Actinic Keratosis
Conditions
Brief summary
To identify the Maximum Tolerated Dose levels of ingenol mebutate gel after once daily treatment for 2 or 3 consecutive days and to evaluate efficacy of ingenol mebutate gel in different doses after once daily treatment for 2 or 3 consecutive days compared to vehicle gel
Interventions
DRUGplacebo
Sponsors
LEO Pharma
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Masking only for Part 2
Intervention model description
Part 1 was an open-label, dose escalation. Part 2 was a randomised, double-blind, parallel group
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects must be competent to understand the nature of the trial and provide informed consent * Part 1: Subjects with 5 to 20 clinically typical, visible and discrete AKs on the face Part 2: Subjects with 5 to 20 clinically typical, visible and discrete AKs on either the face, the balding scalp (the balding part of the scalp should be at least 25 cm2) or a contiguous area of approximately 250 cm2 on the chest * Subject at least 18 years of age * Female subjects must be of either: 1. Non-childbearing potential, i.e. post-menopausal or have a confirmed clinical history of sterility (e.g. the subject is without a uterus) or, 2. Childbearing potential, provided there is a confirmed negative urine pregnancy test prior to trial treatment, to rule out pregnancy * Female subjects of childbearing potential1 must be willing to use effective contraception at trial entry and until completion
Exclusion criteria
* Location of the treatment area (full face, full balding scalp or chest) * 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 within the treatment area * Lesions in the treatment areas that have: * atypical clinical appearance (e.g., hypertrophic, hyperkeratotic or cutaneous horns) and/or, * recalcitrant disease (e.g., did not respond to cryotherapy on two previous occasions * History or evidence of skin conditions other than the trial indication that would interfere with the evaluation of the trial medication (e.g., eczema, unstable psoriasis, xeroderma pigmentosum) * Use of cosmetic or therapeutic products and procedures which could interfere with the assessments of the treatment areas. * Clinical diagnosis/history or evidence of any medical condition that would expose a subject to an undue risk of a significant AE or interfere with assessments of safety and efficacy during the course of the trial, as determined by the investigator's clinical judgment * Any abnormal laboratory tests that are medically significant and would impact the safety of the subjects or the interpretation of the trial results, as determined by the investigator's judgment * Anticipated need for hospitalisation or out-patient surgery during the first 15 days after the first trial medication application. Note that cosmetic/therapeutic procedures are not excluded if they fall outside of the criteria detailed in Prohibited Therapies or Medications * Known sensitivity or allergy to any of the ingredients in ingenol mebutate gel * Presence of acute sunburn within the treatment areas * Current enrolment or participation in an investigational clinical trial within 30 days of entry into this trial. * Subjects previously assigned to treatment in Part 1 or rand * Female subjects who are breastfeeding. * In the opinion of the investigator, the subject is unlikely to comply with the Clinical Study Protocol (e.g. alcoholism, drug dependency or psychotic state)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: To Identify the Maximum Tolerated Dose (MTD) Levels After Once Daily Treatment for 2 or 3 Days | 8 days after initial treatment | Dose tolerability was measures looking at the composite score of Local Skin Responses (LSR). The MTD was defined as the highest dose level with less than 4 subjects out of 12 experiencing dose limiting toxicity (DLT). DLT was defined as one or more of the following three local skin LSRs: * Crusting Grade 4 * Erosion/Ulceration Grade 4 * Vesiculation/Pustulation Grade 4 or two or more of the following five LSRs: * Erythema Grade 4 * Crusting Grade 3 * Swelling Grade 4 * Erosion/Ulceration Grade 3 * Vesiculation/Pustulation Grade 3 The grading is a scale of 1 to 4 (highest grade). |
| Part 2: Number of Subjects With Complete Clearance of AKs | 8 weeks | Number of subjects with complete clearance of Actinic Keratosis lesions (AKs) at week 8 after 2 or 3 consecutive days of treatment with ingenol mebutate gel on the full face, full balding scalp or approximately 250 cm² on the chest |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Reduction in AK Count | From baseline to Week 8 | Reduction in actinic keratosis lesion count from baseline to week 8 (percentage, adjusted for anatomical location and pooled site) |
| Part 2: Number of Subjects With Partial Clearance of AKs | Week 8 | Partial clearance of AKs at Week 8, defined as at least 75% reduction from baseline in the number of clinically visible AKs |
Countries
United States
Participant flow
Pre-assignment details
Part 1: There was 1 of the 82 subjects who withdrew before receiving any treatment but after collection of baseline characteristics. 81 subjects received treatment and all completed the trial. Part 2: There were 2 of the 315 randomized subjects who withdrew consent prior to any baseline characteristics being recorded (therefore they received no treatment) and are excluded from the total number of participants, full analysis set and safety analysis.
