TIRBASKIN is an open-label, phase IV, multicenter, single-cohort, low-interventional CT (EudraCT No. 2022-001251-16) conducted in 30 centers in Spain and 7 in Italy from January 20, 2023, to January 19, 2024, in accordance with the Declaration of Helsinki, the International Council for Harmonisation Good Clinical Practice guidelines, and Spanish and Italian local laws. The study was reviewed by independent ethics committees in each country. All patients signed written informed consent, including consent for publication of photographs, before participating in the trial.

The study population consisted of adults with a clinically typical diagnosis of AK in 1 contiguous area of ≤25cm2 on the face or scalp containing 4–8 nonhyperkeratotic, nonhypertrophic AK lesions, who had not been previously treated in the same area during the previous 6 months. At least 30% of patients previously treated in other small areas (≤25cm2) within the previous >1 to <6 months were enrolled to avoid recall bias related to previous treatments. Patients with clinically atypical or rapidly changing AK lesions, incompletely healed wounds, or suspected basal cell carcinoma (BCC) or SCC were excluded. Moreover, patients receiving cosmetic procedures or treatments that could interfere with study results (ie, immunomodulators, cytotoxic drugs, interferons/interferon inducers, systemic retinoids, or systemic immunosuppressive agents [except for organ transplant recipients under stable immunosuppressive therapy for 6 months]) were also excluded.

Tirbanibulin was applied according to the European Summary of Product Characteristics.5 On day 1 (D1), treatment application was performed at the investigational site. Between D2 and D5, treatment was self-administered once daily at home. Visits were conducted at screening and on D0 (baseline), D8, and D57 (end of study). Total study duration was 12 months, including recruitment, screening, treatment, and follow-up.

The primary endpoint was treatment satisfaction on D57, evaluated with the Treatment Satisfaction Questionnaire for Medication version 9 (TSQM-9).14 TSQM-9 is a validated instrument comprising 3 domains: effectiveness (questions 1–3), convenience (questions 4–6), and global satisfaction (questions 7–9). Questions 1–6 and 9 are scored on a 7-point scale, whereas questions 7 and 8 are scored on a 5-point scale. Subscale scores are transformed to a 0–100 scale, with higher scores representing greater satisfaction.

Secondary endpoints were PROs and ClinROs, organoleptic properties of tirbanibulin, efficacy, safety, and adherence to treatment. PROs were assessed using Skindex-16, TSQM-1.4, and the Expert Panel Questionnaire (EPQ).

Skindex-1615,16 was used to assess percent change from baseline (%CFB) to D57 in skin condition. Skindex-16 is a short, 16-item, patient-completed assessment with 3 domains: symptoms, emotional impact, and functioning. All items are scored on a 7-point numerical analog scale and transformed to a linear 0–100 scale. Higher scores indicate greater impairment.

TSQM-1.4,17 is an extended version of TSQM-9 focused on effectiveness, side effects, convenience, and global satisfaction domains. The global total score ranges from 0 to 100, with higher scores indicating greater satisfaction.

Regarding the EPQ,18 items were designed to be answered by both patients and clinicians, except for item 10, which was designed to be answered only by clinicians. Overall skin appearance was rated from 0 (much worse) to 4 (much improved), and satisfaction with “how skin looks” and “skin texture” was rated from 1 (extremely dissatisfied) to 7 (extremely satisfied). Duration and severity of local tolerability signs (LTSs), impact on daily activities, convenience, ease of use, and overall satisfaction compared with previous AK treatments were rated from 0 (much shorter/better) to 4 (much longer/worse). Likelihood of reconsidering treatment was rated from 0 (very unlikely) to 4 (very likely).

Organoleptic properties of tirbanibulin were assessed at D8 with a Likert-scale questionnaire composed of questions related to the product's characteristics. The Likert scale offered 7 possible responses, from “totally agree” to “totally disagree.”

