SCARFREE-001: Verteporfin for Scar Prevention

Overview

The purpose of this clinical trial is to investigate whether the drug verteporfin can reduce the formation of scars in adult patients undergoing a tummy tuck procedure (abdominoplasty). The main questions the study aims to answer are: * Whether treatment with verteporfin can reduce scar formation in surgical wounds that are closed with sutures, compared with placebo (saline). This will be assessed based on how the scars look after 3 months using a standardized scar assessment questionnaire (Patient and Observer Scar Assessment Scale). * Whether treatment with verteporfin can reduce scar formation in small open wounds created after taking small tissue samples (4 mm), compared with placebo. This will also be assessed after 3 months using the same questionnaire. The researchers will compare three different doses of verteporfin (0.5 mg/mL, 1.0 mg/mL, and 2.0 mg/mL) with placebo. Each participant will receive all three doses as well as placebo, but in different areas of the surgical wound and in different small wounds, allowing comparisons to be made within the same person. Participants will: * Undergo a planned abdominoplasty procedure * During surgery, receive small injections in the skin with either verteporfin or placebo in different parts of the surgical wound. * Have four small wounds (4 mm) created from tissue samples, which will also be treated with verteporfin or placebo. * Attend follow-up visits after 1 week, 1 month, and 3 months, where the scars will be examined. * Have photographs and ultrasound measurements taken of the scars. * Complete questionnaires about their own assessment of the appearance of the scars.

