- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02716714
Clinical Trial of Ingenol Mebutate Gel 0.015% & 0.05% in Actinic Keratosis
April 16, 2018 updated by: Il-Hwan Kim, Korea University
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)
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.
Study Overview
Status
Completed
Conditions
Intervention / Treatment
Detailed 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).
Study Type
Interventional
Enrollment (Actual)
77
Phase
- Phase 4
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
-
Gyeonggi-do
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Ansan-si, Gyeonggi-do, Korea, Republic of, 15355
- Korea University Ansan Hospital
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
17 years and older (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion Criteria:
- Male or female aged ≥ 19 years
- 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
- 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.
- 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:
- Hypersensitivity to any components of the investigational product
- 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)
- Unhealed wound within 5 cm, or basal cell carcinoma or squamous cell carcinoma within 10 cm from the selected treatment area.
- Subjects who received or expected to receive any of the following pharmacotherapy and non-pharmacotherapy or procedures during the treatment and follow-up period
- Subjects who have following disorder or abnormal laboratory result
- 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.
- 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).
- Other conditions by investigator's discretion to be inappropriate for this clinical study.
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: ingenol mebutate gel 0.015%
Applied on face and scalp for three days.
|
-Face or Scalp arm (Referred to Face/Scalp arm): Apply ingenol mebutate gel 0.015% once daily for 3 consecutive days
Other Names:
|
Active Comparator: ingenol mebutate gel 0.05%
Applied on trunk and extremities for two days.
|
-Trunk or Extremities arm (Referred to Trunk/Extremities arm): Apply ingenol mebutate gel 0.05% once daily for 2 consecutive days
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
CC Rate of AK Lesions in the Selected Treatment Area
Time Frame: at day 57
|
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 Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Percentage Change of the Number of AK Lesions in the Selected Treatment Area
Time Frame: Baseline and Day 57
|
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
|
Sustained CC Rate in CC Group
Time Frame: at 6 months
|
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
|
Recurrence Rate in CC Group
Time Frame: at 6 months
|
Recurrence rate in complete clearance(CC) group was analyzed.
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at 6 months
|
Percentage Change of the Number of AK Lesions in the Selected Treatment Area of CC Group
Time Frame: at 6 months from baseline
|
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
|
Change From Baseline in Quality of Life (Skindex-29)
Time Frame: at 29 and 57 days from baseline
|
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
|
Treatment Satisfaction Questionnaire for Medication (TSQM)
Time Frame: at 29 and 57 days from baseline
|
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.
|
at 29 and 57 days from baseline
|
Cosmetic Outcomes Assessment (COA)
Time Frame: at 29 and 57 days from baseline
|
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
|
Time to Relapse in CC Group
Time Frame: at 6 months
|
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
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Medication for Actinic Keratosis
Time Frame: from 57 days to 6 months
|
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
|
Non-Drug Treatment/Surgery for Actinic Keratosis
Time Frame: from 57 days to 6 months
|
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
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Collaborators
Investigators
- Principal Investigator: Ilhwan Kim, MD, Korea University Ansan Hospital
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start
April 1, 2015
Primary Completion (Actual)
June 1, 2016
Study Completion (Actual)
June 1, 2016
Study Registration Dates
First Submitted
January 28, 2016
First Submitted That Met QC Criteria
March 17, 2016
First Posted (Estimate)
March 23, 2016
Study Record Updates
Last Update Posted (Actual)
April 18, 2018
Last Update Submitted That Met QC Criteria
April 16, 2018
Last Verified
April 1, 2018
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- KSSCLK2014-01
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Yes
IPD Plan Description
De-identified individual participant data for all primary and secondary outcome measures will be made within 6months of study completion.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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