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

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ClinicalTrials.gov Identifier: NCT02716714
Recruitment Status : Completed
First Posted : March 23, 2016
Results First Posted : April 18, 2018
Last Update Posted : April 18, 2018
Sponsor:
Collaborators:
LEO Pharma
Chonnam National University Hospital
Severance Hospital
Ajou University School of Medicine
Asan Medical Center
Samsung Medical Center
Seoul National University Bundang Hospital
Dong-A University Hospital
Korea University Anam Hospital
Seoul National University Hospital
Information provided by (Responsible Party):
Il-Hwan Kim, Korea University

Brief 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.

Condition or disease Intervention/treatment Phase
Actinic Keratosis Drug: ingenol mebutate gel 0.015% Drug: ingenol mebutate gel 0.05% Phase 4

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).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 77 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Study Start Date : April 2015
Actual Primary Completion Date : June 2016
Actual Study Completion Date : June 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: ingenol mebutate gel 0.015%
Applied on face and scalp for three days.
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
Other Name: Picato® gel

Active Comparator: ingenol mebutate gel 0.05%
Applied on trunk and extremities for two days.
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
Other Name: Picato® gel




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. Recurrence Rate in CC Group [ Time Frame: at 6 months ]
    Recurrence rate in complete clearance(CC) group was analyzed.

  4. 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.

  5. 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.

  6. 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.

    • 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.

  7. 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.

  8. 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.


Other Outcome Measures:
  1. 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.

  2. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   19 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02716714


Locations
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Korea, Republic of
Korea University Ansan Hospital
Ansan-si, Gyeonggi-do, Korea, Republic of, 15355
Sponsors and Collaborators
Korea University
LEO Pharma
Chonnam National University Hospital
Severance Hospital
Ajou University School of Medicine
Asan Medical Center
Samsung Medical Center
Seoul National University Bundang Hospital
Dong-A University Hospital
Korea University Anam Hospital
Seoul National University Hospital
Investigators
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Principal Investigator: Ilhwan Kim, MD Korea University

Additional Information:
Publications of Results:

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Responsible Party: Il-Hwan Kim, Professor, Korea University
ClinicalTrials.gov Identifier: NCT02716714    
Other Study ID Numbers: KSSCLK2014-01
First Posted: March 23, 2016    Key Record Dates
Results First Posted: April 18, 2018
Last Update Posted: April 18, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: De-identified individual participant data for all primary and secondary outcome measures will be made within 6months of study completion.
Keywords provided by Il-Hwan Kim, Korea University:
Korean
Additional relevant MeSH terms:
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Keratosis, Actinic
Keratosis
Skin Diseases
Precancerous Conditions
Neoplasms