Safety and Efficacy of Ingenol Mebutate Gel 0.015% for Treatment of AK on the Face in Solid Organ Transplant Recipients

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Completed
• CT.gov ID: NCT02866695
• Collaborator: (none)
• Enrollment: 20
• Location: 1
• Arm: 1
• Actual Duration (Months): 20.8
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

This is a single arm, open-label interventional study of ingenol mebutate 0.015% in solid organ transplant recipients. The investigators plan to treat 20 subjects, 10 kidney transplant recipients and 10 lung transplant recipients. The investigators have selected these two populations as the represent the spectrum of solid organ transplantation: kidney transplant recipients are the largest transplant population, but have lower levels of immunosuppression and skin cancer risk. Lung transplant recipients have the highest burden of skin cancer and actinic keratoses.

Condition or Disease	Intervention/Treatment	Phase
Actinic Keratosis	Drug: ingenol mebutate gel 0.015%	Phase 4

Detailed Description

Actinic keratoses (AK) are patches of dysplastic keratinocytes arising in sun-damaged skin. These lesions are precursors to cutaneous squamous cell carcinoma (SCC), and are treated to prevent progression to SCC. First-line therapy for AK include cryotherapy and curettage, which target clinically visible lesions but do not address the subclinical lesions in the field of ultraviolet radiation damage. Field therapy includes topical chemotherapy, immunotherapy, and photodynamic therapy. Ingenol mebutate is the active compound found in Euphorbia peplus sap, and has been approved for treatment of AK in immunocompetent patients. Ingenol mebutate 0.015% is favored over other topical treatments for treatment of AK on the face due to the brief treatment course, high clearance rate, and resolution without sequelae.

Solid organ transplant recipients (OTR) have a high incidence of AK and high risk of developing SCC, and require frequent field therapy. In addition, OTR generally have a higher burden of AK and require treatment of a larger surface area than the 25 cm2 area labeled for ingenol mebutate 0.015%. The investigators plan to investigate the safety and efficacy of ingenol mebutate 0.015% in OTR, with a treatment area up to 100cm2.

This is a single arm, open-label interventional study of ingenol mebutate 0.015% in solid organ transplant recipients. The investigators plan to treat 20 subjects, 10 kidney transplant recipients and 10 lung transplant recipients. The investigators have selected these two populations as the represent the spectrum of solid organ transplantation: kidney transplant recipients are the largest transplant population, but have lower levels of immunosuppression and skin cancer risk. Lung transplant recipients have the highest burden of skin cancer and actinic keratoses.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Safety and Efficacy of Ingenol Mebutate Gel 0.015% for Treatment of Actinic Keratosis on the Face in Solid Organ Transplant Recipients
• Actual Study Start Date: Oct 6, 2016
• Actual Primary Completion Date: Jul 2, 2018
• Actual Study Completion Date: Jul 2, 2018

Arms and Interventions

Arm	Intervention/Treatment
Other: Open label treatment All patients will be treated with ingenol mebutate gel 0.015%. There is no placebo or comparator for this study. The investigator will identify the patient's treatment area at Baseline, and provide a detailed application instruction sheet. The first dose will be applied in clinic under the supervision of the investigator.	Drug: ingenol mebutate gel 0.015%; ingenol mebutate gel 0.015% to be applied on treatment area; Other Names: Picato

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events [From screening to Day 57 or study early termination if applicable]

   To evaluate the safety of ingenol mebutate gel 0.015% on the face in solid organ transplant recipients

Secondary Outcome Measures

1. Number of Participants With a Reduction of Actinic Keratosis [Day 57 (assessed at screening, day 1, day 29, day 57, and study early termination if applicable, clearance at day 57 reported)]

   To evaluate the efficacy of ingenol mebutate for reduction of actinic keratoses on the face in organ transplant recipients.

2. Participant's Local Skin Response Grading Scale [Day 1, Day 4 (assessed at screening, day 1, day 4, day 29, day 57, and study early termination if applicable, results at day 1 and day 4 reported)]

   To investigate the local skin response to ingenol mebutate in organ transplant recipients. Local skin reaction (LSR) will be graded by visual assessment on a 4 point scale where 0=none, 1=mild, 2=moderate, 3=severe. Each of the following four reactions will be graded: erythema, vesiculation/postulation, crusting/scabbing/erosion, and edema/swelling. A composite score will be calculated (range 0-16). A high LSR indicated a worse outcome. LSR assessment will be performed at days 1, 8, 29, and 84.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Adults at least 18 years old.

2. Subject must be a solid organ transplant recipient at least one year from the date of transplantation.

3. Subjects must be in stable health as confirmed by medical history, per investigator judgement.

4. Subjects must be able to read, sign, and understand the informed consent.

5. Subjects have at least 4 and no more than 20 clinically typical (non-hyperkeratotic/hypertrophic), visible actinic keratoses in a treatment area of approximately 100cm2 on the face. Treatment areas will include a single cheek (nasofacial sulcus to tragus, malar cheekbone to jawline and avoiding the lower eyelid and mouth); the forehead (hairline to eyebrows, extending laterally to the root of the helix).

6. Subject must be willing to forego any other treatments on the face, including cryotherapy, tanning bed use and excessive sun exposure while in the study.

7. Subject is willing and able to participate in the study and to comply with all study requirements including concomitant medication and other treatment restrictions.

8. If subject is a female of childbearing potential she must have a negative urine pregnancy test result prior to study treatment initiation and must agree to use an approved method of birth control while enrolled in the study.

Exclusion Criteria:

1. Subjects with an unstable medical condition as deemed by the clinical investigator.

2. Subjects with a history of bone marrow or stem cell transplantation.

3. Subjects with non-melanoma skin cancer on the face.

4. Subjects with hyperkeratotic or hypertrophic AKs.

5. Subjects with any dermatologic disease in the treatment area that may be exacerbated by the treatment proposed or that might impair the evaluation of AKs.

6. Women who are pregnant, lactating, or planning to become pregnant during the study period.

7. Subjects who have previously been treated with ingenol mebutate in study area within the past 8 weeks.

8. Subjects who have used any topical prescription medications for actinic keratosis on the study area within 8 weeks prior to study treatment initiation.

9. Subjects who have used any topical prescription medications for other reason on the study area within 4 weeks prior to study treatment initiation.

10. Subjects who are currently participating in another clinical study or have completed another clinical study with an investigational drug or device on the study area within 30 days prior to study treatment initiation.

11. Subjects with known hypersensitivity to Picato gel or any of the inactive ingredients: isopropyl alcohol, hydroxyethyl cellulose, citric acid monohydrate, sodium citrate, or benzyl alcohol.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSF Dermatology	San Francisco	California	United States	94115

Sponsors and Collaborators

• University of California, San Francisco

Investigators

• Principal Investigator: Sarah Arron, MD, PhD, University of California, San Francisco

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 18, 2016

More Information

Publications

None provided.

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT02866695
• Other Study ID Numbers: Leo AK
• First Posted: Aug 15, 2016
• Last Update Posted: Mar 9, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by University of California, San Francisco: Actinic Keratosis; lung transplant; kidney transplant
• Additional relevant MeSH terms: Keratosis, Actinic; Keratosis

Study Results

Participant Flow

Arm/Group Title	Open Label Treatment
Arm/Group Description	A total of 20 solid organ transplant recipients with 4 to 20 actinic keratoses were enrolled and treated for 3 consecutive days with 4 single-dose tubes of ingenol mebutate gel 0.015% applied to a 100 cm2 area of the face according to study protocol. There was no placebo or comparator for this study. All but 2 participants completed the treatment. One kidney transplant participant forgot to apply the treatment on day 3, but continued in the study. One lung transplant participant who reported pain in the treatment area withdrew from the study after day 2 dosing due to travel considerations and was lost to follow-up.
Period Title: Overall Study
STARTED	20
COMPLETED	18
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Open Label Treatment
Arm/Group Description	All patients will be treated with ingenol mebutate gel 0.015%. There is no placebo or comparator for this study. The investigator will identify the patient's treatment area at Baseline, and provide a detailed application instruction sheet. The first dose will be applied in clinic under the supervision of the investigator. ingenol mebutate gel 0.015%: ingenol mebutate gel 0.015% to be applied on treatment area
Overall Participants	20
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	65.3
Sex: Female, Male (Count of Participants)
Female	6 30%
Male	14 70%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 5%
Not Hispanic or Latino	19 95%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	20 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	20 100%
Organ Transplant Type (Count of Participants)
Lung	9 45%
Kidney	7 35%
Kidney/Pancreas	2 10%
Kidney/Liver	1 5%
Kidney/Heart	1 5%
Years Since Transplant (years) [Mean (Full Range) ]
Mean (Full Range) [years]	10.9

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events
Description	To evaluate the safety of ingenol mebutate gel 0.015% on the face in solid organ transplant recipients
Time Frame	From screening to Day 57 or study early termination if applicable

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Open Label Treatment
Arm/Group Description	A total of 20 solid organ transplant recipients with 4 to 20 actinic keratoses were enrolled and treated for 3 consecutive days with 4 single-dose tubes of ingenol mebutate gel 0.015% applied to a 100 cm2 area of the face according to study protocol. There was no placebo or comparator for this study. All but 2 participants completed the treatment. One kidney transplant participant forgot to apply the treatment on day 3, but continued in the study. One lung transplant participant who reported pain in the treatment area withdrew from the study after day 2 dosing due to travel considerations and was lost to follow-up.
Measure Participants	20
Facial edema	12 60%
Pain in Treatment Area	11 55%
Pruritus	6 30%
Headache	3 15%
Squamous Cell Carcinoma Outside Treatment Area	3 15%
Diarrhea	2 10%
Xerosis	2 10%
Urosepsis	1 5%
Worsening of CKD	3 15%
Hyperglycemia	2 10%
Acute Kidney Injury	1 5%
Hyperkalemia	1 5%
Anemia	1 5%
Hypertriglyceridemia	1 5%

