of the first administration of treatment.
Statistical analyses were performed using SAS® version 9.4 (Cary, NC, USA). Efficacy analyses were conducted on the full analysis set (FAS; all subjects who received study treatment and have a baseline and at least one post-baseline value of any efficacy variable). Duration of effect was described by Kaplan- Meier curves per group and the respective medians of times with associated 2-sided 95% confidence interval (CI). A Cox