Phase 4 Study on Incidence of Squamous Cell Carcinoma and Long-term Safety of Tirbanibulin Ointment and Diclofenac Sodium Gel in Actinic Keratosis
- Trial ID
- 2024-514394-22-00
- Protocol
- M-14789-41
- Sponsor
- Almirall S.A.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the incidence of biopsy-confirmed invasive **Squamous Cell Carcinoma** (SCC) in the selected treatment fields after administration of topical tirbanibulin 10 mg/g ointment or diclofenac sodium 3% gel over a 3-year period. This is clinically relevant as it aims to determine the long-term effectiveness of these treatments in preventing the progression of **Actinic Keratosis** to invasive SCC, a potential skin cancer risk.
Secondary objectives include:
- Evaluating the safety of topical tirbanibulin 10 mg/g ointment and diclofenac sodium 3% gel over the 3-year study period.
- Assessing the effect of tirbanibulin 10 mg/g ointment treatment on patient-reported measures of quality of life, cosmetic outcome, and treatment satisfaction.
Participants
The clinical trial involves a total of **32 participants** diagnosed with **Actinic Keratosis**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific criteria, including the presence of a treatment field (TF) on the face or scalp, excluding certain areas, with 2 to 8 clinically typical, visible, and discrete lesions. The trial does not include a vulnerable population. Participants are required to avoid sunlight or UV light exposure to the face or scalp during the study. The selection process ensured that participants have the ability to understand the study's purpose and risks, comply with the protocol, and provide informed consent. The study does not specify any particular lifestyle considerations such as diet or physical activity.
Plans and Procedures
The clinical trial is a **Phase IV**, multi-centre, randomized, evaluator-blinded, active-controlled study designed to assess the incidence of **squamous cell carcinoma** (SCC) and evaluate the long-term safety of **tirbanibulin** 10 mg/g ointment and **diclofenac sodium** 3% gel in adult patients with **actinic keratosis** on the face or scalp. The trial will span a period of three years, with the estimated recruitment start date being October 24, 2022, and the estimated end date being July 31, 2027. The study involves a randomized allocation of participants to either the test product, tirbanibulin ointment, or the comparator product, diclofenac sodium gel, with both products administered via cutaneous use.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), presence of a treatment field (TF) on the face or scalp with specific characteristics, and the ability to comply with study requirements. Following the screening, participants will be randomized and commence treatment, with follow-up visits scheduled to monitor safety and efficacy outcomes. The primary endpoint is the proportion of patients with histologically confirmed invasive SCC in the TF over the study period. Secondary endpoints include adverse events (AEs) and serious adverse events (SAEs), the occurrence of other skin cancers, and various safety and satisfaction assessments.
The expected length of participant involvement is up to three years, with conditions for early termination including the development of invasive SCC, significant adverse reactions, or withdrawal of consent. Participants are required to avoid sunlight or UV light exposure to the face or scalp during the study and must adhere to effective birth control measures if applicable. The study aims to provide comprehensive data on the long-term safety and efficacy of the treatments, contributing valuable insights into the management of actinic keratosis.
Treatment
The clinical trial involves the use of two topical treatments for the management of **actinic keratosis** on the face or scalp. The first treatment is **Solaraze 30 mg/g Gel**, which contains the active substance **diclofenac sodium**. This pharmaceutical form is a gel, intended for **cutaneous use**. The maximum daily dose is 2 grams, with a total maximum dose of 1080 grams over a treatment period of up to 90 days. The gel is applied directly to the affected area, and participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.
The second treatment is **Klisyri 10 mg/g Ointment**, which contains the active substance **tirbanibulin**. This ointment is also designed for **cutaneous use**. The maximum daily dose is 1 gram, with a total maximum dose of 30 grams over a treatment period of up to 5 days. The ointment is applied to the affected area, and compliance is similarly monitored through scheduled evaluations. Both treatments are provided by ALMIRALL, S.A., and are chemically derived substances. The trial is designed to compare the incidence of squamous cell carcinoma and evaluate the long-term safety of these treatments.
Efficacy
Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the proportion of patients with histologically confirmed invasive **Squamous Cell Carcinoma (SCC)** in the treatment field (TF) over the 3-year study period. Secondary endpoints include the incidence of adverse events (AEs) and serious adverse events (SAEs) over the same period, the proportion of patients with any other skin cancer (excluding SCC) in the TF, and the time to occurrence of invasive SCC from baseline in the TF. Additionally, the trial will evaluate the proportion of patients requiring rescue treatment after one treatment course and at any time during the study, as well as the proportion of patients with no lesions after treatment of the first recurrence with tirbanibulin during the first 52 weeks.
