Trial Outcomes & Findings for Efficacy and Safety of Ingenol Mebutate Gel for Actinic Keratosis Applied on Large Area on Face, Scalp or Chest (NCT NCT02361216)

NCT ID: NCT02361216

Last Updated: 2025-03-10

Results Overview

Complete resolution of actinic keratosis (AKclear100) at Week 8 is defined as 100% reduction from baseline in the number of clinically visible AKs

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 729 participants
• Primary outcome timeframe: 8 weeks
• Results posted on: 2025-03-10

Participant Flow

Subjects were followed for 8 weeks following the first application of investigational medicinal product (IMP) at Day 1 (3-day treatment period including an 8-week follow-up period) and for an additional 12 months following Week 8 (extended 12-month follow-up period).

Participant milestones

Measure	Ingenol Mebutate Gel Treatment once daily for 3 days Ingenol mebutate gel 0.027% or vehicle gel was applied on either the full face, full balding scalp, or within a contiguous area of approximately 250 cm2 on the chest.	Vehicle Gel Treatment once daily for 3 days Vehicle: Vehicle gel
3 Day Treatment and 8 Week Follow/up STARTED	552	177
3 Day Treatment and 8 Week Follow/up COMPLETED	541	158
3 Day Treatment and 8 Week Follow/up NOT COMPLETED	11	19
12-month Follow-up STARTED	541	157
12-month Follow-up COMPLETED	489	130
12-month Follow-up NOT COMPLETED	52	27

Reasons for withdrawal

Measure	Ingenol Mebutate Gel Treatment once daily for 3 days Ingenol mebutate gel 0.027% or vehicle gel was applied on either the full face, full balding scalp, or within a contiguous area of approximately 250 cm2 on the chest.	Vehicle Gel Treatment once daily for 3 days Vehicle: Vehicle gel
3 Day Treatment and 8 Week Follow/up Lack of Efficacy	0	1
3 Day Treatment and 8 Week Follow/up Adverse Event	1	2
3 Day Treatment and 8 Week Follow/up Unacceptable Local Skin Reaction (LSR)	1	0
3 Day Treatment and 8 Week Follow/up Withdrawal by Subject	6	11
3 Day Treatment and 8 Week Follow/up Trial site closed	3	3
3 Day Treatment and 8 Week Follow/up Lost to Follow-up	0	2

Baseline Characteristics

Efficacy and Safety of Ingenol Mebutate Gel for Actinic Keratosis Applied on Large Area on Face, Scalp or Chest

Baseline characteristics by cohort

Measure	Ingenol Mebutate Gel n=552 Participants Treatment once daily for 3 days Ingenol Mebutate	Vehicle n=177 Participants Treatment once daily for 3 days Vehicle: Vehicle gel	Total n=729 Participants Total of all reporting groups
Age, Continuous	68 years n=5 Participants	69 years n=7 Participants	68 years n=5 Participants
Sex: Female, Male Female	149 Participants n=5 Participants	45 Participants n=7 Participants	194 Participants n=5 Participants
Sex: Female, Male Male	403 Participants n=5 Participants	132 Participants n=7 Participants	535 Participants n=5 Participants
Region of Enrollment United States	304 participants n=5 Participants	98 participants n=7 Participants	402 participants n=5 Participants
Region of Enrollment Canada	188 participants n=5 Participants	59 participants n=7 Participants	247 participants n=5 Participants
Region of Enrollment Australia	60 participants n=5 Participants	20 participants n=7 Participants	80 participants n=5 Participants

PRIMARY outcome

Timeframe: 8 weeks

Population: Of the 729 subjects randomised to treatment, 4 did not receive treatment. These 4 subjects (3 subjects in active treatment group and 1 in vehicle group) were excluded from the Full Analysis Set (FAS), which consisted of 725 subjects (549 subjects in active treatment group and 176 in corresponding vehicle group). AKclear100 is based on the FAS

Complete resolution of actinic keratosis (AKclear100) at Week 8 is defined as 100% reduction from baseline in the number of clinically visible AKs

Outcome measures

Measure	Ingenol Mebutate Gel n=549 Participants Treatment once daily for 3 days with ingenol mebutate with 8 week follow-up after initial treatment	Vehicle n=176 Participants Treatment once daily for 3 days vehicle gel with 8 week follow-up after initial treatment
Percentage of Participants With Complete Resolution of Actinic Keratosis (AK)	21.4 percentage of participants	3.4 percentage of participants

SECONDARY outcome

Timeframe: 8 weeks

Population: AKclear75 at Week 8 is based on the full analysis set (FAS)

Partial clearance (AKclear75 ) is defined as a reduction in the number of clinically visible AKs in the selected treatment area by at least 75% compared to baseline.

