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CompletedNCT01600014Updated Mar 10, 2025Results posted

Ingenol Mebutate Gel, 0.015% Repeat Use for Multiple Actinic Keratoses on Face and Scalp

A Phase 3 interventional study of Ingenol mebutate gel, 0.015% and Vehicle gel in Actinic Keratosis, sponsored by LEO Pharma. Completed at 13 sites in 5 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-03-10.

Sponsored by LEO Pharma · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
463
Allocation
Randomized
Ages
18 Years and older
Sex
All
01

Study summary

The purpose of the study is to demonstrate that ingenol mebutate gel is efficacious in treating Actinic Keratoses (AKs) present 8 weeks after initial field treatment or emerging in a previously cleared field.

02

Conditions studied

  • Actinic Keratosis
03

In context

Keratosis, Actinic

364 studies on the registry are indexed under Keratosis, Actinic; 31 are open to participants now.

This study's enrollment of 463 is above the median of 60 across 315 interventional studies indexed under Keratosis, Actinic.

Browse Keratosis, Actinic studies →

Lead sponsor

LEO Pharma is the lead sponsor of 221 studies on the registry; 5 are open to participants now.

Of its 31 completed or terminated interventional studies of FDA-regulated products, 24 (77%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  • Subjects must provide informed consent
  • Subjects with 4 to 8 clinically typical, visible and discrete AKs within a contiguous 25 cm2 treatment area on the face or scalp
  • Subject at least 18 years of age

  • Female subjects must be of either:

    • Non-childbearing potential, i.e. post-menopausal or have a confirmed clinical history of sterility (e.g. the subject is without a uterus) or,
    • Childbearing potential, provided there is a confirmed negative urine pregnancy test prior to study treatment, to rule out pregnancy
  • Female subjects of childbearing potential must be willing to consent to using highly effective methods of contraception

Exclusion criteria

Exclusion Criteria:

  • Location of the selected treatment area:

    • on any location other than the face or scalp
    • on the periorbital skin
    • within 5 cm of an incompletely healed wound
    • within 10 cm of a suspected basal cell carcinoma (BCC) or squamous cell carcinoma (SCC)
  • Prior treatment with ingenol mebutate gel on face or scalp (previous treatment on trunk and extremities acceptable)
  • Selected treatment area lesions that have atypical clinical appearance
  • History or evidence of skin conditions other than the trial indication that would interfere with evaluation of the trial medication in the selected treatment area
  • Anticipated need for hospitalization or out-patient surgery prior to Day 15 in the first treatment cycle
  • Known sensitivity or allergy to any of the ingredients in ingenol mebutate gel
  • Presence of sunburn within the selected treatment area
  • Current enrollment or participation in a clinical trial within 30 days of entry into this study
  • Subjects previously entered first treatment in the trial
  • Female subjects who are breastfeeding
  • Subjects who are institutionalised by court order or by the local authority
  • In the opinion of the investigator, the subject is unlikely to comply with the Clinical Study Protocol

Prohibited Therapies and/or Medications within 2 weeks prior to Day 1

  • Cosmetic or therapeutic procedures within 2 cm of the selected treatment area
  • Use of keratolytic topical therapeutic products within 2 cm of the selected treatment area
  • Use of topical medicated creams, ointments, lotions gels, foams or sprays within 2 cm of the selected treatment area; artificial tanners: within 5 cm of the selected treatment area

Prohibited Therapies and/or Medications: within 4 weeks prior to Day 1

  • Treatment with immunomodulators, cytotoxic drugs or interferon /interferon inducers
  • Treatment with systemic medications that suppress the immune system
  • Treatment/therapy with ultraviolet light A (UVA) or ultraviolet light B (UVB)

Prohibited Therapies and/or Medications within 8 weeks prior to Day 1

  • Treatment with 5-fluorouracil (5-FU), imiquimod, diclofenac sodium, or photodynamic therapy: within 2 cm of the selected treatment area