Participants by arm
| Arm | Count |
|---|---|
| Part 1A: Ingenol Mebutate Gel 0.005% Administration on full face, once daily for 3 days | 3 |
| Part 1A: Ingenol Mebutate Gel 0.008% Administration on full face, once daily for 3 days | 12 |
| Part 1A: Ingenol Mebutate Gel 0.012% Administration on full face, once daily for 3 days | 10 |
| Part 1A: Ingenol Mebutate Gel 0.018% Administration on full face, once daily for 3 days | 12 |
| Part 1A: Ingenol Mebutate Gel 0.027% Administration on full face, once daily for 3 days | 12 |
| Part 1A: Ingenol Mebutate Gel 0.04% Administration on full face, once daily for 3 days | 10 |
| Part 1B: Ingenol Mebutate Gel 0.04% Administration on full face, once daily for 2 days | 11 |
| Part 1B: Ingenol Mebutate Gel 0.06% Administration on full face, once daily for 2 days | 12 |
| Part 2: Ingenol Mebutate Gel 0.018% for 3 Days Treatment Administration on full face, full balding scalp, or approximately 250 cm² on the chest, once daily for 3 consecutive days
Ingenol mebutate gel 0.018% | 62 |
| Part 2: Ingenol Mebutate Gel 0.027% for 3 Days Treatment Administration on full face, full balding scalp, or approximately 250 cm² on the chest, once daily for 3 consecutive days
Ingenol mebutate gel 0.027% | 64 |
| Part 2: Ingenol Mebutate Gel 0.018% for 2 Days Treatment Administration on full face, full balding scalp, or approximately 250 cm² on the chest, once daily for 2 consecutive days
Ingenol mebutate gel 0.018% | 64 |
| Part 2: Ingenol Mebutate Gel 0.027% for 2 Days Treatment Administration on full face, full balding scalp, or approximately 250 cm² on the chest, once daily for 2 consecutive days
Ingenol mebutate gel 0.027% | 61 |
| Part 2: Vehicle Gel (Placebo)for 2 Days Treatment Vehicle gel administration on full face, full balding scalp, or approximately 250 cm² on the chest, once daily for 2 consecutive days
Vehicle gel (placebo) | 31 |
| Part 2: Vehicle Gel (Placebo) for 3 Days Treatment Vehicle gel administration on full face, full balding scalp, or approximately 250 cm² on the chest, once daily for 3 consecutive days
Vehicle gel (placebo) | 31 |
| Total | 395 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Phase 1 (Part 1) | Subject withdrew after randomization before treatment assignment | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Phase 2 (Part 2) | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Part 1A: Ingenol Mebutate Gel 0.005% | Part 1A: Ingenol Mebutate Gel 0.008% | Part 1A: Ingenol Mebutate Gel 0.012% | Part 1A: Ingenol Mebutate Gel 0.018% | Part 1A: Ingenol Mebutate Gel 0.027% | Part 1A: Ingenol Mebutate Gel 0.04% | Part 1B: Ingenol Mebutate Gel 0.04% | Part 1B: Ingenol Mebutate Gel 0.06% | Part 2: Ingenol Mebutate Gel 0.018% for 3 Days Treatment | Part 2: Ingenol Mebutate Gel 0.027% for 3 Days Treatment | Part 2: Ingenol Mebutate Gel 0.018% for 2 Days Treatment | Part 2: Ingenol Mebutate Gel 0.027% for 2 Days Treatment | Part 2: Vehicle Gel (Placebo)for 2 Days Treatment | Part 2: Vehicle Gel (Placebo) for 3 Days Treatment | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 75.3 years | 69.6 years | 68.7 years | 67.4 years | 69.7 years | 68.0 years | 67.5 years | 71.7 years | 68.0 years | 66.3 years | 66.9 years | 66.1 years | 68.4 years | 69.0 years | 68.0 years |
| Region of Enrollment United States | 3 participants | 12 participants | 10 participants | 12 participants | 12 participants | 10 participants | 11 participants | 12 participants | 62 participants | 64 participants | 64 participants | 61 participants | 31 participants | 31 participants | 395 participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 2 Participants | 1 Participants | 5 Participants | 20 Participants | 15 Participants | 8 Participants | 15 Participants | 3 Participants | 5 Participants | 79 Participants |
