An Equivalence Study of Generic Ingenol Mebutate Gel 0.015% and Picato Gel 0.015% in Subjects With Actinic Keratosis

• Sponsor: Actavis Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03200912
• Collaborator: (none)
• Enrollment: 507
• Locations: 23
• Arms: 3
• Actual Duration (Months): 7.1
• Patients Per Site: 22
• Patients Per Site Per Month: 3.1

Study Details

Study Description

Brief Summary

The objective of this study was to evaluate the safety and therapeutic equivalence of generic ingenol mebutate gel, 0.015% to Picato gel, 0.015% by establishing the therapeutic comparability of the two active products and the superiority of the two active products over the vehicle gel in the treatment of AK on the face and scalp.

Condition or Disease	Intervention/Treatment	Phase
ACTINIC KERATOSIS	Drug: Ingenol Mebutate (Picato®); Drug: Generic Ingenol Mebutate; Drug: Vehicle Foam	Phase 3

Detailed Description

Picato® (ingenol mebutate) gel is the first and only ingenol mebutate product approved by the Food and Drug Administration (FDA) in 2012 for the topical treatment of AKs on the face and scalp (0.015% formulation) and on the trunk and extremities (0.05% formulation). The FDA approved regimen for ingenol mebutate gel, 0.015% for the treatment of AKs on the face and scalp is once-daily application of one unit dose tube for three consecutive days applied to one contiguous skin area of approximately 25 cm2 (e.g., 5 cm x 5 cm).

Study Design

• Study Type: Interventional
• Actual Enrollment: 507 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter Randomized Doubleblind Vehicle-controlled Parallel Comparison Study to Determine Therapeutic Equivalence of Generic Ingenol Mebutate Gel 0.015% and Picato® Gel 0.015% in Subjects With Actinic Keratosis on the Face or Scalp
• Actual Study Start Date: Aug 19, 2016
• Actual Primary Completion Date: Mar 7, 2017
• Actual Study Completion Date: Mar 22, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Picato Picato® (ingenol mebutate) gel, 0.15% (Leo Pharma Inc.) [Reference Listed Drug (RLD)]	Drug: Ingenol Mebutate (Picato®); Brand product; Other Names: RLD
Experimental: Generic Ingenol Mebutate Generic ingenol mebutate gel, 0.15% [Test]	Drug: Generic Ingenol Mebutate; Generic formulated to have the same therapeutic effect of the brand; Other Names: Test
Placebo Comparator: Vehicle Foam Vehicle gel of the test product	Drug: Vehicle Foam; It does not contain active ingredient. A placebo to test the sensitivity of the active treatments.; Other Names: Placebo

Outcome Measures

Primary Outcome Measures

1. Complete Clearance of AK Lesions [57 days]

   Treatment success (complete clearance of AK lesions) at Day 57, where complete clearance of AK lesions was defined as having no (zero) clinically visible AK lesions in the Treatment Area

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 95 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subject was male or non-pregnant female 18 years of age or older.

• Females must have been post-menopausal, surgically sterile, or using an effective method of birth control. Women of childbearing potential (WOCBP) must have had a negative urine pregnancy test (UPT) at Visit 1/Baseline.

• Subject provided written informed consent.

• Subject had a clinical diagnosis of AK at Visit 1/Baseline with at least four, but no more than eight visible and discrete non-hyperkeratotic, non-hypertrophic AK lesions, each at least 4 mm in diameter, within a contiguous 25 cm2 treatment area ("the Treatment Area") located on the face or scalp.

• Subject was willing and able to apply the test article as directed, comply with study instructions, and commit to all follow-up visits for the duration of the study.

• Subject was in good general health and free of any disease state or physical condition that might have impaired evaluation of AK lesions or which, in the investigator's opinion, exposed the subject to an unacceptable risk by study participation.

Exclusion Criteria:

• 1. Subject was pregnant, lactating, or was planning to become pregnant during the study.

• Subject had a location of the selected contiguous 25 cm2 Treatment Area that (a) was within 5 cm of an incompletely healed wound or (b) was in an area containing a lesion that was previously treated with ingenol mebutate.

• Subject had hyperkeratotic, hypertrophic, or large mat-like AKs (e.g., AK >1 cm2 in size) within the contiguous 25 cm2 Treatment Area.

• Subject had more than eight AKs, independent of size, within the selected contiguous 25 cm2 Treatment Area

• Subject had atopic dermatitis, basal cell carcinoma, eczema, psoriasis, rosacea, squamous cell carcinoma, xeroderma pigmentosum, or any other possibly confounding skin conditions within the region of the head that contained the selected Treatment Area (i.e., face or scalp).

• Subject had any skin pathology or condition that, in the investigator's opinion, could have interfered with the evaluation of the test article or required the use of interfering topical, systemic, or surgical therapy.

• Subject was immunosuppressed (e.g., human immunodeficiency virus, systemic malignancy, graft host disease, etc.).

• Subject experienced an unsuccessful outcome from previous ingenol mebutate therapy (an unsuccessful outcome was defined as after a reasonable therapeutic trial with no compliance issues and the topical drug did not work).

• Subject used topical creams, lotions, or gels of any kind within the selected Treatment Area within one day prior to entry into the study.

• Subject had the need or planned to be exposed to artificial tanning devices or excessive sunlight during the study or had used artificial tanners within two weeks of Visit 1/Baseline.

• Subject had used any of the following topical medications on the face or scalp:

• Corticosteroids within two weeks of Visit 1/Baseline;

• Keratolytic-containing therapeutic products or medicated or irritant topical salves within two weeks of Visit 1/Baseline, including, but not limited to, alpha hydroxy acids (e.g., glycolic acid, lactic acid etc. >5%), beta hydroxy acid (salicylic acid >2%), and urea >5%;

• Topical retinoids (e.g., tazarotene, adapalene, tretinoin) within two weeks of Visit 1/Baseline;

• Light treatments (e.g., psoralen plus ultraviolet A therapy, ultraviolet B) within four weeks of Visit 1/Baseline;

• Photodynamic therapy within eight weeks of Visit 1/Baseline;

• 5-fluorouracil, diclofenac, imiquimod, or ingenol mebutate within eight weeks of Visit 1/Baseline; or

• Other topical therapy for actinic keratosis within 2 cm of the selected contiguous 25 cm2 Treatment Area within eight weeks of Visit 1/Baseline.

• Subject had cryodestruction or chemodestruction, surgical excision, curettage, dermabrasion, chemical peel, or laser resurfacing on the Treatment Area (i.e., face or scalp) within two weeks prior to Visit 1/Baseline.

• Subject used any of the following systemic medications:

• Corticosteroid therapy within one month;

• Interferon/interferon inducers, cytotoxic drugs, immuno-modulators, or immunosuppressive therapies within one month;

• Retinoid therapy within six months prior to Visit 1/Baseline.

• Subject had lesions suspicious for skin cancer (skin cancer not ruled out by biopsy) or untreated skin cancers within the selected contiguous 25 cm2 Treatment Area on the face or scalp.

• Subject was enrolled in an investigational drug or device study.

• Subject used an investigational drug or investigational device treatment within one month prior to Visit 1/Baseline.

• Subject had a history of sensitivity to any of the ingredients in the test articles (see Section 9.4.2).

• Subject had any condition which, in the investigator's opinion, would have made it unsafe or precluded the subject's ability to fully participate in this research study.

• Subject was unable to communicate or cooperate with the investigator due to language problems, poor mental development, impaired cerebral function, or physical limitations.

• Subject was known to be noncompliant or was unlikely to comply with the requirements of the study protocol (e.g., due to alcoholism, drug dependency, mental incapacity) in the opinion of the investigator.

