A Trial to Compare the Incidence of Squamous Cell Carcinoma (SCC) and Other Skin Neoplasia on Skin Areas Treated With Ingenol Disoxate Gel or Vehicle Gel for Actinic Keratosis on Face and Chest or Scalp

• Sponsor: LEO Pharma (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03115476
• Collaborator: (none)
• Enrollment: 563
• Locations: 59
• Arms: 3
• Actual Duration (Months): 8.8
• Patients Per Site: 9.5
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

One of the main reasons for treating actinic keratoses (AK) is the wish to lower the risk of progression of AK to squamous cell carcinoma (SCC). This risk is in the order of 1 per 1000 AKs per year, which is in itself a small risk, but since patients can have dozens of AKs and the disease is chronic the cumulative risk for a patient can be substantial.

In this extension protocol of trials LP0084-1193, -1194, -1195 and -1196, LEO will study the incidence of SCCs and other skin neoplasia in vehicle and ingenol disoxate treated patients over a period of 2 years, so that the total follow-up time for each patient will be 3 years and 2 months.

Condition or Disease	Intervention/Treatment	Phase
Actinic Keratosis; Squamous Cell Carcinoma	Drug: ingenol disoxate gel 0.018%; Drug: ingenol disoxate gel 0.037%; Other: Vehicle gel	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 563 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Incidence of Squamous Cell Carcinoma and Other Skin Neoplasia in Subjects With Actinic Keratosis Treated With Ingenol Disoxate Gel 0.018% or 0.037%, or Vehicle Gel
• Actual Study Start Date: Jun 16, 2017
• Actual Primary Completion Date: Mar 12, 2018
• Actual Study Completion Date: Mar 12, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ingenol disoxate gel 0.018%	Drug: ingenol disoxate gel 0.018%; Ingenol disoxate gel is a novel ingenol derivative being developed for field treatment of AKs on treatment areas of up to 250 cm2 (40 in2) on the face, chest and scalp.; Other Names: LEO 43204
Experimental: Ingenol disoxate gel 0.037%	Drug: ingenol disoxate gel 0.037%; Ingenol disoxate gel is a novel ingenol derivative being developed for field treatment of AKs on treatment areas of up to 250 cm2 (40 in2) on the face, chest and scalp.; Other Names: LEO 43204
Placebo Comparator: Vehicle gel	Other: Vehicle gel; Vehicle to ingenol disoxate gel with no active ingredient

Outcome Measures

Primary Outcome Measures

1. Time to First Squamous Cell Carcinoma (SCC) in the Treatment Area [From Visit 2 (6 months after Month 14 of main trial) to first SCC in the treatment area, up to 24 months]

   Time to first squamous cell carcinoma (SCC) in the treatment area. Relative difference between groups (ingenol disoxate vs vehicle) expressed as hazard ratio. The indicated measured values are the observed incidence rates of the SCC in the treatment area which form the basis of the statistical analysis of the time to event analysis

Secondary Outcome Measures

1. Time to First Squamous Cell Carcinoma (SCC) or Other Skin Neoplasia in the Treatment Area [From Visit 2 (6 months after Month 14 of main trial) to first SCC or other skin neoplasia in the treatment area, up to 24 months]

   Time to first squamous cell carcinoma (SCC) or other skin neoplasia in the treatment area. Relative difference between groups (ingenol disoxate vs vehicle) expressed as hazard ratio. The indicated measured values are the observed incidence rates of the SCC in the treatment area which form the basis of the statistical analysis of the time to event analysis

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Signed and dated informed consent has been obtained.

• The subject has been treated in one of the trials LP0084-1193, -1194, -1195, or -1196 and has been evaluated at the end of follow-up visit (month 14) of that trial.

Exclusion Criteria:

• The subject is in need of treatment with ingenol mebutate or ingenol disoxate in the selected treatment area .

• The subject is enrolled in any other interventional clinical trial.

For subjects where there is a gap between end of follow-up visit (month 14) in one of the trials LP0084-1193, -1194, -1195, or -1196 and participation in the current trial:

• The subject has been treated with ingenol mebutate or ingenol disoxate in the selected treatment area after end of follow-up visit (month 14) in one of the trials LP0084-1193, -1194, -1195, or -1196 and until participation in the current trial.