Prohibited Therapies and/or Medications within 6 months prior to Day 1

  • Use of systemic retinoids or biologic/monoclonal antibody therapies
05

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Double (Participant, Investigator)
Enrollment
463 participants (actual)

Study arms

  • Active comparator
    Ingenol mebutate gel, 0.015%

    Topical field treatment once daily for 3 consecutive days on the face or scalp

    Drug: Ingenol mebutate gel, 0.015%

  • Placebo comparator
    Vehicle gel

    Topical field treatment once daily for 3 consecutive days on the face or scalp

    Drug: Vehicle gel

Interventions

  • DrugIngenol mebutate gel, 0.015%

    Topical field treatment once daily for 3 consecutive days within a 25 cm2 treatment area on the face or scalp of AKs present or emerging after an initial treatment with ingenol mebutate gel, 0.015%

  • DrugVehicle gel

    Topical field treatment once daily for 3 consecutive days within a 25 cm2 treatment area on the face or scalp of AKs present or emerging after an initial treatment with ingenol mebutate gel, 0.015%

06

What researchers measure

Primary outcomes

  1. Number of Participants With Complete Clearance of AKs 8 Weeks After Randomisation

    The complete clearance rates 8 weeks after randomisation was compared between ingenol mebutate gel, 0.015% and vehicle gel. Complete clearance was defined as no clinically visible AKs in the Selected Treatment Area (STA)

    Time frame: 8 weeks after randomisation

Secondary outcomes

  1. Number of Participants With Complete Clearance Through to Month 12, Defined as no Clinically Visible AKs and no Lesions Treated in the Selected Treatment Area at Any Time From Last Treatment Cycle Through to Month 12

    The analysis was done separately for the field recalcitrant subgroup, the field recurrent subgroup, and overall for all treated subject (Analysis 1, 2, and 3, respectively)

    Time frame: From last treatment cycle through to Month 12

  2. The Change in AK Count From Randomisation to 8 Weeks After Randomisation

    The change in AK count from randomisation to 8 weeks after randomisation was determined for the field recalcitrant and the field recurrent subgroups

    Time frame: 8 weeks after randomisation

07

Results

Posted May 9, 2016

Participant flow

First Subject First Visit: 04-Jun-2012 Last Subject Last Visit: 05-Feb-2014

1. Cycle & Observation Period D1 to W52
Participant flow — 1. Cycle & Observation Period D1 to W52
MilestoneIngenol Mebutate Gel, 0.015% (1st & 2nd Cycle)Vehicle Gel (2nd Cycle)
Started4500
Completed1620
Not completed2880
Withdrew: Withdrawal by subject240
Withdrew: Included in 2nd cycle2030
Withdrew: Adverse event60
Withdrew: Other270
Withdrew: Exclusion criteria emerging during study140
Withdrew: Protocol violation60
Withdrew: Lost to follow-up80
2. Cycle Recalcitrant Subgroup W8 to W52
Participant flow — 2. Cycle Recalcitrant Subgroup W8 to W52
MilestoneIngenol Mebutate Gel, 0.015% (1st & 2nd Cycle)Vehicle Gel (2nd Cycle)
Started9249
Completed8039
Not completed1210
Withdrew: Death12
Withdrew: Other13
Withdrew: Withdrawal by subject21
Withdrew: Lack of efficacy10
Withdrew: Protocol violation50
Withdrew: Exclusion criteria emerging during study11
Withdrew: Lost to follow-up13
2. Cycl Recurrent Subgroup W26/44 to W52
Participant flow — 2. Cycl Recurrent Subgroup W26/44 to W52
MilestoneIngenol Mebutate Gel, 0.015% (1st & 2nd Cycle)Vehicle Gel (2nd Cycle)
Started4220
Completed3920
Not completed30
Withdrew: Adverse event10
Withdrew: Withdrawal by subject10
Withdrew: Lost to follow-up10

