PEP005 Gel - Biological Effects in Actinic Keratosis Assessed by Reflectance Confocal Microscopy

• ClinicalTrials.gov Identifier: NCT01449513
• Recruitment Status: Completed
• First Posted: October 10, 2011
• Results First Posted: May 27, 2015
• Last Update Posted: May 9, 2016
• Sponsor: LEO Pharma
• Information provided by (Responsible Party): LEO Pharma

Study Description

Brief Summary:

This trial will be conducted to explore the biological effects in the skin following treatment with PEP005 Gel, 0.05% administered for two consecutive days, assessed by reflectance confocal microscopy.

Condition or disease	Intervention/treatment	Phase
Actinic Keratosis	Drug: Ingenol mebutate; Drug: Placebo Gel	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Official Title: A Phase 1, Two-stage, Single-centre, Open Label, Within- and Between-subject Comparison Trial to Explore the Biological Effects of PEP005 (Ingenol Mebutate) Gel, 0.05%, Applied Once Daily for 2 Consecutive Days in Subjects With Actinic Keratosis on the Upper Extrem-ity. A Single-arm First Stage Followed by a Two-arm, Parallel Group, Randomized, Placebo (Vehicle) -Controlled Second Stage
• Study Start Date: September 2011
• Actual Primary Completion Date: May 2012
• Actual Study Completion Date: May 2012

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: PEP005 Gel 0.05%; active ingredient of PEP005: Ingenol mebutate	Drug: Ingenol mebutate; 0.05% Ingenol mebutate Gel once daily for 2 consecutive days; Other Name: PEP005
Placebo Comparator: Placebo Gel; Vehicle of PEP005 Gel	Drug: Placebo Gel; Gel vehicle of PEP005

Outcome Measures

Primary Outcome Measures :

1. Change in Degree of Infiltration [ Time Frame: Baseline to Day 2 ]

   Change from baseline in the degree of infiltration of the epidermis by inflammatory cells following treatment with ingenol mebutate gel, 0.05% as assessed by Reflectance Confocal Microscopy (RCM) in actinic keratosis (AK) skin.This RCM imaging technique is a relatively new non-invasive, real-time evaluation method to generate horizontal skin sections at a resolution comparable to routine histology.

   The degree of infiltration of the epidermis by inflammatory cells will be based on "inflammation/small bright cells" (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. The degree of infiltration of the dermis by inflammatory cells will be based on "inflammatory cells in the dermis" (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel.

2. Change in Degree of Infiltration [ Time Frame: Baseline to Day 2 ]

   Change from baseline in the degree of infiltration of the epidermis by inflammatory cells following treatment with ingenol mebutate gel, 0.05% as assessed by Reflectance Confocal Microscopy (RCM) in Sub actinic keratosis (AK) skin.

   The degree of infiltration of the epidermis by inflammatory cells will be based on "inflammation/small bright cells" (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. The degree of infiltration of the dermis by inflammatory cells will be based on "inflammatory cells in the dermis" (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel.

3. Change in Degree of Infiltration [ Time Frame: Baseline to Day 2 ]

   Change from baseline in the degree of infiltration of the epidermis by inflammatory cells following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in normal skin.

   The degree of infiltration of the epidermis by inflammatory cells will be based on "inflammation/small bright cells" (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. The degree of infiltration of the dermis by inflammatory cells will be based on "inflammatory cells in the dermis" (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel.

4. Change in Degree of Infiltration [ Time Frame: Baseline to Day 3 ]
   Change from baseline in the degree of infiltration of the epidermis by inflammatory cells following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in AK (actinic keratosis) skin
5. Change in Degree of Infiltration [ Time Frame: Baseline to Day 3 ]

   Change from baseline in the degree of infiltration of the epidermis by inflammatory cells following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in Sub AK (actinic keratosis) skin.

   The degree of infiltration of the epidermis by inflammatory cells will be based on "inflammation/small bright cells" (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. The degree of infiltration of the dermis by inflammatory cells will be based on "inflammatory cells in the dermis" (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel.