• The subject has been enrolled in any other interventional clinical trial after end of follow-up visit (month 14) in one of the trials LP0084-1193, -1194, -1195, or -1196 and until participation in the current trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Burke Pharmaceutical Research	Hot Springs	Arkansas	United States	71913
2	Center for Dermatology Clinical Research, Inc.	Fremont	California	United States	94538
3	Dermatology Specialists, Inc	Murrieta	California	United States	92562
4	Dermatology Specialists, Inc.	Oceanside	California	United States	92056
5	Contour Dermatology & Cosmetic Surgery Center	Rancho Mirage	California	United States	92270
6	Skin Surgery Medical Group, Inc.	San Diego	California	United States	92117
7	Therapeutics Clinical Research	San Diego	California	United States	92123
8	University Clinical Trials, Inc.	San Diego	California	United States	92123
9	Southern California Dermatology, Inc.	Santa Ana	California	United States	92701
10	Colorado Medical Research Center, Inc.	Denver	Colorado	United States	80210
11	AboutSkin Dermatology and DermSurgery, PC	Greenwood Village	Colorado	United States	80111
12	Dermatology and Dermatologic Surgery	Danbury	Connecticut	United States	06810
13	The GW Medical Faculty Associates	Washington	District of Columbia	United States	20037
14	Park Avenue Dermatology	Orange Park	Florida	United States	32073
15	Research Institute of the Southeast, LLC	West Palm Beach	Florida	United States	33401
16	Visions Clincal Research	West Palm Beach	Florida	United States	33406
17	MedaPhase	Newnan	Georgia	United States	30263
18	Gwinnett Clinical Research Center, Inc.	Snellville	Georgia	United States	30078
19	Laser & Skin Surgery Center of Indiana	Carmel	Indiana	United States	46032
20	Research Institute of Deaconess Clinic	Evansville	Indiana	United States	47713
21	DermAssociates, PC	Rockville	Maryland	United States	20850
22	ActivMed Practices & Research, Inc.	Methuen	Massachusetts	United States	01844
23	Clarkston Skin Research	Clarkston	Michigan	United States	48346
24	Clinical Studies Group	Henderson	Nevada	United States	89074
25	The Dermatology Group, P.C.	Verona	New Jersey	United States	07044
26	Skin Search of Rochester, Inc.	Rochester	New York	United States	14623
27	Center for Clinical Studies	Houston	Texas	United States	77065
28	Suzanne Bruce and Associates, P.A., The Center for Skin Research	Katy	Texas	United States	77494
29	Austin Institute for Clinical Research, Inc.	Pflugerville	Texas	United States	78660
30	Premier Clinical Research	Spokane	Washington	United States	99202
31	Investigational Site	Surrey	British Columbia	Canada	V3R 6A7
32	Investigational Site	Vancouver	British Columbia	Canada	V6E 4M3
33	Investigational Site	Winnipeg	Manitoba	Canada	R3C 0N2
34	Investigational Site	Fredericton	New Brunswick	Canada	E3B 1G9
35	Investigational Site	Ajax	Ontario	Canada	L1S 7K8
36	Investigational Site	Barrie	Ontario	Canada	L4M 7G1
37	Investigational Site	London	Ontario	Canada	N6A 3H7
38	Investigational Site	Mississauga	Ontario	Canada	L5H 1G9
39	Investigational Site	Peterborough	Ontario	Canada	K9J 5K2
40	Investigational Site	Waterloo	Ontario	Canada	N2J 1C4
41	Investigational Site	Drummondville	Quebec	Canada	J2B 5L4
42	Investigational Site	Chambray les Tours		France	37170
43	Investigational Site	Nice		France	06202 Cedex 3
44	Investigational Site	Saint Etienne		France	42055 Cedex 2
45	Investigational Site	Berlin		Germany	10117
46	Investigational Site	Dresden		Germany	1097
47	Investigational Site	Frankfurt am Main		Germany	60590
48	Investigational Site	Hamburg		Germany	22391
49	Investigational Site	Hannover		Germany	30159
50	Investigational Site	Münster		Germany	48149
51	Investigational Site	Recklinghausen		Germany	45657
52	Investigational Site	Schweinfurt		Germany	97421
53	Investigational Site	Badalona	Barcelona	Spain	08916
54	Investigational Site	Pamplona	Navarra	Spain	31008
55	Investigational Site	Valencia		Spain	46026
56	Investigational Site	Dundee	Angus	United Kingdom	DD1 9SY
57	Investigational Site	Airdrie	Lanarkshire	United Kingdom	ML6 OJS
58	Investigational Site	Middlesborough	North Yorkshire	United Kingdom	TS4 3BW
59	Investigational Site	Redhill	Surrey	United Kingdom	RH1 5RH

