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

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.

Study Overview

• Status: Completed
• Conditions: Actinic Keratoses
• Intervention / Treatment: Drug: 5-fluorouracil 4% (Tolak); Device: Dexeryl

• Study Type: Interventional
• Enrollment (Actual): 146
• Phase: Phase 4

Contacts and Locations

Study Locations

• France
  • Arras, France
    • Private practice Maire
  • Nantes, France
    • CHU de Nantes hotel-Dieu
  • Pau, France
    • CHU PAU
  • Poitiers, France
    • CHU Poitiers
  • Saint-Étienne, France
    • CHU St Etienne Hôpital Nord
• Germany
  • Bochum, Germany
    • Kath. Klinikum Bochum St. Josef-Hospital
  • Bonn, Germany
    • MVZ Dermatologisches Zentrum Bonn GmbH
  • Freising, Germany
    • Private Practice Kurzen
  • Hamburg, Germany
    • Dermatologikum Hamburg
  • Mainz-Bretzenheim, Germany
    • Private practice Quist
  • Witten, Germany, 58453
    • Hautarztpraxis
  • Witten, Germany
    • CentroDerm Clinic
• Italy
  • Brescia, Italy
    • Uni Clinic Brescia
  • Catania, Italy
    • Uni Clinic Catania
  • Coppito, Italy
    • Uni Clinic L'Aquila
  • Genova, Italy
    • Policlinico San Martino
  • Messina, Italy
    • University of Messina
  • Modena, Italy
    • Uni Clinic Modena
  • Napoli, Italy
    • NAPLES VANVITELLI UNIVERSITI (Federico II Hospital)
  • Reggio Emilia, Italy
    • Azienda Unità Sanitaria Locale - IRCCS
  • Roma, Italy
    • Catholic University Fondazione Policlinico Universitario A. Gemelli
  • Terracina, Italy
    • Sapienza University of Rome - Polo Pontino
• Spain
  • Barcelona, Spain
    • Centre medic Congres
  • Bilbao, Spain
    • Hospital Alfredo Espinosa
  • Madrid, Spain
    • Hospital Universitario Infanta Leonor
  • Valencia, Spain
    • Instituto Valenciano de Oncología,
  • Villajoyosa, Spain
    • Hospital Marina Baixa

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Participants are eligible only if all of the following criteria apply:

Age

1. Participant must be more than 18 years old inclusive, at the time of signing the informed consent.

   Type of Participant and Disease Characteristics

2. Individuals with a clinical diagnosis of actinic keratosis (AK).
3. 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.

4. 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

5. 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

6. 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

7. 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

1. With AK lesions within treatment areas which are hyperkeratotic or which are clinically suspected to be squamous cell carcinoma (SCC).
2. With pre-existing local skin reactions with a total score ≥ 3.
3. History of hypersensitivity to the ingredients of Tolak® or Dexeryl®.
4. With a known allergy to peanut or soya.

5. Non postmenopausal or non surgically sterile woman considered as WOCBP, pregnant or breastfeeding women.

   Prior/Concomitant Therapy

6. Under systemic 5-fluorouracil or any systemic cancer treatment within eight weeks prior to the study.
7. 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.
8. Treated with systemic steroids, immunosuppressants or immunomodulators within four weeks prior to the study.
9. Under prescription retinoids or topical steroids in the treatment area(s) within four weeks prior to the study.
10. With known dihydropyrimidinedehydrogénase (DPD) deficiency or under treatment with brivudine, sorivudine or analogues within 4 weeks prior to starting the study.
11. Treated with glycolic acid products and alpha-hydroxy products in the treatment area(s) within four weeks prior to starting the study.

12. Treated with chemical peeling products in the treatment area(s) within eight weeks prior to starting the study.

    Prior/Concurrent Clinical Study Experience

13. Is participating in another clinical trial
14. 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
15. Is a family member of the Investigator or any associate, colleague, and employee assisting in the conduct of the study (secretary, nurse, technician,…)
16. Is in a position likely to represent a conflict of interest
17. Has forfeited his / her freedom by administrative or legal award or is under guardianship

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Pierre Fabre Medicament
• Collaborators: Clinact
• Investigators: Principal Investigator: Eggert STOCKFLETH, Pr., Kath. Klinikum Bochum St. Josef-Hospital

Study record dates

Study Major Dates

• Study Start (Actual): February 16, 2021
• Primary Completion (Actual): January 31, 2022
• Study Completion (Actual): January 31, 2022

Study Registration Dates

• First Submitted: March 18, 2021
• First Submitted That Met QC Criteria: April 30, 2021
• First Posted (Actual): May 6, 2021

Study Record Updates

• Last Update Posted (Actual): September 19, 2022
• Last Update Submitted That Met QC Criteria: September 15, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Precancerous Conditions; Keratosis, Actinic; Keratosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Fluorouracil
• Other Study ID Numbers: W00118 CR 401; 2020-000851-11 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes