Actinic Keratosis
Conditions
Brief summary
The objective of the trial is to investigate efficacy and safety of ingenol mebutate gel for actinic keratosis applied to large treatment areas once daily for three consecutive days on face, scalp or chest.
Interventions
DRUGIngenol Mebutate
OTHERVehicle
Vehicle gel
Sponsors
LEO Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
Subjects with 5 to 20 clinically typical, visible and discrete, actinic keratosis (AKs) non-hyperkeratotic and non-hypertrophic AKs within a selected treatment area of sun-damaged skin on either: * The full face * The full balding scalp * A contiguous area of approximately 250 cm2 on the chest
Exclusion criteria
* Location of the treatment area (full face, full balding scalp or chest) within 5 cm of an incompletely healed wound or within 5 cm of a suspected basal cell carcinoma (BCC) or squamous cell carcinoma (SCC). * Previously assigned treatment in this clinical trial or previously participated in a clinical trial in the LEO clinical programme on ingenol mebutate gel for larger treatment areas. * Treatment with ingenol mebutate gel in the selected treatment area within the last 12 months. * Lesions in the treatment area that have: atypical clinical appearance (e.g. cutaneous horn) and/or, recalcitrant disease (e.g., did not respond to cryotherapy on two previous occasions).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Complete Resolution of Actinic Keratosis (AK) | 8 weeks | Complete resolution of actinic keratosis (AKclear100) at Week 8 is defined as 100% reduction from baseline in the number of clinically visible AKs |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Partial Clearance at Week 8 | 8 weeks | 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. |
| Percentage of Participants With Partial Clearance at Week 4 | 4 weeks | 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. |
| Percent Reduction From Baseline in AK Count | 8 weeks | Percent reduction in AK count in the selected treatment area at Week 8 |
Countries
United States
Participant flow
Recruitment details
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).
Participants by arm
| Arm | Count |
|---|---|
| Ingenol Mebutate Gel Treatment once daily for 3 days
Ingenol Mebutate | 552 |
| Vehicle Treatment once daily for 3 days
Vehicle: Vehicle gel | 177 |
| Total | 729 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 3 Day Treatment and 8 Week Follow/up | Adverse Event | 1 | 2 |
| 3 Day Treatment and 8 Week Follow/up | Lack of Efficacy | 0 | 1 |
| 3 Day Treatment and 8 Week Follow/up | Lost to Follow-up | 0 | 2 |
| 3 Day Treatment and 8 Week Follow/up | Trial site closed | 3 | 3 |
| 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 |
Baseline characteristics
| Characteristic | Ingenol Mebutate Gel | Vehicle | Total |
|---|---|---|---|
| Age, Continuous | 68 years | 69 years | 68 years |
| Region of Enrollment Australia | 60 participants | 20 participants | 80 participants |
| Region of Enrollment Canada | 188 participants | 59 participants | 247 participants |
| Region of Enrollment United States | 304 participants | 98 participants | 402 participants |
| Sex: Female, Male Female | 149 Participants | 45 Participants | 194 Participants |
| Sex: Female, Male Male | 403 Participants | 132 Participants | 535 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 549 | 0 / 176 |
| other Total, other adverse events | 394 / 549 | 18 / 176 |
| serious Total, serious adverse events | 8 / 549 | 2 / 176 |
Outcome results
Primary
Percentage of Participants With Complete Resolution of Actinic Keratosis (AK)
Complete resolution of actinic keratosis (AKclear100) at Week 8 is defined as 100% reduction from baseline in the number of clinically visible AKs
Time frame: 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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ingenol Mebutate Gel | Percentage of Participants With Complete Resolution of Actinic Keratosis (AK) | 21.4 percentage of participants |
| Vehicle | Percentage of Participants With Complete Resolution of Actinic Keratosis (AK) | 3.4 percentage of participants |
Comparison: AKclear100 at Week 8: full analysis set. The null hypothesis was that there is no difference at Week 8 in AKclear100 rates between ingenol mebutate gel 0.027% and vehicle gel. This hypothesis was tested against the 2-sided alternative of a difference between the 2 treatment groups.p-value: <0.00195% CI: [2.82, 14]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Partial Clearance at Week 4
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.
Time frame: 4 weeks
Population: AKclear75 at Week 4 is based on the full analysis set (FAS)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ingenol Mebutate Gel | Percentage of Participants With Partial Clearance at Week 4 | 59.8 percentage of participants |
| Vehicle | Percentage of Participants With Partial Clearance at Week 4 | 9.2 percentage of participants |
Comparison: The p-values for secondary endpoints have been corrected by the Holm-Bonferroni method to account for multiplicity. The pre-specified multiplicity adjustment by the Holm-Bonferroni method requires the ordering of the p-values for the secondary endpoints by size.p-value: <0.00195% CI: [4.04, 10.5]Mantel Haenszel
Secondary
Percentage of Participants With Partial Clearance at Week 8
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.
Time frame: 8 weeks
Population: AKclear75 at Week 8 is based on the full analysis set (FAS)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ingenol Mebutate Gel | Percentage of Participants With Partial Clearance at Week 8 | 59.4 percentage of participants |
| Vehicle | Percentage of Participants With Partial Clearance at Week 8 | 8.9 percentage of participants |
Comparison: The p-values for secondary endpoints have been corrected by the Holm-Bonferroni method to account for multiplicity. The prespecified multiplicity adjustment by the Holm-Bonferroni method requires the ordering of the p-values for the secondary endpoints by size.p-value: <0.00195% CI: [4.16, 11.1]Cochran-Mantel-Haenszel
Secondary
Percent Reduction From Baseline in AK Count
Percent reduction in AK count in the selected treatment area at Week 8
Time frame: 8 weeks
Population: Percent reduction in AK count is based on the full analysis set (FAS)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ingenol Mebutate Gel | Percent Reduction From Baseline in AK Count | 75.7 percentage reduction of AK count |
| Vehicle | Percent Reduction From Baseline in AK Count | 12.7 percentage reduction of AK count |
Comparison: The p-values for secondary endpoints have been corrected by the Holm-Bonferroni method to account for multiplicity. The prespecified multiplicity adjustment by the Holm-Bonferroni method requires the ordering of the p-values for the secondary endpoints by size.p-value: <0.00195% CI: [0.24, 0.32]Cochran-Mantel-Haenszel