Sponsors and Collaborators

• LEO Pharma

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jul 25, 2017
• Statistical Analysis Plan - May 27, 2018

More Information

Publications

None provided.

• Responsible Party: LEO Pharma
• ClinicalTrials.gov Identifier: NCT03115476
• Other Study ID Numbers: LP0084-1369; 2017-000228-85
• First Posted: Apr 14, 2017
• Last Update Posted: Oct 15, 2019
• Last Verified: Jun 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Squamous Cell; Keratosis, Actinic; Keratosis

Study Results

Participant Flow

Pre-assignment Detail	1234 participants were randomised and applied investigational medicinal product (IMP) in the trials LP0084-1193, -1194, -1195, -1196 (main trials, Period 1). A total of 563 participants from the main trials continued and were enrolled into this extension follow-up trial (LP0084-1369, Period 2).

Arm/Group Title	Ingenol Disoxate Gel 0.018%	Ingenol Disoxate Gel 0.037%	Vehicle Gel
Arm/Group Description	ingenol disoxate gel 0.018%: Ingenol disoxate gel is a novel ingenol derivative being developed for field treatment of actinic keratoses (AKs) on treatment areas of up to 250 cm2 (40 in2) on the face, chest and scalp.	ingenol disoxate gel 0.037%: Ingenol disoxate gel is a novel ingenol derivative being developed for field treatment of actinic keratoses AKs on treatment areas of up to 250 cm2 (40 in2) on the face, chest and scalp.	Vehicle gel to Ingenol disoxate gel with no active ingredient
Period Title: Main Trials (LP0084-119x)
STARTED	407	418	409
COMPLETED	407	418	409
NOT COMPLETED	0	0	0
Period Title: Main Trials (LP0084-119x)
STARTED	191	210	162
COMPLETED	0	0	0
NOT COMPLETED	191	210	162

Baseline Characteristics

Arm/Group Title	Ingenol Disoxate Gel 0.018%	Ingenol Disoxate Gel 0.037%	Vehicle Gel	Total
Arm/Group Description	ingenol disoxate gel 0.018%: Ingenol disoxate gel is a novel ingenol derivative being developed for field treatment of AKs on treatment areas of up to 250 cm2 (40 in2) on the face, chest and scalp.	ingenol disoxate gel 0.037%: Ingenol disoxate gel is a novel ingenol derivative being developed for field treatment of AKs on treatment areas of up to 250 cm2 (40 in2) on the face, chest and scalp.	Vehicle gel of ingenol disoxate gel	Total of all reporting groups
Overall Participants	191	210	162	563
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	57 29.8%	55 26.2%	43 26.5%	155 27.5%
>=65 years	134 70.2%	155 73.8%	119 73.5%	408 72.5%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	69	71	69	70
Sex: Female, Male (Count of Participants)
Female	67 35.1%	0 0%	30 18.5%	97 17.2%
Male	124 64.9%	210 100%	132 81.5%	466 82.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	9 4.7%	3 1.4%	0 0%	12 2.1%
Not Hispanic or Latino	182 95.3%	206 98.1%	162 100%	550 97.7%
Unknown or Not Reported	0 0%	1 0.5%	0 0%	1 0.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
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	190 99.5%	209 99.5%	162 100%	561 99.6%
More than one race	1 0.5%	0 0%	0 0%	1 0.2%
Unknown or Not Reported	0 0%	1 0.5%	0 0%	1 0.2%
Region of Enrollment (participants) [Number]
Canada	43 22.5%	62 29.5%	53 32.7%	158 28.1%
United States	98 51.3%	104 49.5%	70 43.2%	272 48.3%
United Kingdom	12 6.3%	13 6.2%	12 7.4%	37 6.6%
France	2 1%	6 2.9%	4 2.5%	12 2.1%
Germany	19 9.9%	25 11.9%	17 10.5%	61 10.8%
Spain	17 8.9%	0 0%	6 3.7%	23 4.1%
Fitzpatrick skin type (Count of Participants)
Type I	34 17.8%	26 12.4%	28 17.3%	88 15.6%
Type II	109 57.1%	116 55.2%	94 58%	319 56.7%
Type III	42 22%	54 25.7%	35 21.6%	131 23.3%
Type IV	4 2.1%	13 6.2%	4 2.5%	21 3.7%
Type V	2 1%	1 0.5%	1 0.6%	4 0.7%