• Subject was previously enrolled in the same study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dermatology Specialists, Inc.	Oceanside	California	United States	92056
2	Horizons Clinical Research Ctr., LLC	Denver	Colorado	United States	80220
3	The Center for Clinical and Cosmetic Research	Aventura	Florida	United States	33180
4	Moore Clinical Research	Brandon	Florida	United States	33511
5	Savin Medical Group Research Center	Miami Lakes	Florida	United States	33014
6	Tory P. Sullivan, M.D., P.A.	North Miami Beach	Florida	United States	33162
7	MedaPhase, Inc.	Newnan	Georgia	United States	30263
8	Northwest Clinical Trials, Inc.	Boise	Idaho	United States	83704
9	Arlington Dermatology	Arlington Heights	Illinois	United States	60005
10	Christie Clinic, LLC	Champaign	Illinois	United States	61820
11	University Dermatology & Vein Clinic, LLC	Darien	Illinois	United States	60561
12	Forefront Dermatology	Carmel	Indiana	United States	46032
13	Dawes Fretzin Clinical Research Group, LLC	Indianapolis	Indiana	United States	46256
14	The Indiana Clinical Trials Center	Plainfield	Indiana	United States	46168
15	The South Bend Clinic,LLC	South Bend	Indiana	United States	46617
16	Minnesota Clinical Study Center	Fridley	Minnesota	United States	55432
17	MediSearch Clinical Trials	Saint Joseph	Missouri	United States	64506
18	Academic Dermatology Associates	Albuquerque	New Mexico	United States	87106
19	Dermatology Consulting Services	High Point	North Carolina	United States	27262
20	Omega Medical Research, 400 Bald Hill Road, Warwick, RI 02886	Warwick	Rhode Island	United States	02886
21	Palmetto Clinical Trial Services	Fountain Inn	South Carolina	United States	29644
22	Dermatology Associates of Knoxville, PC	Knoxville	Tennessee	United States	37917
23	DermReseach New Braunfels	New Braunfels	Texas	United States	78130

Sponsors and Collaborators

• Actavis Inc.

Investigators

• Study Director: Oleg Khatsenko, PhD, Actavis Inc.

Study Documents (Full-Text)

• Study Protocol - May 26, 2016
• Statistical Analysis Plan - Nov 29, 2016

More Information

Publications

None provided.

• Responsible Party: Actavis Inc.
• ClinicalTrials.gov Identifier: NCT03200912
• Other Study ID Numbers: 094-8152-301
• First Posted: Jun 27, 2017
• Last Update Posted: Jan 14, 2020
• Last Verified: Jan 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Keratosis, Actinic; Keratosis

Study Results

Participant Flow

Pre-assignment Detail	The populations for this study included the Safety Population, the Per-Protocol Population, and the modified Intent-to-Treat (mITT) population.

Arm/Group Title	Generic Ingenol Mebutate	Picato (Ingenol Mebutate)	Vehicle Gel
Arm/Group Description	Generic ingenol mebutate gel, 0.015% [Test] Generic Ingenol Mebutate: Generic formulated to have the same therapeutic effect of the brand	Picato® (ingenol mebutate) gel, 0.015% (Leo Pharma Inc.) [Reference Listed Drug (RLD)] Ingenol Mebutate (Picato®): Brand product	Vehicle gel of the test product Vehicle Gel: It does not contain active ingredient. A placebo to test the sensitivity of the active treatments.
Period Title: Overall Study
STARTED	170	169	168
COMPLETED	166	166	164
NOT COMPLETED	4	3	4

Baseline Characteristics

Arm/Group Title	Generic Ingenol Mebutate	Picato (Ingenol Mebutate)	Vehicle Gel	Total
Arm/Group Description	Generic ingenol mebutate gel, 0.015% [Test] Generic Ingenol Mebutate: Generic formulated to have the same therapeutic effect of the brand	Picato® (ingenol mebutate) gel, 0.015% (Leo Pharma Inc.) [Reference Listed Drug (RLD)] Ingenol Mebutate (Picato®): Brand product	Vehicle gel of the test product Vehicle Gel: It does not contain active ingredient. A placebo to test the sensitivity of the active treatments.	Total of all reporting groups
Overall Participants	170	169	168	507
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	70.2 (9.7)	68.9 (8.6)	70.2 (9.4)	69.8 (9.3)
Sex: Female, Male (Count of Participants)
Female	31 18.2%	32 18.9%	35 20.8%	98 19.3%
Male	139 81.8%	137 81.1%	133 79.2%	409 80.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	15 8.8%	14 8.3%	14 8.3%	43 8.5%
Not Hispanic or Latino	155 91.2%	155 91.7%	154 91.7%	464 91.5%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	1 0.6%	1 0.2%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%
White	170 100%	168 99.4%	167 99.4%	505 99.6%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 0.6%	0 0%	1 0.2%

