Frequency and Intensity of Local Reactions in Patients Treated With 4% 5-FU vs 4% 5-FU Associated With an Emollient Cream: a Randomised, Controlled Clinical Trial

Study Overview
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Brief Summary
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Transient local skin reactions with topical Actinic Keratosis treatments such as 5-FluoroUracil (5-FU) often lead to non-adhesion from patients and thus to treatment failure. In regards to 5-FU treatment, these local reactions are related to the pharmacological action of the molecule. The current therapeutic challenge is to reduce the local reactions induced by 5-FU without interfering with its efficacy, in particular by the use of an emollient cream. The aim of the present study is to investigate how the use of an emollient, namely Dexeryl, could improve the local skin reactions occurring during 4 weeks of a 4% 5-FU treatment.

Official Title
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Frequency and Intensity of Local Reactions in Patients Treated With 4% 5-FU vs 4% 5-FU Associated With an Emollient Cream: a Randomised, Controlled Clinical Trial

Conditions
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Actinic Keratoses

Intervention / Treatment
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* Drug: 5-fluorouracil 4% (Tolak)
* Device: Dexeryl


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants are eligible only if all of the following criteria apply: Age Participant must be more than 18 years old inclusive, at the time of signing the informed consent. Type of Participant and Disease Characteristics Individuals with a clinical diagnosis of actinic keratosis (AK). Individuals harboring 5 or more clinically recognizable (palpable and/or visible to unaided eye) AK lesions of the face, and/or ears and/or scalp. The AK lesions must be clinically typical non hypertrophic and/or nonhyperkeratotic. Subject in good general condition and free of any disease state or condition which, in the investigator's opinion, could impair evaluation of actinic keratosis or could expose the subject to an unacceptable risk by study participation. Sex Male or female. A Female participant is eligible to participate if she is not a woman of childbearing potential (WOCBP), defined as postmenopausal (cessation of menses >12 months) or surgically sterile (history of bilateral tubal ligation, bilateral oophorectomy, total hysterectomy). Informed Consent Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Ethical/Legal considerations Affiliated to a social security system, or is a beneficiary (if applicable in the national regulation). Exclusion Criteria: Participants are excluded from the study if any of the following criteria apply: Medical Conditions With AK lesions within treatment areas which are hyperkeratotic or which are clinically suspected to be squamous cell carcinoma (SCC). With pre-existing local skin reactions with a total score ≥ 3. History of hypersensitivity to the ingredients of Tolak® or Dexeryl®. With a known allergy to peanut or soya. Non postmenopausal or non surgically sterile woman considered as WOCBP, pregnant or breastfeeding women. Prior/Concomitant Therapy Under systemic 5-fluorouracil or any systemic cancer treatment within eight weeks prior to the study. Under any other topical AK treatments or therapies (e.g., Cryotherapy or Photodynamic therapy) in the treatment area(s) within eight weeks prior to starting the study. Treated with systemic steroids, immunosuppressants or immunomodulators within four weeks prior to the study. Under prescription retinoids or topical steroids in the treatment area(s) within four weeks prior to the study. With known dihydropyrimidinedehydrogénase (DPD) deficiency or under treatment with brivudine, sorivudine or analogues within 4 weeks prior to starting the study. Treated with glycolic acid products and alpha-hydroxy products in the treatment area(s) within four weeks prior to starting the study. Treated with chemical peeling products in the treatment area(s) within eight weeks prior to starting the study. Prior/Concurrent Clinical Study Experience Is participating in another clinical trial Has participated in another clinical trial within the last 30 days, has received treatment with known remnant effects or undergone investigation liable to interfere with the present clinical trial Other Exclusions Is a family member of the Investigator or any associate, colleague, and employee assisting in the conduct of the study (secretary, nurse, technician,…) Is in a position likely to represent a conflict of interest Has forfeited his / her freedom by administrative or legal award or is under guardianship

