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

Actinic Keratosis Clinical Trial

Official title:

A Multi-center, OPen, InvEstigator Initiated Phase IV Clinical TRial to 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 (PERFECT)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02716714
• Other study ID #: KSSCLK2014-01
• Status: Completed
• Phase: Phase 4
• First received: January 28, 2016
• Last updated: April 16, 2018
• Start date: April 2015
• Est. completion date: June 2016

Study information

• Verified date: April 2018
• Source: Korea University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 77
• Est. completion date: June 2016
• Est. primary completion date: June 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 19 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Actinic Keratosis
• Keratosis
• Keratosis, Actinic

Intervention

Drug:
• 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
• 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

Locations

Country	Name	City	State
Korea, Republic of	Korea University Ansan Hospital	Ansan-si	Gyeonggi-do

Sponsors (11)

Lead Sponsor	Collaborator
Korea University	Ajou University School of Medicine, Asan Medical Center, Chonnam National University Hospital, Dong-A University Hospital, Korea University Anam Hospital, LEO Pharma, Samsung Medical Center, Seoul National University Bundang Hospital, Seoul National University Hospital, Severance Hospital

Country where clinical trial is conducted

Korea, Republic of, 

References & Publications (16)

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. — View Citation

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. Review. — View Citation

Callen JP, Bickers DR, Moy RL. Actinic keratoses. J Am Acad Dermatol. 1997 Apr;36(4):650-3. Review. — View Citation

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 2 — View Citation

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/j — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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.2 — View Citation

Rossi R, Mori M, Lotti T. Actinic keratosis. Int J Dermatol. 2007 Sep;46(9):895-904. Review. — View Citation

Salasche SJ. Epidemiology of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol. 2000 Jan;42(1 Pt 2):4-7. Review. — View Citation

Schmitt JV, Miot HA. Actinic keratosis: a clinical and epidemiological revision. An Bras Dermatol. 2012 May-Jun;87(3):425-34. Review. — View Citation

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. — View Citation

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 Oc — View Citation

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. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Medication for Actinic Keratosis	The count of participants in complete clearance(CC) group and Non-CC group who administered medication for actinic keratosis on the selected treatment area after Day 57 was collected.	from 57 days to 6 months
Other	Non-Drug Treatment/Surgery for Actinic Keratosis	The count of participants in complete clearance(CC) group and Non-CC group who received non-drug treatment/surgery for actinic keratosis on the selected treatment area after Day 57 was collected.	from 57 days to 6 months
Primary	CC Rate of AK Lesions in the Selected Treatment Area	Complete Clearance (CC) means that clearance of all visible AK lesions in the selected treatment area and Investigator-rated actinic keratiosis(AK) lesion complete clearance (CC) rate at the selected treatment area on day 57 was analyzed.	at day 57
Secondary	Percentage Change of the Number of AK Lesions in the Selected Treatment Area	Percentage change from baseline in the number of actinic keratiosis(AK) lesions in the selected treatment area on Day 57 was analyzed.	Baseline and Day 57
Secondary	Sustained CC Rate in CC Group	Sustained Complete Clearance means that Complete Clearance was maintained until Month 6 in complete clearance (CC) group and sustained complete clearance(CC) rate at month 6 for complete clearance(CC) group was analyzed.	at 6 months
Secondary	Recurrence Rate in CC Group	Recurrence rate in complete clearance(CC) group was analyzed.	at 6 months
Secondary	Percentage Change of the Number of AK Lesions in the Selected Treatment Area of CC Group	Percentage change from baseline in the number of actinic keratiosis(AK) lesions at Month 6 in the selected treatment area in complete clearance(CC) Group was analyzed.	at 6 months from baseline
Secondary	Change From Baseline in Quality of Life (Skindex-29)	Skindex-29 is a self-administered QoL questionnaire comprised of 29 items scored on a 5-point scale (0=never, 1=rarely, 2=sometimes, 3=often, 4=all the time) covering 3 domains: emotional (10 items), symptomatic (7 items), and functional (12 items), with domain scores ranging from 0 to 40, 28, and 48, respectively. Lower scores for each of the domains represents a better Quality of life.	at 29 and 57 days from baseline
Secondary	Treatment Satisfaction Questionnaire for Medication (TSQM)	Participants personally completed the tool to evaluate satisfaction with drug treatment. It consisted of 4 areas of Effectiveness, side effect, convenience, and global satisfaction, with a total of 14 sub-items. The full mark is 100, and it is divided in four stages as follows.; Very good: 76 -100 score; Good: 51-75 score; Not bad: 26-50 score; Bad: 0-25 score Scores for each area ranged from 0 to 100, with higher scores indicating that fewer side effects had occurred and greater treatment satisfaction.	at 29 and 57 days from baseline
Secondary	Cosmetic Outcomes Assessment (COA)	The investigator rated the subject's Cosmetic Outcomes Assessment(COA) using 5 grades (Very good, Good, No change, Bad, Very bad), and results were as follows.	at 29 and 57 days from baseline
Secondary	Time to Relapse in CC Group	Time to relapse in complete clearance(CC) Group was analyzed. Median survival time with 95% confidence interval was calculated by Kaplan-Meier method.	at 6 months

External Links

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