Outcome measures

PrimaryNumber of Participants With Complete Clearance of AKs 8 Weeks After Randomisation

The complete clearance rates 8 weeks after randomisation was compared between ingenol mebutate gel, 0.015% and vehicle gel. Complete clearance was defined as no clinically visible AKs in the Selected Treatment Area (STA)

Time frame:
8 weeks after randomisation
Reported as:
Number · participants
Number of Participants With Complete Clearance of AKs 8 Weeks After Randomisation
participantsIngenol Mebutate Gel, 0.015% Field Recalcitrant SubgroupVehicle Gel Field Recalcitrant SubgroupIngenol Mebutate Gel 0.015% Field Recurrent SubgroupVehicle Gel Field Recurrent Subgroup
Number of Participants With Complete Clearance of AKs 8 Weeks After Randomisation439255
Statistical analysis
  • Ingenol Mebutate Gel, 0.015% Field Recalcitrant Subgroup vs Vehicle Gel Field Recalcitrant Subgroup · Cochran-Mantel-Haenszel · p = 0.001 (Chi-square test for stratified data with a significance level of 5%. No adjustment for multiple tests was needed, due to the analyses were based on distinct subject groups) · Risk ratio (rr): 2.44 · 95% CI 1.32 to 4.51Cochran-Mantel-Haenszel ratio of clearance rates (Ingenol mebutate relative to Vehicle) adjusted for anatomical location and country
  • Ingenol Mebutate Gel 0.015% Field Recurrent Subgroup vs Vehicle Gel Field Recurrent Subgroup · Cochran-Mantel-Haenszel · p = 0.013 (Chi-square test for stratified data with a significance level of 5%. No adjustment for multiple tests was needed, due to the analyses were based on distinct subject groups) · Risk ratio (rr): 2.37 · 95% CI 1.07 to 5.25Cochran-Mantel-Haenszel ratio of clearance rates (Ingenol mebutate relative to Vehicle) adjusted for anatomical location and week of randomisation
SecondaryNumber of Participants With Complete Clearance Through to Month 12, Defined as no Clinically Visible AKs and no Lesions Treated in the Selected Treatment Area at Any Time From Last Treatment Cycle Through to Month 12

The analysis was done separately for the field recalcitrant subgroup, the field recurrent subgroup, and overall for all treated subject (Analysis 1, 2, and 3, respectively)

Time frame:
From last treatment cycle through to Month 12
Reported as:
Number · participants
Number of Participants With Complete Clearance Through to Month 12, Defined as no Clinically Visible AKs and no Lesions Treated in the Selected Treatment Area at Any Time From Last Treatment Cycle Through to Month 12
participantsOpen Label Only (1st Cycle)Ingenol Mebutate Gel, 0.015% Field Recalcitrant SubgroupVehicle Gel Field Recalcitrant SubgroupIngenol Mebutate Gel 0.015% Field Recurrent SubgroupVehicle Gel Field Recurrent Subgroup
Number of Participants With Complete Clearance Through to Month 12, Defined as no Clinically Visible AKs and no Lesions Treated in the Selected Treatment Area at Any Time From Last Treatment Cycle Through to Month 12124172133
Statistical analysis
  • Ingenol Mebutate Gel, 0.015% Field Recalcitrant Subgroup vs Vehicle Gel Field Recalcitrant Subgroup · Cochran-Mantel-Haenszel · p = 0.016 (A closed test procedure was chosen where the evaluation process stopped when the first non-significant results were observed thus securing that the overall significance level did not exceed 5% for multiple testing) · Risk ratio (rr): 4.41 · 95% CI 1.10 to 17.62Cochran-Mantel-Haenszel ratio of clearance rates (Ingenol mebutate relative to Vehicle) adjusted for anatomical location and country
  • Ingenol Mebutate Gel 0.015% Field Recurrent Subgroup vs Vehicle Gel Field Recurrent Subgroup · Cochran-Mantel-Haenszel · p = 0.10 (A closed test procedure was chosen where the evaluation process stopped when the first non-significant results were observed thus securing that the overall significance level did not exceed 5% for multiple testing) · Risk ratio (rr): 2.24 · 95% CI 0.78 to 6.47Cochran-Mantel-Haenszel ratio of clearance rates (Ingenol mebutate relative to Vehicle) adjusted for anatomical location and country
  • Open Label Only (1st Cycle) vs Ingenol Mebutate Gel, 0.015% Field Recalcitrant Subgroup vs Ingenol Mebutate Gel 0.015% Field Recurrent Subgroup · Percent cleared subjects: 50.0 · 95% CI 44.0 to 56.1Estimation based on completers only.
SecondaryThe Change in AK Count From Randomisation to 8 Weeks After Randomisation

