Clinical Trial of Ingenol Mebutate Gel 0.015% & 0.05% in Actinic Keratosis

NCT ID: NCT02716714

Last Updated: 2018-04-18

Study Results

Results available

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE4

Total Enrollment

77 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-04-30

Study Completion Date

2016-06-30

Brief Summary

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This study evaluate the efficacy and safety of ingenol mebutate gel 0.015% on face and scalp \& 0.05% on trunk and extremities in Korean patient with actinic keratosis.

Detailed Description

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The mechanism of action of ingenol mebutate for actinic keratosis(AK) treatment involves a rapid induction of necrosis followed by neutrophil-mediated, antibody-dependent cellular cytotoxicity (ADCC) of residual lesion. As the ingenol mebutate infiltrates the cell membrane, it increases intracellular Ca2+ concentration which leads to mitochondrial swelling and disruption of mitochondrial membrane within hours. The release of intra-mitochondrial Ca2+ into the cytoplasm leads to depletion of adenosine triphosphate (ATP) and a rapid induction of cell death by necrosis. This process occurs within 1 hour of application, which explains why the treatment period requires only 2 or 3 days of treatment. As the next phase, the cellular necrosis is accompanied by a robust inflammatory response through the release of proinflammatory cytokines from skin cells and tumor cells undergoing necrosis. The release of these proinflammatory cytokines into the dysplastic cells mediates the process of neutrophil recruitment through paracrine signaling and activation of endothelial cells. Here, the neutrophil mediated ADCC occurs, where activated neutrophils attach to the fragment, crystallized (Fc) parts of antibodies of dysplastic cells and destroys the residual dysplastic epidermal cells. In this way, the ingenol mebutate eradicates any residual tumor cells and prevents recurrence of actinic keratosis.As described above, the rapid effect and dual mechanism of action of ingenol mebutate gel allows not only a short-course therapy (2 or 3 days of application) for the elimination of actinic keratosis but also, the benefit for eradication of any residual lesions preventing the recurrence and the progression of AK into squamous cell carcinoma (SCC).

Conditions

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Actinic Keratosis

Study Design

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Allocation Method

NON_RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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ingenol mebutate gel 0.015%

Applied on face and scalp for three days.

Group Type ACTIVE_COMPARATOR

ingenol mebutate gel 0.015%

Intervention Type DRUG

-Face or Scalp arm (Referred to Face/Scalp arm): Apply ingenol mebutate gel 0.015% once daily for 3 consecutive days

ingenol mebutate gel 0.05%

Applied on trunk and extremities for two days.

Group Type ACTIVE_COMPARATOR

ingenol mebutate gel 0.05%

Intervention Type DRUG

-Trunk or Extremities arm (Referred to Trunk/Extremities arm): Apply ingenol mebutate gel 0.05% once daily for 2 consecutive days

Interventions

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ingenol mebutate gel 0.015%

-Face or Scalp arm (Referred to Face/Scalp arm): Apply ingenol mebutate gel 0.015% once daily for 3 consecutive days

Intervention Type DRUG

ingenol mebutate gel 0.05%

-Trunk or Extremities arm (Referred to Trunk/Extremities arm): Apply ingenol mebutate gel 0.05% once daily for 2 consecutive days

Intervention Type DRUG

Other Intervention Names

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Picato® gel Picato® gel

Eligibility Criteria

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Inclusion Criteria

1. Male or female aged ≥ 19 years
2. Histopathologically diagnosed AK patients with at least 1 macroscopic and discrete lesion within a contiguous 25 cm2 (e.g. 5 cm x 5 cm) of treatment area
3. The treatment area including the lesion must be accessible to apply the investigational product. However, the lesions on lips, mucosa, outer ear (concha) and those around eyes are excluded.
4. Subjects who signed the written informed consent prior to perform any study-related procedures or assessments, including photographs of their treatment area for documentation and efficacy assessment.