Efficacy profile was assessed by the percentage of patients with complete clearance (CC), defined as a 100% reduction in lesions within the application area, and the percentage of patients with partial clearance (PC), defined as a reduction of ≥75% of lesions, at D57. The percentage of patients with PC included patients with CC. Furthermore, the number of AK lesions at D57 and the percent reduction in AK lesion count were assessed. Efficacy was also assessed in patients defined as immunosuppressed and in subgroups according to lesion location (face vs scalp) and age (<65 vs ≥65 years).

Safety profile was assessed by the incidence and severity of adverse events (AEs) and LTSs (erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosions/ulcerations) on a grading scale ranging from 0 (absent) to 3 (severe). Application-site reactions such as itching, burning, stinging, tenderness, or pain were not classified as LTSs and were reported as AEs. LTSs were also evaluated in patients who achieved CC.

Treatment adherence was recorded using a self-administered patient diary (D0 to D4), including questions related to treatment dosage and frequency, AEs, and reasons for missed or delayed doses.

Variables were analyzed descriptively using appropriate statistical methods. Continuous data were summarized by mean, SD, 95%CI, median, first and third quartiles, minimum, and maximum. Categorical data were presented as absolute and relative frequencies (n and %). Bilateral 95% confidence limits are presented as appropriate. Patients were included in each analysis based on available data. No imputation was made for missing data. All analyses were performed using SAS version 9.4 (SAS Institute, Inc, Cary, NC, USA).

A total of 334 patients (262 in Spain and 72 in Italy) applied at least 1 dose of tirbanibulin and were included in the full analysis set (FAS) and safety population. The evaluable population included 328 patients who completed the TSQM-9 assessment and the study at D57.

A total of 52.7% of patients were diagnosed with AK on the scalp, and the mean number of AK lesions at baseline was 5.9 (SD, 1.4). Mean age was 74.8 years (SD, 8.6), and most patients were male (83.5%). Moreover, 6 patients (1.8%) were immunosuppressed (Table 1).

A total of 334 patients (262 in Spain and 72 in Italy) applied at least 1 dose of tirbanibulin and were included in the full analysis set (FAS) and safety population. The evaluable population included 328 patients who completed the TSQM-9 assessment and the study at D57.

A total of 52.7% of patients had AK on the scalp, and the mean number of AK lesions at baseline was 5.9 (SD, 1.4). Mean age was 74.8 years (SD, 8.6), and most patients were male (83.5%). Moreover, 6 immunosuppressed patients (1.8%) were included (Table 1).

Patients reported high satisfaction with tirbanibulin at D57 across TSQM-9 domains (Fig. 1). The highest satisfaction was reported for convenience of use (mean score, 82.8), followed by global satisfaction (mean score, 76.9) and effectiveness (mean score, 73.6). [Note: the first 95%CI appears inconsistent in the source because 82.8 cannot correspond to 71.3–76.0. I did not invent a corrected interval.]

Fig. 1.

Patients’ reported satisfaction with tirbanibulin treatment (TSQM-9). TSQM, Treatment Satisfaction Questionnaire for Medication.

The %CFB in the symptoms, emotions, and functioning domains of Skindex-16 was 64.8%, P<.0001; 57.3%, P<.0001; and 45.2%, P=.0002, respectively (Fig. 2).

Fig. 2.

Evaluation of PROs: AK symptoms and impact on emotions and functioning (Skindex-16). AK, actinic keratosis; CFB, change from baseline; PRO, patient-reported outcome.

Most patients (82.9%) did not experience any side effects, even slight ones, whereas 17.1% did. Side effects were reported as bothering patients a little or not at all (75.0% of patients), interfering a little or not at all with physical health and ability to function (98.2% of patients), interfering minimally or not at all with mental functioning (100% of patients), and affecting overall satisfaction minimally or not at all (82.1% of patients) (Fig. 3).

Fig. 3.