The change in AK count from randomisation to 8 weeks after randomisation was determined for the field recalcitrant and the field recurrent subgroups

Time frame:
8 weeks after randomisation
Reported as:
Mean · AK count
The Change in AK Count From Randomisation to 8 Weeks After Randomisation
AK countIngenol Mebutate Gel, 0.015% Field Recalcitrant SubgroupVehicle Gel Field Recalcitrant SubgroupIngenol Mebutate Gel 0.015% Field Recurrent SubgroupVehicle Gel Field Recurrent Subgroup
The Change in AK Count From Randomisation to 8 Weeks After Randomisation-1.41 ± 1.49-0.51 ± 1.65-1.52 ± 1.49-0.85 ± 0.99
Statistical analysis
  • Ingenol Mebutate Gel, 0.015% Field Recalcitrant Subgroup vs Vehicle Gel Field Recalcitrant Subgroup · ANCOVA · p = <0.001 (A closed test procedure was chosen where the evaluation process stopped when the first non-significant results were observed thus securing that the overall significance level did not exceed 5% for multiple testing) · Mean difference (net): -0.88 · 95% CI -1.38 to -0.38Using baseline observation carried forward (BOCF) as the imputation method.
  • Ingenol Mebutate Gel, 0.015% Field Recalcitrant Subgroup vs Vehicle Gel Field Recalcitrant Subgroup · ANCOVA · p = <0.001 (A closed test procedure was chosen where the evaluation process stopped when the first non-significant results were observed thus securing that the overall significance level did not exceed 5% for multiple testing) · Mean difference (net): -1.01 · 95% CI -1.52 to -0.51Sensitivity analysis using complete cases
  • Ingenol Mebutate Gel 0.015% Field Recurrent Subgroup vs Vehicle Gel Field Recurrent Subgroup · ANCOVA · p = 0.008 (Formal statistical significance could not be established because of the closed test procedure where the first secondary endpoint tested (12 months clearance) did not reach statistical significance in the recurrent subgroup) · Mean difference (net): -0.69 · 95% CI -1.19 to -0.19Using BOCF as the imputation method, the difference in the adjusted mean AK count between the ingenol mebutate and vehicle groups