| Sex: Female, Male Male | 3 Participants | 11 Participants | 9 Participants | 10 Participants | 11 Participants | 8 Participants | 10 Participants | 7 Participants | 42 Participants | 49 Participants | 56 Participants | 46 Participants | 28 Participants | 26 Participants | 316 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 12 | 0 / 10 | 0 / 12 | 0 / 12 | 0 / 10 | 0 / 11 | 0 / 11 | 0 / 62 | 0 / 64 | 0 / 64 | 0 / 61 | 0 / 31 | 0 / 31 |
| other Total, other adverse events | 1 / 3 | 7 / 12 | 9 / 10 | 10 / 12 | 12 / 12 | 10 / 10 | 11 / 11 | 10 / 11 | 58 / 62 | 59 / 64 | 60 / 64 | 58 / 61 | 8 / 31 | 8 / 31 |
| serious Total, serious adverse events | 0 / 3 | 0 / 12 | 0 / 10 | 0 / 12 | 0 / 12 | 0 / 10 | 0 / 11 | 0 / 11 | 0 / 62 | 0 / 64 | 0 / 64 | 0 / 61 | 0 / 31 | 0 / 31 |
Outcome results
Primary
Part 1: To Identify the Maximum Tolerated Dose (MTD) Levels After Once Daily Treatment for 2 or 3 Days
Dose tolerability was measures looking at the composite score of Local Skin Responses (LSR). The MTD was defined as the highest dose level with less than 4 subjects out of 12 experiencing dose limiting toxicity (DLT). DLT was defined as one or more of the following three local skin LSRs: * Crusting Grade 4 * Erosion/Ulceration Grade 4 * Vesiculation/Pustulation Grade 4 or two or more of the following five LSRs: * Erythema Grade 4 * Crusting Grade 3 * Swelling Grade 4 * Erosion/Ulceration Grade 3 * Vesiculation/Pustulation Grade 3 The grading is a scale of 1 to 4 (highest grade).
Time frame: 8 days after initial treatment
Population: The composite (sum) score was obtained by summing the 6 individual LSRs
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1A: Ingenol Mebutate Gel 0.005% | Part 1: To Identify the Maximum Tolerated Dose (MTD) Levels After Once Daily Treatment for 2 or 3 Days | 0 Participants |
| Part 1A: Ingenol Mebutate Gel 0.008% | Part 1: To Identify the Maximum Tolerated Dose (MTD) Levels After Once Daily Treatment for 2 or 3 Days | 0 Participants |
| Part 1A: Ingenol Mebutate Gel 0.012% | Part 1: To Identify the Maximum Tolerated Dose (MTD) Levels After Once Daily Treatment for 2 or 3 Days | 0 Participants |
| Part 1A: Ingenol Mebutate Gel 0.018% | Part 1: To Identify the Maximum Tolerated Dose (MTD) Levels After Once Daily Treatment for 2 or 3 Days | 1 Participants |
| Part 1A: Ingenol Mebutate Gel 0.027% | Part 1: To Identify the Maximum Tolerated Dose (MTD) Levels After Once Daily Treatment for 2 or 3 Days | 1 Participants |
| Part 1A: Ingenol Mebutate Gel 0.04% | Part 1: To Identify the Maximum Tolerated Dose (MTD) Levels After Once Daily Treatment for 2 or 3 Days | 4 Participants |
| Part 1B: Ingenol Mebutate Gel 0.04% | Part 1: To Identify the Maximum Tolerated Dose (MTD) Levels After Once Daily Treatment for 2 or 3 Days | 1 Participants |
| Part 1B: Ingenol Mebutate Gel 0.06% | Part 1: To Identify the Maximum Tolerated Dose (MTD) Levels After Once Daily Treatment for 2 or 3 Days | 0 Participants |
Primary
Part 2: Number of Subjects With Complete Clearance of AKs
Number of subjects with complete clearance of Actinic Keratosis lesions (AKs) at week 8 after 2 or 3 consecutive days of treatment with ingenol mebutate gel on the full face, full balding scalp or approximately 250 cm² on the chest
Time frame: 8 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1A: Ingenol Mebutate Gel 0.005% | Part 2: Number of Subjects With Complete Clearance of AKs | 15 participants |
| Part 1A: Ingenol Mebutate Gel 0.008% | Part 2: Number of Subjects With Complete Clearance of AKs | 19 participants |
| Part 1A: Ingenol Mebutate Gel 0.012% | Part 2: Number of Subjects With Complete Clearance of AKs | 25 participants |