2. Secondary Outcome

Title	Number of Participants With a Reduction of Actinic Keratosis
Description	To evaluate the efficacy of ingenol mebutate for reduction of actinic keratoses on the face in organ transplant recipients.
Time Frame	Day 57 (assessed at screening, day 1, day 29, day 57, and study early termination if applicable, clearance at day 57 reported)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Open Label Treatment
Arm/Group Description	A total of 20 solid organ transplant recipients with 4 to 20 actinic keratoses were enrolled and treated for 3 consecutive days with 4 single-dose tubes of ingenol mebutate gel 0.015% applied to a 100 cm2 area of the face according to study protocol. There was no placebo or comparator for this study. All but 2 participants completed the treatment. One kidney transplant participant forgot to apply the treatment on day 3, but continued in the study. One lung transplant participant who reported pain in the treatment area withdrew from the study after day 2 dosing due to travel considerations and was lost to follow-up.
Measure Participants	20
75% Clearance of Actinic Keratoses at Day 57	12 60%
100% Clearance of Actinic Keratoses at Day 57	8 40%

3. Secondary Outcome

Title	Participant's Local Skin Response Grading Scale
Description	To investigate the local skin response to ingenol mebutate in organ transplant recipients. Local skin reaction (LSR) will be graded by visual assessment on a 4 point scale where 0=none, 1=mild, 2=moderate, 3=severe. Each of the following four reactions will be graded: erythema, vesiculation/postulation, crusting/scabbing/erosion, and edema/swelling. A composite score will be calculated (range 0-16). A high LSR indicated a worse outcome. LSR assessment will be performed at days 1, 8, 29, and 84.
Time Frame	Day 1, Day 4 (assessed at screening, day 1, day 4, day 29, day 57, and study early termination if applicable, results at day 1 and day 4 reported)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Open Label Treatment
Arm/Group Description	A total of 20 solid organ transplant recipients with 4 to 20 actinic keratoses were enrolled and treated for 3 consecutive days with 4 single-dose tubes of ingenol mebutate gel 0.015% applied to a 100 cm2 area of the face according to study protocol. There was no placebo or comparator for this study. All but 2 participants completed the treatment. One kidney transplant participant forgot to apply the treatment on day 3, but continued in the study. One lung transplant participant who reported pain in the treatment area withdrew from the study after day 2 dosing due to travel considerations and was lost to follow-up.
Measure Participants	20
Baseline Local Skin Reaction Composite Score	1.2 (0.8)
Day 4 Local Skin Reaction Composite Score	11.7 (4.2)

Adverse Events

Time Frame	Each participant was assessed for 57 days from the start of treatment.
Adverse Event Reporting Description	CTC Adverse Events Grading Criteria version 4.0 was used to define adverse events
Arm/Group Title	Open Label Treatment
Arm/Group Description	A total of 20 solid organ transplant recipients with 4 to 20 actinic keratoses were enrolled and treated for 3 consecutive days with 4 single-dose tubes of ingenol mebutate gel 0.015% applied to a 100 cm2 area of the face according to study protocol. There was no placebo or comparator for this study. All but 2 participants completed the treatment. One kidney transplant participant forgot to apply the treatment on day 3, but continued in the study. One lung transplant participant who reported pain in the treatment area withdrew from the study after day 2 dosing due to travel considerations and was lost to follow-up.
All Cause Mortality
	Open Label Treatment
	Affected / at Risk (%)	# Events
Total	0/20 (0%)
Serious Adverse Events
	Open Label Treatment
	Affected / at Risk (%)	# Events
Total	5/20 (25%)
Blood and lymphatic system disorders
Anemia	1/20 (5%)	1
Gastrointestinal disorders
Diarrhea	1/20 (5%)	1
Metabolism and nutrition disorders
Hypertriglyceridemia	1/20 (5%)	1
Renal and urinary disorders
Urosepsis	1/20 (5%)	1
Chronic Kidney Disease	1/20 (5%)	1
Other (Not Including Serious) Adverse Events
	Open Label Treatment
	Affected / at Risk (%)	# Events
Total	10/20 (50%)
Blood and lymphatic system disorders
Neutropenia	1/20 (5%)	1
Metabolism and nutrition disorders
Hyperglycemia	2/20 (10%)	2
Renal and urinary disorders
Acute Kidney Injury	4/20 (20%)	4
Hyperkalemia	1/20 (5%)	1
Hypocalcemia	1/20 (5%)	1
Hyponatremia	2/20 (10%)	2
Hypoalbuminemia	2/20 (10%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.