Adverse events

Collected over 8-week treatment periods (1st or 2nd cycle). Non-serious events are listed at a 2% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Ingenol Mebutate 0.015% Gel (1. Cycle)—7/450 (1.6%)197/450 (43.8%)
Ingenol Mebutate 0.015% Gel (2. Cycle)—1/134 (0.7%)61/134 (45.5%)
Vehicle Gel (2. Cycle)—3/69 (4.3%)19/69 (27.5%)
Most frequent serious events
Showing 10 of 11
Most frequent serious events
EventIngenol Mebutate 0.015% Gel (1. Cycle)Ingenol Mebutate 0.015% Gel (2. Cycle)Vehicle Gel (2. Cycle)
Squamous cell carcinoma of skinNeoplasms benign, malignant and unspecified (incl cysts and polyps)0/4500/1341/69
Bowen's diseaseNeoplasms benign, malignant and unspecified (incl cysts and polyps)0/4500/1341/69
ProstatismReproductive system and breast disorders0/4500/1341/69
ArthralgiaMusculoskeletal and connective tissue disorders0/4501/1340/69
Basal cell carcinomaNeoplasms benign, malignant and unspecified (incl cysts and polyps)1/4500/1340/69
Squamous cell carcinomaNeoplasms benign, malignant and unspecified (incl cysts and polyps)1/4500/1340/69
KeratoacanthomaNeoplasms benign, malignant and unspecified (incl cysts and polyps)1/4500/1340/69
Prostate cancerNeoplasms benign, malignant and unspecified (incl cysts and polyps)1/4500/1340/69
Myocardial infarctionCardiac disorders1/4500/1340/69
Lung disorderRespiratory, thoracic and mediastinal disorders1/4500/1340/69
Most frequent other events
Showing 10 of 12
Most frequent other events
EventIngenol Mebutate 0.015% Gel (1. Cycle)Ingenol Mebutate 0.015% Gel (2. Cycle)Vehicle Gel (2. Cycle)
Actinic keratosisSkin and subcutaneous tissue disorders43/45021/1343/69
Application site painGeneral disorders62/45015/1340/69
Basal cell carcinomaNeoplasms benign, malignant and unspecified (incl cysts and polyps)19/4505/1346/69
Squamous cell carcinoma of skinNeoplasms benign, malignant and unspecified (incl cysts and polyps)0/4504/1344/69
Application site pruritusGeneral disorders20/4507/1341/69
HeadacheNervous system disorders21/4500/1342/69
Eyelid oedemaEye disorders17/4500/1340/69
Periorbital oedemaEye disorders15/4500/1340/69
Oral herpesInfections and infestations0/4500/1342/69
Bowen's diseaseNeoplasms benign, malignant and unspecified (incl cysts and polyps)0/4503/1340/69

Baseline characteristics

Age, Continuous
Age, Continuous(years)Ingenol Mebutate 0.015% Gel (1.& 2. Cycle)
Mean71.7 ± 8.7
Sex: Female, Male
Sex: Female, Male(Participants)Ingenol Mebutate 0.015% Gel (1.& 2. Cycle)
Female53
Male397
08

Study locations

13 sites
  • St John of God Dermatology
    Subiaco, 6008, Australia
  • Stratica Medical
    Edmonton, Alberta T5K 1X3, Canada
  • Skin Care Centre
    Vancouver, British Columbia V5Z 4E8, Canada
  • Dermadvances Research
    Winnipeg, Manitoba R3C 1R4, Canada
  • Durondel C.P. Inc./Dermatology Clinic
    Moncton, New Brunswick E1C 8X3, Canada
  • UltraNova Skincare
    Barrie, Ontario L4M 6L2, Canada
  • SKiN Centre for Dermatology
    Peterborough, Ontario K9J 1Z2, Canada
  • Windsor Clinical Research Inc.
    Windsor, Ontario N8W 5L7, Canada
  • Innovaderm Research Inc.
    Montreal, Quebec H2K 4L5, Canada
  • Centre de Recherche Dermatologique
    Quebec, G1V 4X7, Canada
  • CHU de Nantes
    Nantes, Loire-Atlantique 6 44000, France
  • Universitätsklinikum Tübingen
    Tübingen, 72076, Germany
  • Central Manchester University Hosptial
    Manchester, Greater Manchester M13 9WL, United Kingdom
09

References and documents

Individual participant data

Plan to share: No

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Mar 10, 2025, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT01600014
Lead sponsor
LEO Pharma
Responsible party
Sponsor
First posted
May 16, 2012
Start date
May 2012
Primary completion
Feb 2014
Completion
Feb 2014
Results posted
May 9, 2016
Last update
Mar 10, 2025

Study contacts

Claus Garbe, MD
principal investigator · University Hospital Tuebingen

Oversight

Data monitoring committee
No
View the source record on ClinicalTrials.gov ↗

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