IM Versus 5-FU Versus IMI Versus MAL-PDT in Treatment of Actinic Keratosis

Study Overview
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Brief Summary
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A multi-centre randomised controled single blind clinical phase IV trial with the aim to determine the most effective treatment in terms of lesion reduction, costs and patient satisfaction in treatment of actinic keratosis (AK), when comparing topical treatment with photodynamic therapy (PDT), 5% 5-fluorouracil (5-FU) cream, 5% Imiquimod (IMI) cream and ingenol mebutate (IM) gel.

Detailed Description
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Skin cancer is the most common cancer in Caucasians and therefore a major public health issue. Its incidence is increasing rapidly. Actinic keratosis (AK) is the most prevalent precancerous chronic skin condition. It can transform into squamous cell carcinoma (SCC). AK's generally arise in a skin area that has diffuse precancerous damage, a phenomenon called field cancerization. Because of its precancerous character, it is advised to treat AK and herewith prevent development into SCC. The most frequently used field-directed treatments in the Netherlands are photodynamic therapy (PDT), topical 5% f-fluorouracil (5% 5-FU) and topical 5% Imiquimod (5% IMI). Lately another topical product is approved by Dutch healthcare insurances: Ingenol mebutate (IM). Up to date, which treatment the patient will receive, does not rely on evidence-based-medicine, but generally on the preference of the physician. Current national and international guidelines state no clear recommendations for the best choice of therapy. The aim of this study determine which treatment is the most effective treatment in terms of lesion reduction, costs and patient satisfaction when comparing topical treatment with photodynamic therapy (PDT), 5% 5-fluorouracil (5-FU) cream, 5% Imiquimod (IMI) cream and ingenol mebutate (IM) gel, in treatment of actinic keratosis (AK).

Official Title
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Topical Ingenol Mebutate Versus 5% 5-fluorouracil Versus 5% Imiquimod Versus Photodynamic Therapy in Treatment of Actinic Keratosis: a Multi-centre Randomized Efficacy and Cost-effectiveness Study

Conditions
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Keratosis, Actinic

Intervention / Treatment
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* Drug: Imiquimod
* Drug: 5-fluorouracil
* Drug: Ingenol mebutate
* Procedure: methylaminolevulinate photodynamic therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients older than 18 years Fitzpatrick skintype I-IV Clinically confirmed diagnosis of AK One joint area of minimal 25 cm2 and maximal 100 cm2 of AK Minimum of 5 AK lesions AK Olsen grade I-III Location: head/neck area Exclusion Criteria: Received any kind of treatment for AK in the past 3 months (non)melanoma skin cancer in target area Immuno-compromised status Use of systemic retinoid in the past 3 months Use of immunosuppressant drugs in the past 3 months and / or at time of treatment (such as oral glucocorticoids, cytostatic, antibodies, drug acting on immunophilins, interferon, opioids, Tumor Necrosis Factor (TNF) binding proteins, mycofenolate mofetil (MMF), biologic agents). inhalation corticosteroids / nasal corticosteroids are permitted. Porphyria Not able to give informed consent Allergy to study drugs or peanut/nut/soy products Pregnant and breastfeeding women Female in child bearing potential not using contraceptive measures, during and till 3 months post-treatment Genetic skin cancer disorders Not understanding Dutch language

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Imiquimod<br>three times a week once daily during 4 consecutive weeks. Prior to treatment: curettage | Drug: 5-fluorouracil<br>* during 4 (consecutive) weeks twice daily. Prior to treatment: curettage<br>* Other names: Efudix;Drug: Ingenol mebutate<br>* during 3 (consecutive) days once daily. Prior to treatment: curettage<br>* Other names: Picato;Procedure: methylaminolevulinate photodynamic therapy<br>* methylaminolevulinate photodynamic therapy; one session. Prior to treatment: curettage<br>* Other names: MAL-PDT;|
| Active Comparator: 5-Fluorouracil<br>during 4 (consecutive) weeks twice daily. Prior to treatment: curettage | Drug: Imiquimod<br>* three times a week once daily during 4 consecutive weeks. Prior to treatment: curettage<br>* Other names: Aldara;Drug: Ingenol mebutate<br>* during 3 (consecutive) days once daily. Prior to treatment: curettage<br>* Other names: Picato;Procedure: methylaminolevulinate photodynamic therapy<br>* methylaminolevulinate photodynamic therapy; one session. Prior to treatment: curettage<br>* Other names: MAL-PDT;|
| Active Comparator: Ingenol mebutate 0.015%<br>during 3 (consecutive) days once daily. Prior to treatment: curettage | Drug: Imiquimod<br>* three times a week once daily during 4 consecutive weeks. Prior to treatment: curettage<br>* Other names: Aldara;Drug: 5-fluorouracil<br>* during 4 (consecutive) weeks twice daily. Prior to treatment: curettage<br>* Other names: Efudix;Procedure: methylaminolevulinate photodynamic therapy<br>* methylaminolevulinate photodynamic therapy; one session. Prior to treatment: curettage<br>* Other names: MAL-PDT;|
| Active Comparator: MAL-PDT<br>methylaminolevulinate photodynamic therapy; one session. Prior to treatment: curettage | Drug: Imiquimod<br>* three times a week once daily during 4 consecutive weeks. Prior to treatment: curettage<br>* Other names: Aldara;Drug: 5-fluorouracil<br>* during 4 (consecutive) weeks twice daily. Prior to treatment: curettage<br>* Other names: Efudix;Drug: Ingenol mebutate<br>* during 3 (consecutive) days once daily. Prior to treatment: curettage<br>* Other names: Picato;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| treatment succes | the proportion of patients with ≥75% lesion reduction in the number of AK lesions counted at baseline in the treatment area 12 months post final treatment (≥ 75% patient clearance at 12 months). | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| treatment failure | proportion of participants with <75% reduction in number of AK lesions after 3 and 12 months post final treatment compared to baseline (<75% patient clearance at 3 and 12 months). | 12 months | 
| Treatment succes at 3 months post treatment | proportion of participants with ≥75% reduction in number of AK lesions at 3 months post final treatment (≥ 75% patient clearance at 3 months). | 3 months | 
| complete lesion clearance | proportion of lesions with 100% clearance in all treated patients at 3 and 12 months post final treatment. | 12 months | 
| SCC | Proportion of patients who develop a SCC in the treatment area during study follow-up. | 12 months | 
| side effects | local skin reactions reported in patient diary, visual analogue score (VAS), Patient-reported adverse events | 12 months | 
| Cosmetic outcome | based on a Cosmetic questionnaire, filled in on baseline, 3 + 12 months | 3 and 12 months | 
| patient satisfaction | Skindex-29 questionnaire (quality of life) , Actinic Keratosis Quality of Life (AKQoL) questionnaire; filled in on baseline, 3 + 12 months | 12 months | 
| treatment compliance | defined as the number of applied treatments as percentage of the number of prescribed treatments, based on patient diaries and weighing returned medication. | 3 months | 
| Overall decrease in AK | Decrease in number AK from baseline per patient, at 3 and 12 months post final treatment. | 3 and 12 months | 
| Cost-effectiveness | Healthcare/treatment costs | 12 months | 
| Investigator Global Improvement Indices | Investigator Global Improvement Indices (IGII) at 3 and 12 months post final treatment. | 3 and 12 months | 
| Number of new lesions | Number of new lesions at 3 and 12 months post final treatment | 3 and 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Keratosis, Actinic, Treatment Outcome, cost-effectiveness, economic evaluation, imiquimod, photodynamic therapy, topical fluorouracil, ingenol mebutate