Adults (≥ 18 years of age) who had undergone dermatologic surgery were considered for inclusion in the study if they had at least two newly formed scars 1–10 cm in length on similar body regions. The subjects had to be enrolled within 3 weeks after the surgery but after the wounds were closed, the scars were controlled and, if applicable, the suture material had been removed. Included subjects could not have had a known history of keloids or hypertrophic scars. Additional exclusion criteria included dermatologic resurfacing procedures or noninvasive skin-tightening procedures, such as medium or deep chemical peeling, dermabrasion, or laser therapy in the area intended to be treated within 8 weeks before enrollment; an infection, a wound, or eczema in the skin area intended to be treated; known hypersensitivity to any ingredient in the OIP; or an ongoing severe or uncontrolled systemic disease, malignant tumor, or known human immunodeficiency virus infection. Subjects could also not be taking or planning to take systemic corticosteroids or topical corticosteroids for the skin area intended to be treated. Women could not be pregnant or breastfeeding and, if of childbearing potential, had to be using an effective method of birth control.
Study Conduct and Assessments
At the baseline visit (day 1), the investigator selected two similar scars from comparable skin areas excluding the upper back (to reduce the risk of scar dehiscence). The scars were randomized 1:1 to the OIP (Contractubex® Overnight Intensive Patch, Merz Pharmaceuticals GmbH) or no patch via a computerized randomization program (RANCODE Version 3.6, IDV Datenanalyse und Versuchsplanung, Gauting, Germany). Subjects were not blinded, but the investigators were blinded to the randomization and treatment received for each scar. For scars treated with the OIP, every night before going to bed, subjects cleaned and dried the scar and applied a new OIP covering the scar completely. The OIP had to be left in place overnight for at least 6 h and up to 12 h. Subjects had to continue treatment for at least 12 weeks, although they could choose to continue for an additional 12 weeks. During the study, subjects could not apply systemic or topical corticosteroids to the scars; undergo dermatological resurfacing or noninvasive skin-tightening procedures including medium/deep chemical peeling, dermabrasion, or laser therapy in the treatment area; apply topical agents containing active ingredients (e.g., self-tanning agents); receive excessive sun exposure (e.g., outdoor work or tanning bed); or apply hydrating lotions in the treated area.
At baseline (day 1), week 6, week 12, and (if the subject remained in the study) week 24 visits, the investigators assessed scar quality using the observer-evaluated Patient and Observer Scar Assessment Scale (POSAS), and the subjects completed the patient-evaluated POSAS. Throughout the study, investigators and all other individuals involved in conducting it were blinded to which scar had been treated with the OIP. The observer-evaluated POSAS includes vascularization, pigmentation, thickness, relief, and pliability, each scored on a scale from 1 (normal skin) to 10 (worst imaginable skin) so that the total score ranges from 5 (best scar appearance) to 50 (worst scar appearance), and the patient-evaluated POSAS includes pain, itching, color, stiffness, thickness, and irregularity, also scored from 1 to 10 (least severe to most severe) so that the total score ranges from 6 (best scar appearance) to 60 (worst scar appearance) [17].
At all post-baseline visits, subjects and investigators also completed the Global Aesthetic Improvement Scale (GAIS) [18], in which 1 = worse, 2 = no change, 3 = improved, 4 = much improved, and 5 = very much improved. In addition, subjects completed a global comfort assessment scale (1 = very good; 2 = good; 3 = moderate; 4 = poor) and rated their satisfaction with scar appearance (satisfied, partially satisfied, or dissatisfied).
Adverse events (AEs) were recorded by investigators at each visit along with severity, relationship to the treatment, outcome, and expectedness.
Study Size
The sample size was estimated based on the results of a previous investigation with Contractubex® gel (Merz Pharmaceuticals, unpublished observations). With a mean change from baseline in POSAS of − 8.7 ± 5.65 for the gel and − 6.1 ± 6.71 for untreated scars and a correlation of − 0.2, 120 randomized subjects were estimated to provide 83.7% power to show a significant difference at α = 0.05 using a two-sided paired t test.
Statistical analysis
The primary effectiveness variable was the change in the observer-evaluated POSAS between baseline and week 12. Secondary effectiveness variables included the absolute change from baseline in the total score of the observer-evaluated POSAS to weeks 6 and 24; the absolute change from baseline in the total score of the patient-evaluated POSAS to weeks 6, 12, and 24; and the investigator- and subject-evaluated GAIS at weeks 6, 12, and 24. Differences in POSAS scores between OIP-treated and untreated scars were examined by analysis of covariance, with treatment and pooled site as fixed effects, subject as a random effect, and missing data replaced using the last observation carried forward. The main analyses were performed in the full analysis set, which was defined as all subjects for whom the primary effectiveness variable was available. In a post hoc analysis, differences in GAIS between groups were analyzed by analysis of variance, with treatment and pooled site as fixed effect and subject as random effect.
The primary safety assessment was the occurrence of treatment-emergent AEs (TEAEs), which was calculated for all subjects exposed to the OIP at least once.
All analyses were performed using SAS version 9.2 or higher (SAS Institute, Cary, NC, USA). A two-sided p-value below 0.05 was considered to indicate statistical significance.