Other secondary endpoints involve safety assessments such as vital signs and physical examinations over 3 years, changes from baseline in Skindex-16 scores (covering Symptoms, Emotions, and Functioning) by arm and by visit, cosmetic outcomes, and Treatment Satisfaction Questionnaire for Medication transformed scores by arm and by visit. These efficacy parameters will be measured and collected at specified timepoints throughout the study, ensuring a comprehensive evaluation of the long-term safety and effectiveness of tirbanibulin 10 mg/g ointment and diclofenac sodium 3% gel in treating actinic keratosis on the face or scalp.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female and ≥18 years old
- A TF on the face or scalp (excluding lips, eyelids, ears, and inside the nostrils), that: • Is a contiguous area measuring 25 cm2, • Contains 2 to 8 clinically typical, visible, and discrete AK lesions, and • Has an overall clinical picture that is consistent with Olsen grade 1 (see Appendix 3 of the protocol)
- If a WOCBP, ie, fertile, defined as a female in the life period from menarche and until becoming post-menopausal (no menses for 12 months without an alternative medical cause) or permanently sterile (with hysterectomy, bilateral salpingectomy or bilateral oophorectomy at least 3 months prior to Screening), she must: • Have a negative urine pregnancy test using a highly sensitive method at screening and on Day 1 prior to treatment administration. • Be using effective methods of birth control. • Agree to have pregnancy tests while in the study and at the end of the study (according to the Schedule of Assessments in Table 1 of the protocol)
- Patients should be willing to avoid sunlight or UV light exposure, including the use of tanning beds, to the face or scalp during the study
- Patients should have the ability to understand the purpose and risks of the study, willingness and ability to comply with the protocol, and provide written informed consent in accordance with institutional and regulatory guidelines
Exclusion Criteria
- The location of the TF is: a) On any location other than the face or scalp. b) Within 5 cm of an incompletely healed wound. c) Within 10 cm of a suspected basal cell carcinoma (BCC) or other neoplasm. d) On the lips, eyelids, ears, or inside the nostrils, periorbital, perioral, or the skin surrounding the nostrils.
- Presence in the TF of: a) Clinically atypical and/or rapidly changing AK lesions b) Hyperkeratotic or hypertrophic lesions, recalcitrant disease (had cryosurgery on 2 previous occasions), and/or cutaneous horn. c) Confluent AK lesions (ie, non-discrete lesions, as per inclusion criterion 2). d) Persisting AK lesions at the screening visit following topical treatment with diclofenac sodium 3% gel.
- History of any malignant skin tumour in the TF or history of skin tumour in any region of the body which has metastasized or in which metastasis within the study period is likely.
- History of any malignant tumour with systemic antitumor treatment (including radiotherapy) within 12 weeks prior to the Screening Visit or systemic antitumor treatment is expected while on the study.
- Immunocompromised patients, including patients with a history of chronic systemic lymphoma or chronic myeloid leukaemia, or organ transplant recipients.
- Any other dermatological disease that causes difficulty with examination within the treatment area
- Anticipated need for inpatient hospitalization or inpatient surgery during the study.
- Previous treatment with tirbanibulin 10 mg/g ointment in the selected TF.
- Treatment with 5-fluorouracil, imiquimod, ingenol mebutate, diclofenac, photodynamic therapy, or other topical treatments for AK within the TF or within 2 cm of the TF, within 8 weeks prior to the Screening Visit.
- Use of the following therapies and/or medications within 4 weeks prior to the Screening Visit: a) Treatment with cytotoxic drugs (eg, cyclophosphamide, vinblastine, chlorambucil, methotrexate) b) Treatment with systemic medications that modulate and/or suppress the immune system (eg, cyclosporine, prednisone, methotrexate, alefacept, infliximab, interferons or interferon inducers) c) Use of systemic retinoids (eg, isotretinoin, acitretin, bexarotene)
- Use of the following therapies and/or medications within 2 weeks prior to the Screening Visit: a) Cosmetic or therapeutic procedures (eg, use of liquid nitrogen, surgical excision, curettage, dermabrasion, medium or greater depth chemical peel, laser resurfacing) within the TF or within a 2 cm margin of the selected TF. b) Acid-containing therapeutic products (eg, salicylic acid or fruit acids, such as alpha and beta-hydroxyl acids and glycolic acids), topical retinoids, or light chemical peels within the TF or within a 2 cm margin of the selected TF. c) Topical steroids within the TF or within a 2 cm margin of the selected TF. d) Artificial tanners within the TF or within a 5 cm margin of the selected TF
- History of sensitivity and/or allergy to any of the ingredients in the study medications to tirbanibulin, diclofenac, or nonsteroidal anti-inflammatory drugs (ie, NSAIDs).
- A skin disease (eg, atopic dermatitis, psoriasis, eczema) or condition (eg, scarring, open wounds) that, in the opinion of the Investigator, might interfere with the study conduct or evaluations, or which exposes the patient to unacceptable risk by study participation.
- Significant uncontrolled or unstable medical diseases or conditions that, in the opinion of the Investigator, would expose the patient to unacceptable risk by study participation
- Females who are pregnant or nursing or who are intending to become pregnant
- Participated in an investigational drug study during which an investigational study medication was administered within 30 days or 5 half-lives of the investigational product, whichever is longer, prior to screening
- Patient who is an employee or a relative to an employee at the research site or Almirall
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 24 Oct 2022 | 116 |
 Germany | Not Recruiting | 24 Oct 2022 | 51 |
 Italy | Not Recruiting | 24 Oct 2022 | 95 |
 Poland | Not Recruiting | 24 Oct 2022 | 50 |
 Spain | Not Recruiting | 24 Oct 2022 | 106 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Solaraze 30 mg/g Gel | Comparator | GEL | CUTANEOUS USE | 2 | 90 | PRD296269 |
Klisyri 10 mg/g ointment | Test | OINTMENT | CUTANEOUS USE | 1 | 5 | PRD9189852 |