Tolerance and Performance of Cyto-selective Difluoroethane-based Cryotherapy in the Treatment of Brown Spots

Study Overview
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Brief Summary
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CS5_1 study aim to evaluate the tolerance and to adjust the mode of administration of 4 different conditions of cryotherapy treatments applied on the brown spots of the face and hand with 3 prototypes. Each treatment corresponds to a combination of a specific sequence of a cryogenic spray and of a frequency of application. The study will evaluate 3 prototypes : Prototype 1 : from (815-v1 001) to (815-v1 100) Prototype 2 : from (815-v1 101) to (815-v1 150) Prototype 3 : from (815-v1 151) to (815-v1 200)

Detailed Description
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Rational: Solar lentigo is a harmless patch of darkened skin. It results from exposure to ultraviolet (UV) radiation, which causes local proliferation of melanocytes and accumulation of melanin within the skin cells (keratinocytes). Solar lentigos or lentigines are very common, especially in people over the age of 40 years. Solar lentigines are found on sun-exposed sites, particularly the face or the back of hands. Cryotherapy is more and more used to improve skin appearance and currently used to treat lentigo spot. However, the cryogenic gas (conventional cryotherapy - liquid nitrogen) creates a dermabrasion of the skin surface and person receiving this kind of treatment presents an impaired skin during a few days following the treatment as temporary damage of stratum corneum, erythema, scars, burns. Following the side effects occurring after conventional cryotherapy application, the Sponsor has developed some devices using difluoroethane, manufactured by CRYONOVE PHARMA, already available on the local and international markets, e.g. CRYOBEAUTY MAINS and CRYOBEAUTY CORPS. To continue it research and development activities, it seems interesting for the sponsor to select other sequences of a cryogenic spray which could be used for lentigo treatment with a same benefit for the consumers without any safety outcomes. Design: The study is a proof of performance designed to be interventional, monocentric, randomized and double blinded. Intervention: Three prototypes of devices are evaluated in 4 different conditions. A total of 168 brown spots are needed (84 brown spots on the face and 84 brown spots on the hands). Each treatment corresponds to a combination of a specific sequence of a cryogenic spray and of a frequency of application. Prototypes (815-v1 001) to (815-v1 200) will be applied on brown spots located on the face and/or hands. Each spot will be treated six times by a defined prototype (always the same prototype on the same spot all along the study) according to specific frequencies (evry day, every week or every 2 weeks).The application order of the different prototypes will be defined by randomization. Prior to any study device application, the dermatologist will assess the adverse events and will decide if the period between two consecutive applications should be extended or not. The dermatologist will verify that the skin has not been treated by cosmetic products (no presence of cream that could interfere with the treatment) and is dry. An operator previously trained by the dermatologist will apply the study device to the patient's face or/and hand. Subjects will be lying down, and the prototypes will be administered upside down for the applications on the face and sitting for the applications on the hands. For the application on the hands, the hands will be placed flat on the table and the prototypes will be applied upside down. During applications on the face, subjects will wear diving goggles protecting the eyes from cryogenic gas. The patient follow-up visits are from Day 0 to 6 months.

Official Title
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Evaluation of the Tolerance and Performance (Mode of Administration) of Cyto-selective Difluoroethane-based Cryotherapy in the Treatment of Brown Spots