Outcome Measures

1. Primary Outcome

Title	Time to First Squamous Cell Carcinoma (SCC) in the Treatment Area
Description	Time to first squamous cell carcinoma (SCC) in the treatment area. Relative difference between groups (ingenol disoxate vs vehicle) expressed as hazard ratio. The indicated measured values are the observed incidence rates of the SCC in the treatment area which form the basis of the statistical analysis of the time to event analysis
Time Frame	From Visit 2 (6 months after Month 14 of main trial) to first SCC in the treatment area, up to 24 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set: 1234 subjects who were randomised and applied IMP in one of 4 Main Trials

Arm/Group Title	Ingenol Disoxate Gel 0.018%	Ingenol Disoxate Gel 0.037%	Vehicle Gel
Arm/Group Description	ingenol disoxate gel 0.018%: Ingenol disoxate gel is a novel ingenol derivative being developed for field treatment of AKs on treatment areas of up to 250 cm2 (40 in2) on the face, chest and scalp.	ingenol disoxate gel 0.037%: Ingenol disoxate gel is a novel ingenol derivative being developed for field treatment of AKs on treatment areas of up to 250 cm2 (40 in2) on the face, chest and scalp.	Vehicle gel: Ingenol disoxate gel is a novel ingenol derivative being developed for field treatment of AKs on treatment areas of up to 250 cm2 (40 in2) on the face, chest and scalp.
Measure Participants	407	418	409
Number (95% Confidence Interval) [SCC events per 100 patient years]	2.77	0.88	1.26

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ingenol Disoxate Gel 0.018%, Ingenol Disoxate Gel 0.037%, Vehicle Gel
	Comments	Relative difference between groups (ingenol disoxate vs vehicle) expressed as hazard ratio
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.43
	Comments
	Method	likelihood ratio test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.43
	Confidence Interval	(2-Sided) 95%; 0.61 to 3.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Time to First Squamous Cell Carcinoma (SCC) or Other Skin Neoplasia in the Treatment Area
Description	Time to first squamous cell carcinoma (SCC) or other skin neoplasia in the treatment area. Relative difference between groups (ingenol disoxate vs vehicle) expressed as hazard ratio. The indicated measured values are the observed incidence rates of the SCC in the treatment area which form the basis of the statistical analysis of the time to event analysis
Time Frame	From Visit 2 (6 months after Month 14 of main trial) to first SCC or other skin neoplasia in the treatment area, up to 24 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set: 1234 subjects who were randomised and applied IMP in one of 4 Main Trials

Arm/Group Title	Ingenol Disoxate Gel 0.018%	Ingenol Disoxate Gel 0.037%	Vehicle Gel
Arm/Group Description	ingenol disoxate gel 0.018%: Ingenol disoxate gel is a novel ingenol derivative being developed for field treatment of AKs on treatment areas of up to 250 cm2 (40 in2) on the face, chest and scalp.	ingenol disoxate gel 0.037%: Ingenol disoxate gel is a novel ingenol derivative being developed for field treatment of AKs on treatment areas of up to 250 cm2 (40 in2) on the face, chest and scalp.	Vehicle gel: Ingenol disoxate gel is a novel ingenol derivative being developed for field treatment of AKs on treatment areas of up to 250 cm2 (40 in2) on the face, chest and scalp.
Measure Participants	407	418	409
Number (95% Confidence Interval) [SCC events per 100 patient years]	10.24	2.84	3.19