6. Change in Degree of Infiltration [ Time Frame: Baseline to Day 3 ]

   Change from baseline in the degree of infiltration of the epidermis by inflammatory cells following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in normal skin

   The degree of infiltration of the epidermis by inflammatory cells will be based on "inflammation/small bright cells" (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. The degree of infiltration of the dermis by inflammatory cells will be based on "inflammatory cells in the dermis" (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel.

7. Change in Degree of Infiltration [ Time Frame: Baseline to Day 8 ]

   Change from baseline in the degree of infiltration of the epidermis by inflammatory cells following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in AK (actinic keratosis) skin

   The degree of infiltration of the epidermis by inflammatory cells will be based on "inflammation/small bright cells" (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. The degree of infiltration of the dermis by inflammatory cells will be based on "inflammatory cells in the dermis" (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel.

8. Change in Degree of Infiltration [ Time Frame: Baseline to Day 8 ]

   Change from baseline in the degree of infiltration of the epidermis by inflammatory cells following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in Sub AK (actinic keratosis) skin

   The degree of infiltration of the epidermis by inflammatory cells will be based on "inflammation/small bright cells" (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. The degree of infiltration of the dermis by inflammatory cells will be based on "inflammatory cells in the dermis" (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel.

9. Change in Degree of Infiltration [ Time Frame: Baseline to Day 8 ]

   Change from baseline in the degree of infiltration of the epidermis by inflammatory cells following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in normal skin

   The degree of infiltration of the epidermis by inflammatory cells will be based on "inflammation/small bright cells" (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. The degree of infiltration of the dermis by inflammatory cells will be based on "inflammatory cells in the dermis" (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel.

10. Change in Degree of Infiltration [ Time Frame: Baseline to Day 57 ]

    Change from baseline in the degree of infiltration of the epidermis by inflammatory cells following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in AK (actinic keratosis) skin

    The degree of infiltration of the epidermis by inflammatory cells will be based on "inflammation/small bright cells" (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. The degree of infiltration of the dermis by inflammatory cells will be based on "inflammatory cells in the dermis" (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel.

11. Change in Degree of Infiltration [ Time Frame: Baseline to Day 57 ]

    Change from baseline in the degree of infiltration of the epidermis by inflammatory cells following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in Sub AK (actinic keratosis) skin

    The degree of infiltration of the epidermis by inflammatory cells will be based on "inflammation/small bright cells" (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. The degree of infiltration of the dermis by inflammatory cells will be based on "inflammatory cells in the dermis" (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel.

12. Change in Degree of Infiltration [ Time Frame: Baseline to Day 57 ]

    Change from baseline in the degree of infiltration of the epidermis by inflammatory cells following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in normal skin

    The degree of infiltration of the epidermis by inflammatory cells will be based on "inflammation/small bright cells" (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. The degree of infiltration of the dermis by inflammatory cells will be based on "inflammatory cells in the dermis" (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel.

