Evaluation of 5-Fluorouracil and Calcipotriol Combination Therapy Versus 5-Fluorouracil Monotherapy in Actinic Keratosis: A Multicenter Randomized Controlled Trial

The primary objective of this study is to evaluate whether a four or six-day treatment with a combination of **5-Fluorouracil** and **calcipotriol** is non-inferior to a four-week monotherapy of 5-Fluorouracil in terms of the 1-year probability of treatment success in patients with **actinic keratosis**. Treatment success is defined as a reduction of 75% or more in the number of actinic keratosis lesions in the treatment area. This objective is clinically relevant as it aims to determine if a shorter treatment duration with combination therapy can achieve similar efficacy, potentially improving patient compliance and reducing treatment burden.

Secondary objectives include:

• Comparing the clearance rate in both treatment groups.
• Comparing the recurrence rate in both groups.
• Comparing adverse effects.
• Comparing treatment compliance.
• Comparing patient satisfaction.
• Comparing the quality of life.
• Investigating the long-term risk of cutaneous squamous cell carcinoma (cSCC) development as an exploratory objective.

The clinical trial focuses on evaluating treatment efficacy for **actinic keratosis**. The study population includes both male and female adults aged 18 years and older. Participants are required to have a clinical and dermoscopical diagnosis of actinic keratosis, with lesions present in specific areas such as the face, ears, scalp, neck, shawl area, sun-exposed chest, or upper extremities. The trial targets individuals with at least four actinic keratosis lesions within a continuous treatment area of up to 100 cm², classified as Olsen grade I-III. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of a combination therapy using **fluorouracil** and **calcipotriol** compared to **fluorouracil** monotherapy in the treatment of **actinic keratosis**. This is a multicenter, randomized, controlled trial with a double-blind design to ensure unbiased results. The trial is categorized as a low-intervention study, indicating minimal health risks and no significant invasive procedures for participants. The estimated duration of the trial is from September 2024 to March 2029, with the primary objective being to assess the non-inferiority of the combination therapy in achieving a 75% reduction in **actinic keratosis** lesions over a one-year period.

Participants will be involved in the study for a maximum of six weeks, depending on the treatment group assignment. The trial includes several key visits: an initial screening visit to confirm eligibility, followed by treatment visits where the topical application of the study medications will be administered. Follow-up visits are scheduled at 3 and 12 months post-treatment to evaluate the primary and secondary endpoints, including the proportion of patients achieving partial and complete clearance of lesions, changes in the Actinic Keratosis Area and Severity Index (AKASI) score, and recurrence rates. The end-of-study visit will occur at 12 months post-treatment to assess long-term outcomes and patient satisfaction.

Participants are expected to adhere to the treatment regimen, with adherence being monitored through patient diaries and follow-up assessments. Conditions that may lead to early termination from the study include non-compliance with the treatment protocol, withdrawal of consent, or the occurrence of moderate to severe adverse effects. The trial aims to provide comprehensive data on the efficacy and safety of the combination therapy, contributing valuable insights into the management of **actinic keratosis**.

The clinical trial involves the use of two topical medications for the treatment of **actinic keratosis**. The first experimental medication is **Efudix 5% cream**, which contains the active substance **fluorouracil**. This medication is formulated as a cream and is applied topically. The maximum daily dose is two applications per day, with a total maximum dose of 56 applications over a treatment period of four weeks. The cream is manufactured by Mylan Products Limited and is authorized under the marketing authorization number PL 46302/0128. The treatment is designed to be applied directly to the affected skin areas, and participant compliance is monitored through regular assessments.

The second medication used in the trial is **Calcipotriol Ointment 50 micrograms/g**, containing the active substance **calcipotriol**. This ointment is also applied topically, with a maximum daily dose of two applications per day and a total maximum dose of 12 applications over a treatment period of six days. The ointment is produced by Sandoz Ltd and holds the marketing authorization number PL 04416/0700. The application of the ointment is intended to be consistent with the dosing schedule, and adherence is evaluated through participant follow-up visits.

The trial compares the efficacy of a combination therapy of **5-Fluorouracil** and **Calcipotriol** against **5-Fluorouracil** monotherapy. The primary objective is to determine if the combination therapy is non-inferior to the monotherapy in achieving a ≥75% reduction in the number of actinic keratosis lesions within the treatment area over a one-year period. The study is structured as a multicentre randomized controlled trial, ensuring rigorous assessment of treatment outcomes.

Efficacy in this clinical trial will be assessed by evaluating the treatment success of a combination therapy of **5-Fluorouracil** and Calcipotriol compared to **5-Fluorouracil** monotherapy in patients with actinic keratosis. The primary endpoint is the proportion of patients achieving treatment success, defined as a ≥75% reduction in the number of actinic keratosis lesions in the treatment area, at 12 months post-treatment. Secondary endpoints include the proportion of patients achieving treatment success at 3 months post-treatment, complete clearance of lesions at 3 and 12 months, and the mean percentage change in lesions compared to baseline at these timepoints.

Additional secondary endpoints involve the mean change in the Actinic Keratosis Area and Severity Index (AKASI) score, recurrence rate, retreatment necessity, adverse effects, patient satisfaction, quality of life measured by the Skindex-17 questionnaire, and treatment adherence. These parameters will be measured at baseline, 1 week after treatment, and at 3 and 12 months post-treatment. The exploratory endpoint is the long-term probability of cutaneous squamous cell carcinoma (cSCC) development, expressed as the 3-year cumulative probability. Efficacy assessments will be conducted using validated scales and patient-reported outcomes, ensuring a comprehensive evaluation of the treatment's impact.