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ingenol Disoxate Gel 0.018%, Ingenol Disoxate Gel 0.037%, Vehicle Gel
	Comments	relative difference between treatment groups (ingenol disoxate gel vs vehicle) expressed as hazard ratio
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	likelihood ratio test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.99
	Confidence Interval	(2-Sided) 95%; 1.17 to 3.62
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	From first visit in this trial until the end of the trial i.e a period of up to 9 months as the trial was prematurely discontinued
Adverse Event Reporting Description	Only adverse events (AE) in the treatment area were collected, Serious AEs (SAE) outside treatment area were collected only if deemed related by the investigator to the study drug. This means that death not considered related to AEs in the treatment area is not included in the SAE table but are included in the All Course Mortality table For 1 subject the actual treatment was different from the planned treatment due to an error. Safety information is reported based on the actual treatment
Arm/Group Title	Ingenol Disoxate Gel 0.018%		Ingenol Disoxate Gel 0.037%		Vehicle Gel
Arm/Group Description	ingenol disoxate gel 0.018%: Ingenol disoxate gel is a novel ingenol derivative being developed for field treatment of AKs on treatment areas of up to 250 cm2 (40 in2) on the face, chest and scalp.		ingenol disoxate gel 0.037%: Ingenol disoxate gel is a novel ingenol derivative being developed for field treatment of AKs on treatment areas of up to 250 cm2 (40 in2) on the face, chest and scalp.		Vehicle gel: Ingenol disoxate gel is a novel ingenol derivative being developed for field treatment of AKs on treatment areas of up to 250 cm2 (40 in2) on the face, chest and scalp.
All Cause Mortality
	Ingenol Disoxate Gel 0.018%		Ingenol Disoxate Gel 0.037%		Vehicle Gel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/191 (0.5%)		0/211 (0%)		2/161 (1.2%)
Serious Adverse Events
	Ingenol Disoxate Gel 0.018%		Ingenol Disoxate Gel 0.037%		Vehicle Gel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/191 (0%)		1/211 (0.5%)		0/161 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant melanoma	0/191 (0%)	0	1/211 (0.5%)	1	0/161 (0%)	0
Other (Not Including Serious) Adverse Events
	Ingenol Disoxate Gel 0.018%		Ingenol Disoxate Gel 0.037%		Vehicle Gel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/191 (8.4%)		6/211 (2.8%)		10/161 (6.2%)
General disorders
Application site scar	8/191 (4.2%)	8	5/211 (2.4%)	5	7/161 (4.3%)	7
Application site papules	1/191 (0.5%)	1	0/211 (0%)	0	0/161 (0%)	0
Injury, poisoning and procedural complications
Inflammation of wound	1/191 (0.5%)	1	0/211 (0%)	0	0/161 (0%)	0
Skin abrasion	0/191 (0%)	0	1/211 (0.5%)	1	0/161 (0%)	0
Scar	1/191 (0.5%)	1	0/211 (0%)	0	0/161 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of skin	2/191 (1%)	2	0/211 (0%)	0	3/161 (1.9%)	3
Basal cell carcinoma	4/191 (2.1%)	4	0/211 (0%)	0	0/161 (0%)	0
Bowen's disease	3/191 (1.6%)	3	0/211 (0%)	0	1/161 (0.6%)	1
Skin and subcutaneous tissue disorders
Rosacea	1/191 (0.5%)	1	0/211 (0%)	0	0/161 (0%)	0

Limitations/Caveats

Early termination leading to small numbers of subjects analyzed

More Information

Certain Agreements

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

LEO Pharma acknowledges the investigator right to publish the entire results of the study, irrespective of outcome. LEO Pharma retains the right to have any publication submitted to LEO Pharma for review. Investigators must undertake not to submit any part of their individual data for publication without the prior consent of LEO Pharma.