Outcome measures

Measure	Ingenol Mebutate Gel n=549 Participants Treatment once daily for 3 days with ingenol mebutate with 8 week follow-up after initial treatment	Vehicle n=176 Participants Treatment once daily for 3 days vehicle gel with 8 week follow-up after initial treatment
Percentage of Participants With Partial Clearance at Week 8	59.4 percentage of participants	8.9 percentage of participants

SECONDARY outcome

Timeframe: 4 weeks

Population: AKclear75 at Week 4 is based on the full analysis set (FAS)

Partial clearance (AKclear75) defined as a reduction in the number of clinically visible AKs in the selected treatment area by at least 75% compared to baseline.

Outcome measures

Measure	Ingenol Mebutate Gel n=549 Participants Treatment once daily for 3 days with ingenol mebutate with 8 week follow-up after initial treatment	Vehicle n=176 Participants Treatment once daily for 3 days vehicle gel with 8 week follow-up after initial treatment
Percentage of Participants With Partial Clearance at Week 4	59.8 percentage of participants	9.2 percentage of participants

SECONDARY outcome

Timeframe: 8 weeks

Population: Percent reduction in AK count is based on the full analysis set (FAS)

Percent reduction in AK count in the selected treatment area at Week 8

Outcome measures

Measure	Ingenol Mebutate Gel n=549 Participants Treatment once daily for 3 days with ingenol mebutate with 8 week follow-up after initial treatment	Vehicle n=176 Participants Treatment once daily for 3 days vehicle gel with 8 week follow-up after initial treatment
Percent Reduction From Baseline in AK Count	75.7 percentage reduction of AK count Interval 73.9 to 77.3	12.7 percentage reduction of AK count Interval 3.0 to 21.4

Adverse Events

Ingenol Mebutate Gel

Serious events: 8 serious events

Other events: 394 other events

Deaths: 0 deaths

Vehicle

Serious events: 2 serious events

Other events: 18 other events

Deaths: 0 deaths

Serious adverse events

Measure	Ingenol Mebutate Gel n=549 participants at risk Treatment once daily for 3 days Ingenol Mebutate	Vehicle n=176 participants at risk Treatment once daily for 3 days Vehicle: Vehicle gel
Cardiac disorders Myocardial Infarction	0.18% 1/549 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.	0.57% 1/176 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.
Cardiac disorders Bradycardia	0.18% 1/549 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.	0.00% 0/176 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.
Cardiac disorders Coronary Artery Occlusion	0.18% 1/549 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.	0.00% 0/176 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.
Injury, poisoning and procedural complications Sternal Fracture	0.18% 1/549 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.	0.57% 1/176 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.
Injury, poisoning and procedural complications Overdose	0.18% 1/549 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.	0.00% 0/176 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.
Gastrointestinal disorders Small Intestinal Obstruction	0.18% 1/549 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.	0.00% 0/176 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.
Musculoskeletal and connective tissue disorders Back Pain	0.18% 1/549 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.	0.00% 0/176 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lymphoma	0.18% 1/549 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.	0.00% 0/176 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.
Respiratory, thoracic and mediastinal disorders Haemothorax	0.18% 1/549 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.	0.00% 0/176 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.
Injury, poisoning and procedural complications Femur Fracture	0.00% 0/549 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.	0.57% 1/176 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.
Injury, poisoning and procedural complications Rib Fracture	0.00% 0/549 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.	0.57% 1/176 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.
Injury, poisoning and procedural complications Spinal Fracture	0.00% 0/549 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.	0.57% 1/176 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.

Other adverse events

Measure	Ingenol Mebutate Gel n=549 participants at risk Treatment once daily for 3 days Ingenol Mebutate	Vehicle n=176 participants at risk Treatment once daily for 3 days Vehicle: Vehicle gel
General disorders Application Site Pain	63.8% 350/549 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.	2.3% 4/176 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.
General disorders Application Site Pruritus	37.0% 203/549 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.	4.0% 7/176 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.
General disorders Application Site Discomfort	5.1% 28/549 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.	1.1% 2/176 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.
General disorders application site parasthesia	2.6% 14/549 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.	1.1% 2/176 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.
Nervous system disorders headache	4.0% 22/549 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.	2.3% 4/176 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.
Eye disorders eyelid oedema	2.6% 14/549 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.	0.00% 0/176 • 14 Months A total of 729 subjects were randomised to treatment, of whom 4 did not receive treatment with IMP. These 4 subjects (3 subjects from the active treatment group and 1 from the corresponding vehicle group) were excluded from the Full Analysis Set, which consisted of 725 subjects (549 subjects in the active treatment group and 176 in the corresponding vehicle group). The Safety Analysis Set was the same as the Full Analysis Set.

Additional Information

Clinical Trial Disclosure Manager

LEO Pharma A/S

Email: disclosure@leo-pharma.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place