Outcome Measures

1. Primary Outcome

Title	Complete Clearance of AK Lesions
Description	Treatment success (complete clearance of AK lesions) at Day 57, where complete clearance of AK lesions was defined as having no (zero) clinically visible AK lesions in the Treatment Area
Time Frame	57 days

Outcome Measure Data

Analysis Population Description

AK Complete Clearance Rate at Day 57 (PP population)

Arm/Group Title	Generic Ingenol Mebutate	Picato (Ingenol Mebutate)	Vehicle Gel
Arm/Group Description	Generic ingenol mebutate gel, 0.015% [Test] Generic Ingenol Mebutate: Generic formulated to have the same therapeutic effect of the brand	Picato® (ingenol mebutate) gel, 0.015% (Leo Pharma Inc.) [Reference Listed Drug (RLD)] Ingenol Mebutate (Picato®): Brand product	Vehicle gel of the test product Vehicle Gel: It does not contain active ingredient. A placebo to test the sensitivity of the active treatments.
Measure Participants	137	144	139
Count of Participants [Participants]	45 26.5%	44 26%	7 4.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Generic Ingenol Mebutate, Picato (Ingenol Mebutate)
	Comments
	Type of Statistical Test	Equivalence
	Comments	Primary Efficacy Endpoint - AK Complete Clearance Rates at Day 57 (PP and mITT Populations)
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.29
	Confidence Interval	(2-Sided) 90%; -7.55 to 12.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse event data was collected from the time of the study start until end of study on Day 57 of the study.
Arm/Group Title	Generic Ingenol Mebutate		Picato (Ingenol Mebutate)		Vehicle Gel
Arm/Group Description	Generic ingenol mebutate gel, 0.015% [Test] Generic Ingenol Mebutate: Generic formulated to have the same therapeutic effect of the brand		Picato® (ingenol mebutate) gel, 0.015% (Leo Pharma Inc.) [Reference Listed Drug (RLD)] Ingenol Mebutate (Picato®): Brand product		Vehicle gel of the test product Vehicle Gel: It does not contain active ingredient. A placebo to test the sensitivity of the active treatments.
All Cause Mortality
	Generic Ingenol Mebutate		Picato (Ingenol Mebutate)		Vehicle Gel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/170 (17.1%)		29/169 (17.2%)		24/168 (14.3%)
Serious Adverse Events
	Generic Ingenol Mebutate		Picato (Ingenol Mebutate)		Vehicle Gel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/170 (1.2%)		0/169 (0%)		2/168 (1.2%)
Cardiac disorders
Atrial fibrillation with hospitalization	1/170 (0.6%)	1	0/169 (0%)	0	0/168 (0%)	0
Infections and infestations
Diverticulitis	1/170 (0.6%)	1	0/169 (0%)	0	0/168 (0%)	0
Pneumonia	0/170 (0%)	0	0/169 (0%)	0	1/168 (0.6%)	1
Breast cellulitis	0/170 (0%)	0	0/169 (0%)	0	1/168 (0.6%)	1
Other (Not Including Serious) Adverse Events
	Generic Ingenol Mebutate		Picato (Ingenol Mebutate)		Vehicle Gel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/170 (17.1%)		29/169 (17.2%)		24/168 (14.3%)