Evaluation of PROs: tirbanibulin side effects (TSQM-1.4). PRO, patient-reported outcome; TSQM, Treatment Satisfaction Questionnaire for Medication.

Overall skin appearance in the treated AK area was considered much or somewhat improved from baseline to D57 by 96.3% of clinicians and 92.5% of patients. A total of 202 patients (61.6%) had received at least 1 prior AK therapy, the most common being cryotherapy (43.0% of patients), sensitizers used in photodynamic/radiation therapy (21.0% of patients), and diclofenac sodium (14.0%). Overall satisfaction with tirbanibulin compared with previous AK treatments was rated as much or somewhat better by 87.7% of clinicians and 81.8% of patients. Similarly, 87.1% of clinicians and 86.3% of patients reported that they would consider tirbanibulin again, if needed. More details are provided in Supplementary Fig. 1.

Among the 328 evaluable patients, 327 (99.7%) completed the questionnaire at D8. Most patients found the general appearance (93.9% of patients) and texture (94.5% of patients) of the product agreeable. Patients also agreed that tirbanibulin was easy to apply (97.3% of patients) (Fig. 4).

Fig. 4.

Overall appreciation of organoleptic characteristics.

At D57, the mean number of old and new AK lesions was 1.1 (SD, 1.6) and 0.1 (SD, 0.3), respectively. The percent reduction in AK lesion count was 83.0% when only old lesions were considered and 82.2% when both old and new lesions were considered (Fig. 5A). A total of 54.3% of patients achieved CC, and 76.8% achieved PC. Fig. 6 shows the evolution of AK lesions in 4 selected patients. Similar results were observed in subgroups according to location and age (Fig. 5B and C) and in immunosuppressed patients (percent reduction in lesion count, 83.3%; CC, 40.0%; PC, 100.0%). CC and PC according to baseline Olsen classification are presented in Supplementary Fig. 2.

Fig. 5.

Complete and partial clearance at day 57 for (A) the overall population; (B) patients with AK lesions on the face or scalp; and (C) patients aged <65 years or ≥65 years. AK, actinic keratosis. Partial clearance is defined as a reduction of ≥75% (includes patients with complete clearance).

Fig. 6.

Clinical clearance at day 8 and day 57 in four cases from the treated sample. AKs, actinic keratoses.

A total of 153 patients (45.8%) reported at least 1 treatment-emergent AE (TEAE). In 38.6% of patients, TEAEs were considered related to treatment (Table 2). Pruritus was the most frequent TEAE, occurring in 27.5% of patients. Regarding severity, grade 3 TEAEs were reported in 3 patients (0.9%) (hypersensitivity, 0.3%; BCC, 0.3%; and hypertension, 0.3%), and grade 4 TEAEs were reported in 1 patient (hypersensitivity, 0.3%). Regarding TEAEs of special interest, 3 patients (0.9%) experienced BCC; however, these BCCs were not located in the AK treatment area and were considered unrelated to treatment. Three patients (0.9%) discontinued treatment because of TEAEs.

At D8, most LTSs were mild or moderate (Table 3). Few patients experienced severe erythema/redness (2.2% of patients), flaking/scaling (0.6% of patients), or crusting/scabs (0.3% of patients). No severe cases of swelling, erosions/ulceration, or vesiculation/pustulation were reported. At D57, LTS assessment was comparable to baseline or better. The mean composite LTS score, calculated as the sum of the scores observed for each sign, was 1.8 (SD, 1.7) and 0.1 (SD, 0.3) out of 18 at D8 and D57, respectively. More than 75% of patients who achieved CC at D57 had an LTS composite score ≤2 at D8 (Supplementary Fig. 3). In the subgroup of patients who achieved CC, only 2.3% experienced severe erythema/redness. Immunosuppressed patients did not experience severe LTSs (Table 3).

A total of 330 patients (98.8%) applied all tirbanibulin doses; 327 (97.9%) completed treatment, and 7 (2.1%) discontinued.