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 5-fluorouracil 4% (Tolak) + Dexeryl<br>This group will apply 5-FU once daily for 4 weeks, and Dexeryl once daily for 8 weeks. | Drug: 5-fluorouracil 4% (Tolak)<br>* Application of Tolak once daily in the evening for 4 weeks<br>Device: Dexeryl<br>* Application of Dexeryl once daily in the morning for 8 weeks<br>|
| Other: 5-fluorouracil 4% (Tolak)<br>This group will only apply 5-FU once daily for 4 weeks. | Drug: 5-fluorouracil 4% (Tolak)<br>* Application of Tolak once daily in the evening for 4 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local Skin Reaction (LSR) total score | Investigator-assessed score: 6 objective items scored from 0-4 (erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, erosion/ulceration) for a minimal score of 0 (best outcome possible), and a maximal score of 24 (worst outcome possible). | at 4 weeks or Last Observation Carried Forward (LOCF) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local Skin Reaction (LSR) total score | Investigator-assessed score: 6 objective items scored from 0-4 (erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, erosion/ulceration) for a minimal score of 0 (best outcome possible), and a maximal score of 24 (worst outcome possible). | at 2 weeks (first follow-up) | 
| Local Skin Reaction (LSR) total score | Investigator-assessed score: 6 objective items scored from 0-4 (erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, erosion/ulceration) for a minimal score of 0 (best outcome possible), and a maximal score of 24 (worst outcome possible). | at 8 weeks (last follow up) | 
| Local Skin Reaction (LSR) items alone | Presence/absence/intensity of each item of the LSR: 6 objective items scored from 0-4 (erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, erosion/ulceration). For each item, 0 is the best outcome possible, 4 is the worst | at 2 weeks (first follow-up) | 
| Local Skin Reaction (LSR) items alone | Presence/absence/intensity of each item of the LSR: 6 objective items scored from 0-4 (erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, erosion/ulceration). For each item, 0 is the best outcome possible, 4 is the worst | at 4 weeks (second follow up) | 
| Local Skin Reaction (LSR) items alone | Presence/absence/intensity of each item of the LSR: 6 objective items scored from 0-4 (erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, erosion/ulceration). For each item, 0 is the best outcome possible, 4 is the worst | at 8 weeks (last follow up) | 
| Subjective signs at each visit | Patient questionnaire evaluating prurit (0-3), stinging/burning (0-3), pain (0-4). 0 is the best outcome, 10 is the worst outcome. | at 2 weeks (first follow-up) | 
| Subjective signs at each visit | Patient questionnaire evaluating prurit (0-3), stinging/burning (0-3), pain (0-4). 0 is the best outcome, 10 is the worst outcome. | at 4 weeks (second follow up) | 
| Subjective signs at each visit | Patient questionnaire evaluating prurit (0-3), stinging/burning (0-3), pain (0-4). 0 is the best outcome, 10 is the worst outcome. | at 8 weeks (last follow up) | 
| Local reactions according to Common Terminology Criteria for Adverse Event (CTCAE) grade 3 or 4 | Intensity grading of adverse events | at 2 weeks (first follow-up) | 
| Local reactions according to Common Terminology Criteria for Adverse Event (CTCAE) grade 3 or 4 | Intensity grading of adverse events | at 4 weeks (second follow up) | 
| Local reactions according to Common Terminology Criteria for Adverse Event (CTCAE) grade 3 or 4 | Intensity grading of adverse events | at 8 weeks (last follow up) | 
| Adverse Events reported by patients or noticed by investigator |  | at 2, 4 and 8 weeks (first follow-up) | 
| Drop outs due to Adverse Events (AE) related to local skin reaction | discontinuation rate | at 2, 4 and 8 weeks (first follow-up) | 
| Use of rescue treatment |  | at 2 weeks (first follow-up) | 
| Use of rescue treatment |  | at 4 weeks (second follow up) | 
| Use of rescue treatment |  | at 8 weeks (last follow up) | 
| Treatment satisfaction (acceptability): measured by Treatment Satisfaction Questionnaire for Medication version 9 (TSQM-9) | The TSQM-9 questionnaire includes nine questions that assess patients' satisfaction by providing score on three scales: effectiveness (questions 1 to 3), convenience (questions 4 to 6) and global satisfaction (questions 7 to 9). The scores of each scale range from 0 to 100, where a higher score indicates a greater satisfaction | at 4 weeks (end of treatment) or at Patient Withdrawal | 
| Treatment adherence | assessed by the participant using a self questionnaire | at 4 weeks | 
| Treatment adherence | assessed by the participant using a self questionnaire | at optional visit (when applicable), up to 8 weeks | 
| Health-related quality of life measured by actinic keratosis quality of life questionnaire (AKQoL) | actinic keratosis quality of life patient questionnaire, for Spain and Germany only. 0 is the best outcome, 27 is the worst outcome | at 8 weeks (last follow up) | 
| Rates of patients with complete and partial clearance rates |  | at 8 weeks (last follow up) | 
| Rates of patients with partial clearance rates |  | at 8 weeks (last follow up) | 
| Percentage change in number of AK lesions |  | at baseline | 
| Percentage change in number of AK lesions |  | at 2 weeks (first follow-up) | 
| Change in number of AK lesions |  | at 2 weeks (first follow-up) | 
| Percentage change in number of AK lesions |  | at 4 weeks (second follow up) | 
| Change in number of AK lesions |  | at 4 weeks (second follow up) | 
| Percentage change in number of AK lesions |  | at 8 weeks (last follow up) | 
| Change in number of AK lesions |  | at 8 weeks (last follow up) |