Conditions
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Lentigo Solar

Intervention / Treatment
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* Device: Prototypes (815-v1 001) to (815-v1 050)
* Device: Prototype (815-v1 051) to (815-v1 100)
* Device: Prototypes (815-v1 101) to (815-v1 150)
* Device: Prototypes (815-v1 151) to (815-v1 200)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female or male. Ages 30 to 75. Phototypes I to IV (according with Fitzpatrick scale). Featuring brown spots (solar lentigos, senile lentigo) on the face and hands ≥ 3 and ≤ 6 mm in diameter (at least 4 spots per subject for phototypes II and III and no specific requirements re accurate number of spots for phototypes I and IV).). Agreeing not to be exposed to the sun (or artificial UV) during the study. Informed, having undergone a general clinical examination attesting to his/her ability to participate in the study. Having given written consent for their participation in the study. No suspicion of carcinoma after investigation by a dermatologist. Exclusion Criteria: Having performed cosmetic treatments (exfoliants, scrubs or self-tanners, manicures, facials, UV ...) in the month before the start of the study, at the level of the face and the hands. Having applied a depraving product in the month prior to the start of the study, at the level of the face and the hands. Having performed cosmetic treatments in a dermatologist (laser, Intense Pulsed Light (IPL) , peeling, creams, cryotherapy ...), at the level of the face and the hands in the last 6 months. With dermatosis, autoimmune disease, systemic, chronic or acute disease, or any other pathology that may interfere with treatment or influence the results of the study (people with diabetes or circulatory problems, allergic to cold, Raynaud's syndrome...). Receiving treatment by general or local (dermo corticoids, corticosteroids, diuretics ...) likely to interfere with the evaluation of the parameter studied. Participating in another study or being excluded from a previous study. Unable to follow the requirements of the protocol. Vulnerable: whose ability or freedom to give or refuse consent is limited. Major protected by law (tutorship, curatorship, safeguarding justice...). People unable to read and write Georgian language. Unable to be contacted urgently over the phone. For female subjects: Pregnant woman (or wishing to be pregnant during study) or while breastfeeding. A woman who does not have a contraceptive method.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 75 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: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Condition 1 : prototypes from (815-v1 001) to (815-v1 050) every day<br>Application on the brown spots of the face and/or hands for the prototypes (815-v1 001) to (815-v1 050) at D0, D1, D2, D3, D4 and D5. | Device: Prototypes (815-v1 001) to (815-v1 050)<br>* Application on brown spots located on the face and/or the hand (6 treatments during the study). An operator previously trained by the dermatologist will apply the study device to the patient's face or/and hand. Subjects will be lying down, and the prototypes will be administered upside down for the applications on the face and sitting for the applications on the hands. For the application on the hands, the hands will be placed flat on the table and the prototypes will be applied upside down. During applications on the face, subjects will wear diving goggles protecting the eyes from cryogenic gas.<br>|
| Experimental: Condition 2 : prototypes from (815-v1 051) to (815-v1 100) every week<br>Application on the brown spots of the face and/or hands for the prototypes (815-v1 051) to (815-v1 100) at D0, D7, D14, D21, D28 and D35. | Device: Prototype (815-v1 051) to (815-v1 100)<br>* Application on brown spots located on the face and/or the hand (6 treatments during the study. An operator previously trained by the dermatologist will apply the study device to the patient's face or/and hand. Subjects will be lying down, and the prototypes will be administered upside down for the applications on the face and sitting for the applications on the hands. For the application on the hands, the hands will be placed flat on the table and the prototypes will be applied upside down. During applications on the face, subjects will wear diving goggles protecting the eyes from cryogenic gas.<br>|
| Experimental: Conditions 3 : prototypes from (815-v1 101) to (815-v1 150) every two weeks<br>Application on the brown spots of the face and/or hands for the prototypes (815-v1 101) to (815-v1 150) at D0, D14, D28, D42, D56 and D70. | Device: Prototypes (815-v1 101) to (815-v1 150)<br>* Application on brown spots located on the face and/or the hand (6 treatments during the study. An operator previously trained by the dermatologist will apply the study device to the patient's face or/and hand. Subjects will be lying down, and the prototypes will be administered upside down for the applications on the face and sitting for the applications on the hands. For the application on the hands, the hands will be placed flat on the table and the prototypes will be applied upside down. During applications on the face, subjects will wear diving goggles protecting the eyes from cryogenic gas.<br>|