Exclusion Criteria

1. Hypersensitivity to any components of the investigational product
2. History or evidence of skin conditions that could interfere with evaluation of the investigational product(e.g., eczema, unstable psoriasis, xeroderma pigmentosa, inflammatory or infectious disease around the selected treatment area)
3. Unhealed wound within 5 cm, or basal cell carcinoma or squamous cell carcinoma within 10 cm from the selected treatment area.
4. Subjects who received or expected to receive any of the following pharmacotherapy and non-pharmacotherapy or procedures during the treatment and follow-up period
5. Subjects who have following disorder or abnormal laboratory result
6. Pregnant, lactating, and childbearing potential women who are unwilling to practice effective contraception; for example, oral contraceptives, hormonal methods, placement of an intrauterine device (IUD) or intrauterine system (IUS), barrier methods (i.e., condom or occlusive cap with spermicidal foam/gel/film/cream/suppository), male sterilization, and abstinence.
7. Subjects who previously underwent another clinical trial within 30 days or 5-times the half-life of previous investigational product prior to baseline (the longer period of time must be considered).
8. Other conditions by investigator's discretion to be inappropriate for this clinical study.
Minimum Eligible Age

19 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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LEO Pharma

INDUSTRY

Sponsor Role collaborator

Chonnam National University Hospital

OTHER

Sponsor Role collaborator

Severance Hospital

OTHER

Sponsor Role collaborator

Ajou University School of Medicine

OTHER

Sponsor Role collaborator

Asan Medical Center

OTHER

Sponsor Role collaborator

Samsung Medical Center

OTHER

Sponsor Role collaborator

Seoul National University Bundang Hospital

OTHER

Sponsor Role collaborator

Dong-A University Hospital

OTHER

Sponsor Role collaborator

Korea University Anam Hospital

OTHER

Sponsor Role collaborator

Seoul National University Hospital

OTHER

Sponsor Role collaborator

Korea University

OTHER

Sponsor Role lead

Responsible Party

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Il-Hwan Kim

Professor

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Ilhwan Kim, MD

Role: PRINCIPAL_INVESTIGATOR

Korea University Ansan Hospital

Locations

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Korea University Ansan Hospital

Ansan-si, Gyeonggi-do, South Korea

Site Status

Countries

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South Korea

References

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Callen JP, Bickers DR, Moy RL. Actinic keratoses. J Am Acad Dermatol. 1997 Apr;36(4):650-3. doi: 10.1016/s0190-9622(97)70265-2. No abstract available.

Reference Type RESULT
PMID: 9092763 (View on PubMed)

Schmitt JV, Miot HA. Actinic keratosis: a clinical and epidemiological revision. An Bras Dermatol. 2012 May-Jun;87(3):425-34. doi: 10.1590/s0365-05962012000300012.

Reference Type RESULT
PMID: 22714759 (View on PubMed)

Brash DE, Ziegler A, Jonason AS, Simon JA, Kunala S, Leffell DJ. Sunlight and sunburn in human skin cancer: p53, apoptosis, and tumor promotion. J Investig Dermatol Symp Proc. 1996 Apr;1(2):136-42.

Reference Type RESULT
PMID: 9627707 (View on PubMed)

Flohil SC, van der Leest RJ, Dowlatshahi EA, Hofman A, de Vries E, Nijsten T. Prevalence of actinic keratosis and its risk factors in the general population: the Rotterdam Study. J Invest Dermatol. 2013 Aug;133(8):1971-8. doi: 10.1038/jid.2013.134. Epub 2013 Mar 19.

Reference Type RESULT
PMID: 23510990 (View on PubMed)

Rossi R, Mori M, Lotti T. Actinic keratosis. Int J Dermatol. 2007 Sep;46(9):895-904. doi: 10.1111/j.1365-4632.2007.03166.x. No abstract available.

Reference Type RESULT
PMID: 17822489 (View on PubMed)

Salasche SJ. Epidemiology of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol. 2000 Jan;42(1 Pt 2):4-7. doi: 10.1067/mjd.2000.103342.

Reference Type RESULT
PMID: 10607349 (View on PubMed)

Kim HS, Cho EA, Bae JM, Yu DS, Oh ST, Kang H, Park CJ, Lee JD, Lee JY, Kim SY, Kim HO, Park YM. Recent trend in the incidence of premalignant and malignant skin lesions in Korea between 1991 and 2006. J Korean Med Sci. 2010 Jun;25(6):924-9. doi: 10.3346/jkms.2010.25.6.924. Epub 2010 May 24.