Introduction and Background: Scar formation after skin injury represents a significant medical challenge with both physical and psychosocial consequences. Scars can cause pain, pruritus, restricted movement, and substantial psychological distress. While adult wound healing typically results in scar formation, fetal wounds heal with minimal or no scarring, suggesting that regenerative, scarless healing is biologically possible under specific conditions. Recent research has identified the Yes-Associated Protein (YAP)/ Transcriptional Co-Activator with PDZ-binding motif (TAZ) signaling pathway as central to fibrosis development. Inhibition of this pathway has shown promising results in experimental fibrosis models. YAP is a mechano-sensitive transcription coactivator regulated by the Hippo pathway. Its activity has emerged as a key determinant of whether injured tissues undergo regenerative healing (restoring normal structure) or fibrotic repair (scar formation). Recent studies across multiple organs indicate that the timing and duration of YAP activity is critical: Transient or timely YAP modulation can promote regeneration, whereas sustained YAP activation or complete loss of YAP often skews healing toward fibrosis. Verteporfin is a Food and Drug Administration (FDA)-approved benzoporphyrin derivative used for treating macular degeneration that also inhibits the YAP/TAZ pathway. Animal studies have demonstrated that verteporfin reduces extracellular matrix deposition in liver, kidney, and retinal fibrosis. Most notably, Mascharak et al. recently showed that a single dose of verteporfin induced scarless wound healing in the Duroc pig, a model with skin healing characteristics closely resembling those of humans. The results were further validated using a human foreskin graft model in nude mice. Despite these promising preclinical results, human evidence for verteporfin's potential as a scar-preventing treatment is lacking. This study represents the first attempt to translate these findings into clinical practice. Aim: The aim of this study is to evaluate the safety and tolerability and to identify the most appropriate dose of intradermal verteporfin for the prevention of scar formation in surgical wounds. The results will pave the way for subsequent studies to further investigate the efficacy of verteporfin's anti-fibrotic properties. Hypothesis: It is hypothesized that a single intradermal administration of verteporfin at the time of surgery will result in a significant reduction in scar formation compared to placebo. Furthermore, a dose-response relationship is expected, with higher concentrations leading to greater improvement in scar quality without compromising wound healing. Finally, it is hypothesized that the treatment to be safe and well tolerated in humans with no serious adverse effects. Study Design: This trial is a phase 2, prospective, randomized, single blinded, placebo-controlled, intra-patient, single center clinical trial where each participant serves as their own control with different dose levels administered to different parts of the wound and different open wounds within the same patient. The total participation period for the individual subjects is 3 months. The single-blinded study design (blinding of participants and outcome assessors, with the operating surgeon unblinded) was selected due to the visible dark green color of verteporfin, which makes full blinding difficult during administration. An intra-patient design was chosen to minimize inter-patient variability in wound healing. Randomization and blinding: Treatment allocation will be randomized using a computer-generated sequence to assign verteporfin dose levels and placebo to wound areas and punch biopsies within each participant. Sample Size: A total of 12 participants has been chosen as an appropriate sample size for this study. Due to the intra-patient design, where each participant contributes eight scar outcomes (four closed and four open wounds), a total of 96 observations will be available for safety assessment, exploratory dose-response analysis and estimation of effect. The underlying statistical considerations are presented below: Fixed effect: treatment dose; random effect: participant. Pairwise comparisons between each verteporfin dose and placebo will be performed using a mixed-effects model with Dunnett's adjustment for multiple testing. Based on previous scar studies, a 6-point difference in POSAS is considered clinically meaningful. Assuming a standard deviation of 5-7 points and intra-subject correlation of 0.3: With 12 participants, each contributing 4 scars per model (closed and open). The design yields sufficient power (≥80%, α = 0.025 per endpoint after Bonferroni correction). Total of 48 observations per model, supporting separate detection of meaningful differences in both scar types. Methods: Verteporfin will be administered by intradermal injection into wound margins at three dose levels: * 0.5 mg/mL * 1.0 mg/mL * 2.0 mg/mL. These dose levels have been established based on preclinical findings on verteporfin's anti-fibrotic properties where 2.0 mg/mL represents the optimal dose in porcine models (with higher doses showing reduced efficacy), 1.0 mg/mL represents the optimal dose in murine models and 0.5 mg/mL is included to determine the minimal effective dose. The drug will be administered after suture in the closed model, and after punch creation in the open model. Punch biopsies will be obtained from the lower abdomen within the pubic hair-bearing region to evaluate whether hair regrowth occurs as part of the regenerative process and to minimize the visibility of any scars resulting from the biopsies. No light activation will be used in this study. Each participant will receive all three dose levels plus one placebo (saline injection) in separate wound segments and separate punch biopsies. A single administration will take place on Day 0 (day of surgery) with no repeat dosing. This timing exploits the critical early YAP/TAZ modulation window. Participants will be monitored at preplanned follow-up visits on Day 7, Month 1 and Month 3 where scar quality will be assessed via the primary endpoint for both the closed and open model: * The Patient and Observer Scar Assessment Scale (POSAS) at 3 months. POSAS scores range from 6 (normal skin) to 60 (worst imaginable scar) and include six clinical parameters: Vascularity, pigmentation, thickness, relief, pliability and surface area. The endpoint is defined as the difference in POSAS score between verteporfin-treated sites and placebo-treated sites within each participant. Study Limitations: This study has several limitations. Firstly, the small sample size of 12 participants and the single-centre design limit the generalizability of the findings and the ability to detect rare adverse events or establish clinical efficacy. Secondly, the study population consists of healthy adults undergoing elective abdominoplasty which provides a homogeneous wound model but does not reflect high-risk groups such as patients with diabetes, smokers or individuals prone to hypertrophic scarring, therefore external validity is limited. The follow-up period of 3 months fails to capture the long-term phases of scar maturation. Additionally, inter-patient dose comparison - while reducing inter-individual variability - introduces the possibility of local interference between the scar segments. Moreover, several outcome measures rely on subjective scar assessment tools (e.g. POSAS, MSS, SCAR-Q) which - despite being validated - carry a risk of observer bias even under blinded evaluation. These limitations will be addressed in future trials with larger study populations, longer follow-up and multicenter variation as well as inclusion of high-risk groups. Feasibility: The intra-patient design significantly enhances feasibility by reducing the required sample size as each participant contributes four treatment sites per wound model (open and closed). Recruitment is therefore considered realistic, as eligible patients are routinely available among those undergoing elective abdominoplasty at Odense University Hospital. All study procedures are integrated into the routine surgical workflow and three follow-up visits consisting only of non-invasive assessments are planned, minimizing participant burden and risk of withdrawal. The research team has full access to surgical facilities, ultrasound equipment and clinical photography tools. Furthermore, the investigational medicinal product, verteporfin, has an established safety profile in humans in other indications, and only a single, local administration is required per participant. Together, these factors ensure that the study is practically, logistically and ethically feasible. Risks, Adverse Events, and Potential Disadvantages: Verteporfin has an established safety profile in ocular use but is administered differently in this study. Therefore, additional or previously unobserved adverse effects may occur. Possible adverse events include: Common, non-serious adverse events * Mild tenderness, redness, or swelling at the injection sites. Rare or potentially serious adverse events * Allergic reaction to verteporfin. * Infection related to the injection procedure or the collection of tissue samples (punch biopsies). Potential longer-term effects * Changes in the cosmetic appearance or irregularity of the scar. * Tissue stiffness in the area surrounding the scar. * Small scars resulting from the punch biopsy procedures. As with any clinical study, there may be risks that are currently unknown. Participants will therefore be asked to inform the study team if they experience any health-related problems during the course of the study. If new or previously unrecognized adverse effects are identified during the study, participants will be informed promptly and will have the opportunity to decide whether they wish to continue their participation. Novelty: This study is the first clinical trial to investigate intradermal verteporfin to reduce scarring in humans. Most available scar treatments focus on symptomatic treatment of cosmetic symptoms addressing established scars rather than preventing their formation. This project offers a unique possibility to introduce a new concept of pharmacological therapy targeting the biological mechanisms of fibrosis (YAP/TAZ signaling pathway) at the time of injury. This study therefore generates safety and preliminary efficacy data for a completely new therapeutic indication of verteporfin with significant translational potential and large global clinical relevance. Clinical Impact: Excessive scarring remains a major unmet clinical challenge with functional, aesthetic, and psychological consequences affecting millions of patients worldwide every year. Current treatment options are limited in efficacy and primarily reactive as they largely focus on the management of established scars rather than prevention. If successful, this study could introduce a paradigm shift in postoperative wound care by demonstrating that scarring can be modulated at the time of injury through targeted biological intervention. Intradermal verteporfin has the potential to become the first pharmacological therapy to actively reduce scar formation by inhibiting fibrotic signaling pathways. The clinical impact is substantial: Improved patient satisfaction after surgeries with better functional and aesthetic outcomes and significant cost savings for healthcare systems. The findings from this study could benefit a wide range of surgical fields, including plastic and reconstructive surgery, orthopedics, general surgery and dermatology. Ultimately, by bridging strong preclinical evidence with clinical data, this study has the potential to lay the foundation for a new standard of care in scar prevention and personalized wound management.