13. Change in Degree of Necrosis [ Time Frame: Baseline to Day 2 ]
    Change from baseline in the degree of necrosis in the epidermis following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in AK (actinic keratosis) skin
14. Change in Degree of Necrosis [ Time Frame: Baseline to Day 2 ]
    Change from baseline in the degree of necrosis in the epidermis following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in Sub AK (actinic keratosis) skin
15. Change in Degree of Necrosis [ Time Frame: Baseline to Day 2 ]
    Change from baseline in the degree of necrosis in the epidermis following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in normal skin
16. Change in Degree of Necrosis [ Time Frame: Baseline to Day 3 ]
    Change from baseline in the degree of necrosis in the epidermis following treatment with ingenol mebutate gel, 0.05% as assessed by RCM(Reflectance Confocal Microscopy) in AK (actinic keratosis) skin
17. Change in Degree of Necrosis [ Time Frame: Baseline to Day 3 ]
    Change from baseline in the degree of necrosis in the epidermis following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in Sub AK (actinic keratosis) skin
18. Change in Degree of Necrosis [ Time Frame: Baseline to Day 3 ]
    Change from baseline in the degree of necrosis in the epidermis following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in normal skin
19. Change in Degree of Necrosis [ Time Frame: Baseline to Day 8 ]
    Change from baseline in the degree of necrosis in the epidermis following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in AK (actinic keratosis) skin
20. Change in Degree of Necrosis [ Time Frame: Baseline to Day 8 ]
    Change from baseline in the degree of necrosis in the epidermis following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in Sub AK (actinic keratosis) skin
21. Change in Degree of Necrosis [ Time Frame: Baseline to Day 8 ]
    Change from baseline in the degree of necrosis in the epidermis following treatment with ingenol mebutate gel,0.05% as assessed by RCM (Reflectance Confocal Microscopy) in normal skin
22. Change in Degree of Necrosis [ Time Frame: Baseline to Day 57 ]
    Change from baseline in the degree of necrosis in the epidermis following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in AK (actinic keratosis) skin
23. Change in Degree of Necrosis [ Time Frame: Baseline to Day 57 ]
    Change from baseline in the degree of necrosis in the epidermis following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in Sub AK (actinic keratosis) skin
24. Change in Degree of Necrosis [ Time Frame: Baseline to Day 57 ]
    Change from baseline in the degree of necrosis in the epidermis following treatment with ingenol mebutate gel, 0.05% as assessed by RCM in normal skin

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Male or female subjects at least 18 years of age
2. Subjects with AK lesions and subclinical AK lesions within a contiguous 25 cm2 area on the upper extremity
3. Subjects must have a 25 cm2 area of normal skin on the inner upper arm
4. Female subjects must be of either:• Non-childbearing potential, post-menopausal, or have a confirmed clinical history of sterility or • Childbearing potential, with a confirmed negative urine pregnancy test prior to exposure.
5. Female subjects of childbearing potential must be willing to consent to using high effective methods of contraception
6. Ability to follow trial instructions and likely to complete all trial requirements
7. Obtained written informed consent prior to any trial-related procedures

Exclusion Criteria:

1. Location of the selected treatment areas:• Within 5 cm of an incompletely healed wound or infected area of the skin • Within 10 cm of a suspected basal cell carcinoma (BCC) or squamous cell carcinoma(SCC)
2. History or evidence of skin conditions other than the trial indication that would interfere with evaluation of the investigational product
3. Clinical diagnosis/history or evidence of any medical condition that would expose a subject to an undue risk of a significant AE or interfere with assessments of safety during the course of the trial, as determined by Investigator clinical judgment
4. Anticipated need for in-patient hospitalisation or in-patient surgery during the trial period.
5. Current participation in any other interventional clinical trial
6. Subjects who have received treatment with any non-marketed drug product within the last two months
7. Previous enrolment in this clinical trial
8. Prohibited Therapies and/or Medications 2 weeks prior to the Screening visit within 2 cm of selected treatment area:•Cosmetic or therapeutic procedures •Use of acid-containing therapeutic products • Use of topical salves or topical steroids
9. Prohibited Therapies and/or Medications: within 4 weeks prior to the Screening visit: • Treatment with immunomodulators, cytotoxic drugs or interferon/interferon inducers,systemic medications that suppress the immune system, or with UVB
10. Prohibited Therapies and/or Medications: within 8 weeks prior to the Screening visit: • Treatment with 5-FU, imiquimod, diclofenac, or photodynamic therapy: within 2 cm of the selected treatment areas.
11. Use of systemic retinoids

Contacts and Locations

Locations

Germany

Charité - Universitätsmedizin Berlin

Berlin, Germany, 10117

Sponsors and Collaborators

LEO Pharma

Investigators

• Principal Investigator: Eggert Stockfleth, Prof Dr med; Charite University, Berlin, Germany

More Information

• Responsible Party: LEO Pharma
• ClinicalTrials.gov Identifier: NCT01449513
• Other Study ID Numbers: LP0041-03
• First Posted: October 10, 2011
• Results First Posted: May 27, 2015
• Last Update Posted: May 9, 2016
• Last Verified: April 2016

Additional relevant MeSH terms:

Keratosis, Actinic; Keratosis; Skin Diseases; Precancerous Conditions; Neoplasms