Reference Type RESULT
PMID: 20514316 (View on PubMed)

Slaper H, Velders GJ, Daniel JS, de Gruijl FR, van der Leun JC. Estimates of ozone depletion and skin cancer incidence to examine the Vienna Convention achievements. Nature. 1996 Nov 21;384(6606):256-8. doi: 10.1038/384256a0.

Reference Type RESULT
PMID: 8918873 (View on PubMed)

Nelson CG. Diclofenac gel in the treatment of actinic keratoses. Ther Clin Risk Manag. 2011;7:207-11. doi: 10.2147/TCRM.S12498. Epub 2011 Jun 15.

Reference Type RESULT
PMID: 21753882 (View on PubMed)

Stockfleth E, Ferrandiz C, Grob JJ, Leigh I, Pehamberger H, Kerl H; European Skin Academy. Development of a treatment algorithm for actinic keratoses: a European Consensus. Eur J Dermatol. 2008 Nov-Dec;18(6):651-9. doi: 10.1684/ejd.2008.0514. Epub 2008 Oct 27.

Reference Type RESULT
PMID: 18955209 (View on PubMed)

Anderson L, Schmieder GJ, Werschler WP, Tschen EH, Ling MR, Stough DB, Katsamas J. Randomized, double-blind, double-dummy, vehicle-controlled study of ingenol mebutate gel 0.025% and 0.05% for actinic keratosis. J Am Acad Dermatol. 2009 Jun;60(6):934-43. doi: 10.1016/j.jaad.2009.01.008.

Reference Type RESULT
PMID: 19467365 (View on PubMed)

Vegter S, Tolley K. A network meta-analysis of the relative efficacy of treatments for actinic keratosis of the face or scalp in Europe. PLoS One. 2014 Jun 3;9(6):e96829. doi: 10.1371/journal.pone.0096829. eCollection 2014.

Reference Type RESULT
PMID: 24892649 (View on PubMed)

Lebwohl M, Dinehart S, Whiting D, Lee PK, Tawfik N, Jorizzo J, Lee JH, Fox TL. Imiquimod 5% cream for the treatment of actinic keratosis: results from two phase III, randomized, double-blind, parallel group, vehicle-controlled trials. J Am Acad Dermatol. 2004 May;50(5):714-21. doi: 10.1016/j.jaad.2003.12.010.

Reference Type RESULT
PMID: 15097955 (View on PubMed)

Rosen RH, Gupta AK, Tyring SK. Dual mechanism of action of ingenol mebutate gel for topical treatment of actinic keratoses: rapid lesion necrosis followed by lesion-specific immune response. J Am Acad Dermatol. 2012 Mar;66(3):486-93. doi: 10.1016/j.jaad.2010.12.038. Epub 2011 Nov 4.

Reference Type RESULT
PMID: 22055282 (View on PubMed)

Lebwohl M, Swanson N, Anderson LL, Melgaard A, Xu Z, Berman B. Ingenol mebutate gel for actinic keratosis. N Engl J Med. 2012 Mar 15;366(11):1010-9. doi: 10.1056/NEJMoa1111170.

Reference Type RESULT
PMID: 22417254 (View on PubMed)

Lebwohl M, Shumack S, Stein Gold L, Melgaard A, Larsson T, Tyring SK. Long-term follow-up study of ingenol mebutate gel for the treatment of actinic keratoses. JAMA Dermatol. 2013 Jun;149(6):666-70. doi: 10.1001/jamadermatol.2013.2766.

Reference Type RESULT
PMID: 23553119 (View on PubMed)

Related Links

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http://www.nice.org.uk/guidance/csgstim/resources/improving-outcomes-for-people-with-skin-tumoursincluding-melanoma-the-manual-2006-guidance2

National Institute for Clinical Excellence. Guidance on Cancer Services:Improving outcomes for people with skin tumours including melanoma. The manual. February 2006.

Other Identifiers

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KSSCLK2014-01

Identifier Type: -

Identifier Source: org_study_id

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