Actinic Keratosis
Conditions
Brief 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.
Interventions
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%
Sponsors
LEO Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Complete Clearance of AKs 8 Weeks After Randomisation | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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) |
| The Change in AK Count From Randomisation to 8 Weeks After Randomisation | 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 |
Countries
Australia, Canada, France, Germany, United Kingdom
Participant flow
Recruitment details
First Subject First Visit: 04-Jun-2012 Last Subject Last Visit: 05-Feb-2014
Pre-assignment details
A total of 463 subjects were enrolled, 13 of whom were screening failures. 450 subjects were allocated to open label treatment with ingenol mebutate gel (1st cycle) and subsequently administered a 2nd cycle in a randomised vehicle controlled setting, if eligible for repeat use
Participants by arm
| Arm | Count |
|---|---|
| Ingenol Mebutate 0.015% Gel (1.& 2. Cycle) Open label topical field treatment once daily for 3 consecutive days with ingenol mebutate 0.015% gel (1st cycle) within a 25 cm\^2 treatment area on the face or scalp, followed by observation and/or controlled repeat use (2nd cycle) treatment of recalcitrant or recurrent AK lesions | 450 |
| Total | 450 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 1. Cycle & Observation Period D1 to W52 | Adverse Event | 6 | 0 |
| 1. Cycle & Observation Period D1 to W52 | Exclusion Criteria Emerging during Study | 14 | 0 |
| 1. Cycle & Observation Period D1 to W52 | Included in 2nd cycle | 203 | 0 |
| 1. Cycle & Observation Period D1 to W52 | Lost to Follow-up | 8 | 0 |
| 1. Cycle & Observation Period D1 to W52 | Other | 27 | 0 |
| 1. Cycle & Observation Period D1 to W52 | Protocol Violation | 6 | 0 |
| 1. Cycle & Observation Period D1 to W52 | Withdrawal by Subject | 24 | 0 |
| 2. Cycle Recalcitrant Subgroup W8 to W52 | Death | 1 | 2 |
| 2. Cycle Recalcitrant Subgroup W8 to W52 | Exclusion Criteria Emerging during Study | 1 | 1 |
| 2. Cycle Recalcitrant Subgroup W8 to W52 | Lack of Efficacy | 1 | 0 |
| 2. Cycle Recalcitrant Subgroup W8 to W52 | Lost to Follow-up | 1 | 3 |
| 2. Cycle Recalcitrant Subgroup W8 to W52 | Other | 1 | 3 |
| 2. Cycle Recalcitrant Subgroup W8 to W52 | Protocol Violation | 5 | 0 |
| 2. Cycle Recalcitrant Subgroup W8 to W52 | Withdrawal by Subject | 2 | 1 |
| 2. Cycl Recurrent Subgroup W26/44 to W52 | Adverse Event | 1 | 0 |
| 2. Cycl Recurrent Subgroup W26/44 to W52 | Lost to Follow-up | 1 | 0 |
| 2. Cycl Recurrent Subgroup W26/44 to W52 | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Ingenol Mebutate 0.015% Gel (1.& 2. Cycle) |
|---|---|
| Age, Continuous | 71.7 years STANDARD_DEVIATION 8.7 |
| Sex: Female, Male Female | 53 Participants |
| Sex: Female, Male Male | 397 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 197 / 450 | 61 / 134 | 19 / 69 |
| serious Total, serious adverse events | 7 / 450 | 1 / 134 | 3 / 69 |
Outcome results
Primary
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ingenol Mebutate Gel, 0.015% Field Recalcitrant Subgroup | Number of Participants With Complete Clearance of AKs 8 Weeks After Randomisation | 43 participants |
| Vehicle Gel Field Recalcitrant Subgroup | Number of Participants With Complete Clearance of AKs 8 Weeks After Randomisation | 9 participants |
| Ingenol Mebutate Gel 0.015% Field Recurrent Subgroup | Number of Participants With Complete Clearance of AKs 8 Weeks After Randomisation | 25 participants |
| Vehicle Gel Field Recurrent Subgroup | Number of Participants With Complete Clearance of AKs 8 Weeks After Randomisation | 5 participants |
Comparison: The analysis type was superiority between groups. In total 141 subjects were includedp-value: 0.00195% CI: [1.32, 4.51]Cochran-Mantel-Haenszel
Comparison: The analysis type was superiority between groups. In total 62 subjects were includedp-value: 0.01395% CI: [1.07, 5.25]Cochran-Mantel-Haenszel
Secondary
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ingenol Mebutate Gel, 0.015% Field Recalcitrant 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 12 | 124 participants |
| Vehicle Gel Field Recalcitrant 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 12 | 17 participants |
| Ingenol Mebutate Gel 0.015% 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 12 | 2 participants |
| Vehicle 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 12 | 13 participants |
| Vehicle 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 12 | 3 participants |
Comparison: The analysis type was superiority between groups. In total 141 subjects were includedp-value: 0.01695% CI: [1.1, 17.62]Cochran-Mantel-Haenszel
Comparison: The analysis type was superiority between groups. In total 62 subjects were includedp-value: 0.195% CI: [0.78, 6.47]Cochran-Mantel-Haenszel
Comparison: Subjects randomised to vehicle were not included in the estimate of the overall clearance rate for the repeat-use regimen, from last treatment throught to Month 12. Instead, the subjects randomised to ingenol mebutate were given higher weights to reflect the hypothetical scenario where all randomised subjects were given active treatment during the repeat use cycle95% CI: [44, 56.1]
Secondary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ingenol Mebutate Gel, 0.015% Field Recalcitrant Subgroup | The Change in AK Count From Randomisation to 8 Weeks After Randomisation | -1.41 AK count | Standard Deviation 1.49 |
| Vehicle Gel Field Recalcitrant Subgroup | The Change in AK Count From Randomisation to 8 Weeks After Randomisation | -0.51 AK count | Standard Deviation 1.65 |
| Ingenol Mebutate Gel 0.015% Field Recurrent Subgroup | The Change in AK Count From Randomisation to 8 Weeks After Randomisation | -1.52 AK count | Standard Deviation 1.49 |
| Vehicle Gel Field Recurrent Subgroup | The Change in AK Count From Randomisation to 8 Weeks After Randomisation | -0.85 AK count | Standard Deviation 0.99 |
Comparison: The analysis type was superiority between groups. In total 141 subjects were includedp-value: <0.00195% CI: [-1.38, -0.38]ANCOVA
Comparison: The analysis type was superiority between groups. In total 141 subjects were includedp-value: <0.00195% CI: [-1.52, -0.51]ANCOVA
Comparison: The analysis type was superiority between groups. In total 62 subjects were includedp-value: 0.00895% CI: [-1.19, -0.19]ANCOVA