| Experimental: Condition 4 : prototypes from (815-v1 151) to (815-v1 200) every two weeks<br>Application on the brown spots of the face and/or hands for the prototypes (815-v1 151) to (815-v1 200) at D0, D14, D28, D42, D56 and D70. | Device: Prototypes (815-v1 151) to (815-v1 200)<br>* Application on brown spots located on the face and/or the hand (6 treatments during the study. An operator previously trained by the dermatologist will apply the study device to the patient's face or/and hand. Subjects will be lying down, and the prototypes will be administered upside down for the applications on the face and sitting for the applications on the hands. For the application on the hands, the hands will be placed flat on the table and the prototypes will be applied upside down. During applications on the face, subjects will wear diving goggles protecting the eyes from cryogenic gas.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline skin hyperpigmentation | The evaluation will be performed visually on the selected spots. A scale in 6 points (0 to 5) will be used : 0=Clear of hyperpigmentation; 1= Almost clear of hyperpigmentation; 2=mild, but noticeable hyperpigmentation; 3=moderate hyperpigmentation (medium brown in quality); 4=severe hyperpigmentation (dark brown in quality); 5= very severe hyperpigmentation (very dark brown, almost black in quality). | Day 0, Day 7, Day 14, Day 21, Day 28, Day 35, Day 42, Day 49, Day 56, Day 70,Day 84 and Day 0 + 6 months | 
| Change from baseline skin hypopigmentation | The evaluation will be performed visually on the selected spots. A scale in 5 points will be used (0 to 4): 0=no hypopigmented lesion; 1= very slight area of hypopigmentation of very small size and very slightly fairer than the surrounding skin; 2= slight area of hypopigmentation of small size and slightly fairer than the surrounding skin; 3= moderate : area of hypopigmentation of moderate size and much fairer than the surrounding skin; 4= severe : area of hypopigmentation of large size and much fairer than the surrounding skin. | Day 0, Day 7, Day 14, Day 21, Day 28, Day 35, Day 42, Day 49, Day 56, Day 70,Day 84 and Day 0 + 6 months | 
| Change from baseline skin appearance | The evaluation will be performed visually on the selected spots and surrounded spotless skin area around the spot skin to assess erythema, oedema blister, bubble, scars, micro-bruise, hematoma, dryness,desquamation, fissures/cracks, roughness,crust, pink spots and papules. A scale in 5 points (0 to 4) will be used : 0=none; 1=very mild; 2=mild; 3=moderate; 4=severe. | Day 0, Day 7, Day 14, Day 21, Day 28, Day 35, Day 42, Day 49, Day 56, Day 70,Day 84 and Day 0 + 6 months | 
| Change from baseline skin sensation | The evaluation will be performed visually on the selected spots and around the spot skin to assess tightness, stinging, itching, warm and burning sensation. A scale in 5 points (0 to 4) will be used : 0=none; 1=very mild; 2=mild; 3=moderate; 4=severe. | Day 0, Day 7, Day 14, Day 21, Day 28, Day 35, Day 42, Day 49, Day 56, Day 70,Day 84 and Day 0 + 6 months | 
| Self-assesment of pain by VAS | The pain of the treatment will be assessed by the Visual Analogue Scale (VAS) at time T0 on the treated area. The pain assessed is that felt during the application of the devices. It will be collected from the patient within 5 minutes of application. The VAS is made up of a 10-centimeter line anchored by two ends of the pain. One end is the maximum pain imaginable. The other end is no pain. | Day 0 | 
| Change from baseline spots visibility | Standardized photographs will be taken using a Dermatoscope C-Cube® (PIXIENCE). The capture will be taken on the previously selected lentigo (and spotless surrounding each spot in the same acquisition) and a spotless area (one on face (same as clinical evaluation) and far from a lentigo spot). | Day 0, Day 7, Day 14, Day 21, Day 28, Day 35, Day 42, Day 49, Day 56, Day 70,Day 84 and Day 0 + 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Self assessment of skin appearance | The skin appearance will be assessed by subjects through a 3 items questionnaire. It allows obtaining the subjective appraisal of subject on the treatments using the following 5-point scale: agree, quite agree neither agree, nor disagree quite disagree disagree. The items are the following: The spot seems clearer. The size of the spot seems reduced. The spot seems less visible. | Day 0, Day 7, Day 14, Day 21, Day 28, Day 35, Day 42, Day 49, Day 56, Day 70,Day 84 and Day 0 + 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cryotherapy, Hyperpigmentation, Skin Diseases