Cardiac disorders
Atrial fibrillation	1/170 (0.6%)		0/169 (0%)		0/168 (0%)
Eye disorders
Conjunctival hyperaemia	0/170 (0%)		0/169 (0%)		1/168 (0.6%)
Eye irritation	0/170 (0%)		1/169 (0.6%)		0/168 (0%)
Eye swelling	0/170 (0%)		1/169 (0.6%)		0/168 (0%)
Abdominal pain upper	0/170 (0%)		1/169 (0.6%)		0/168 (0%)
Dental caries	0/170 (0%)		1/169 (0.6%)		0/168 (0%)
General disorders
Application site erythema	1/170 (0.6%)		0/169 (0%)		0/168 (0%)
Application site inflammation	1/170 (0.6%)		0/169 (0%)		0/168 (0%)
Application site pain	6/170 (3.5%)		6/169 (3.6%)		0/168 (0%)
Application site pruritus	3/170 (1.8%)		2/169 (1.2%)		0/168 (0%)
Application site swelling	0/170 (0%)		1/169 (0.6%)		0/168 (0%)
Infections and infestations
Breast cellulitis	0/170 (0%)		0/169 (0%)		1/168 (0.6%)
Bronchitis	0/170 (0%)		1/169 (0.6%)		1/168 (0.6%)
Diverticulitis	1/170 (0.6%)		0/169 (0%)		0/168 (0%)
Eye infection	0/170 (0%)		0/169 (0%)		1/168 (0.6%)
Fungal infection	0/170 (0%)		0/169 (0%)		1/168 (0.6%)
Herpes zoster	1/170 (0.6%)		1/169 (0.6%)		0/168 (0%)
Influenza	1/170 (0.6%)		1/169 (0.6%)		0/168 (0%)
Nasopharyngitis	3/170 (1.8%)		3/169 (1.8%)		7/168 (4.2%)
Pneumonia	1/170 (0.6%)		0/169 (0%)		1/168 (0.6%)
Sinusitus	0/170 (0%)		3/169 (1.8%)		0/168 (0%)
Tooth abscess	1/170 (0.6%)		1/169 (0.6%)		1/168 (0.6%)
Tooth infection	1/170 (0.6%)		0/169 (0%)		0/168 (0%)
Upper respiratory tract infection	2/170 (1.2%)		0/169 (0%)		6/168 (3.6%)
Injury, poisoning and procedural complications
Arthropod bite	0/170 (0%)		1/169 (0.6%)		0/168 (0%)
Arthropod sting	1/170 (0.6%)		1/169 (0.6%)		0/168 (0%)
Laceration	1/170 (0.6%)		0/169 (0%)		0/168 (0%)
Ligament sprain	0/170 (0%)		0/169 (0%)		1/168 (0.6%)
Metabolism and nutrition disorders
Hyperlipidaemia	0/170 (0%)		0/169 (0%)		1/168 (0.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/170 (0.6%)		0/169 (0%)		1/168 (0.6%)
Back pain	1/170 (0.6%)		0/169 (0%)		0/168 (0%)
Neck pain	0/170 (0%)		0/169 (0%)		1/168 (0.6%)
Osteoarthritis	0/170 (0%)		1/169 (0.6%)		0/168 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	1/170 (0.6%)		1/169 (0.6%)		1/168 (0.6%)
Nervous system disorders
Headache	2/170 (1.2%)		1/169 (0.6%)		1/168 (0.6%)
Parkinson's disease	0/170 (0%)		1/169 (0.6%)		0/168 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/170 (0%)		1/169 (0.6%)		1/168 (0.6%)
Epistaxis	0/170 (0%)		1/169 (0.6%)		0/168 (0%)
Oropharyngeal pain	0/170 (0%)		0/169 (0%)		1/168 (0.6%)
Pulmonary congestion	0/170 (0%)		1/169 (0.6%)		0/168 (0%)
Sinus congestion	1/170 (0.6%)		2/169 (1.2%)		0/168 (0%)
Skin and subcutaneous tissue disorders
Eczema asteatotic	0/170 (0%)		1/169 (0.6%)		0/168 (0%)
Milia	0/170 (0%)		0/169 (0%)		1/168 (0.6%)
Pseudofolliculitis	1/170 (0.6%)		0/169 (0%)		0/168 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS 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.