| Part 1A: Ingenol Mebutate Gel 0.018% | Part 2: Number of Subjects With Complete Clearance of AKs | 13 participants |
| Part 1A: Ingenol Mebutate Gel 0.027% | Part 2: Number of Subjects With Complete Clearance of AKs | 1 participants |
| Part 1A: Ingenol Mebutate Gel 0.04% | Part 2: Number of Subjects With Complete Clearance of AKs | 0 participants |
Comparison: Complete clearance of AKs at Week 8 was to be analysed by log binomial regression with factors treatment group, anatomical location (face/chest or scalp) and analysis site. Due to the low numbers of subjects obtaining complete clearance in the vehicle groups,the proposed model did not converge and Fisher's exact test was used instead to compare active treatments with the respective vehicle arm.p-value: 0.0002Fisher Exact
Comparison: See comment in analysis 1p-value: 0.0037Fisher Exact
Comparison: See comments in analysis 1p-value: 0.0171Fisher Exact
p-value: 0.0001Fisher Exact
Secondary
Part 2: Number of Subjects With Partial Clearance of AKs
Partial clearance of AKs at Week 8, defined as at least 75% reduction from baseline in the number of clinically visible AKs
Time frame: Week 8
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1A: Ingenol Mebutate Gel 0.005% | Part 2: Number of Subjects With Partial Clearance of AKs | 54.8 percentage of participants |
| Part 1A: Ingenol Mebutate Gel 0.008% | Part 2: Number of Subjects With Partial Clearance of AKs | 57.8 percentage of participants |
| Part 1A: Ingenol Mebutate Gel 0.012% | Part 2: Number of Subjects With Partial Clearance of AKs | 76.6 percentage of participants |
| Part 1A: Ingenol Mebutate Gel 0.018% | Part 2: Number of Subjects With Partial Clearance of AKs | 52.5 percentage of participants |
| Part 1A: Ingenol Mebutate Gel 0.027% | Part 2: Number of Subjects With Partial Clearance of AKs | 6.5 percentage of participants |
| Part 1A: Ingenol Mebutate Gel 0.04% | Part 2: Number of Subjects With Partial Clearance of AKs | 12.9 percentage of participants |
Comparison: Analysis of partial clearance of AK's at Week 8 was done in the same way as for the primary outcome (endpoint)p-value: <0.001Fisher Exact
p-value: <0.001Fisher Exact
p-value: <0.001Fisher Exact
p-value: <0.001Fisher Exact
Secondary
Part 2: Reduction in AK Count
Reduction in actinic keratosis lesion count from baseline to week 8 (percentage, adjusted for anatomical location and pooled site)
Time frame: From baseline to Week 8
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1A: Ingenol Mebutate Gel 0.005% | Part 2: Reduction in AK Count | 73.5 Percentage reduction |
| Part 1A: Ingenol Mebutate Gel 0.008% | Part 2: Reduction in AK Count | 70.5 Percentage reduction |
| Part 1A: Ingenol Mebutate Gel 0.012% | Part 2: Reduction in AK Count | 82.9 Percentage reduction |
| Part 1A: Ingenol Mebutate Gel 0.018% | Part 2: Reduction in AK Count | 67.7 Percentage reduction |
| Part 1A: Ingenol Mebutate Gel 0.027% | Part 2: Reduction in AK Count | 4.3 Percentage reduction |
| Part 1A: Ingenol Mebutate Gel 0.04% | Part 2: Reduction in AK Count | 15.7 Percentage reduction |
Comparison: To account for multiple testing among the secondary endpoints, a hierarchical order of testing was determined, where the following evaluation was done separately for each of the four active groups: Provided the primary endpoint was significant at a 1.25% level, the comparison to vehicle in terms of reduction in AK count from baseline to week 8 was tested at a 1.25% level. Provided this test was significant, the second secondary endpoint,partial clearance, was tested(vs. vehicle) at a 1.25% levelp-value: <0.001z-test
Comparison: See comment in analysis 1p-value: <0.001z-test
Comparison: See comment analysis 1p-value: <0.001z-test
Comparison: See comment in analysis 1p-value: <0.001z-test