Actinic Keratosis
Conditions
Brief summary
Part 1: To identify Maximum Tolerated Dose (MTD) levels of LEO 43204 after once daily treatment for two consecutive days Part 2: To evaluate the efficacy of LEO 43204 in two doses after once daily treatment for two consecutive days compared to vehicle
Interventions
DRUGLEO 43204
DRUGPlacebo
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
No
Inclusion criteria
* Part 1: Subjects with 5 to 20 clinically typical, visible and discrete AKs on the arm * Part 2: Subjects with 5 to 20 clinically typical, visible and discrete AKs on the extremities or trunk
Exclusion criteria
* Location of the treatment area * within 5 cm of an incompletely healed wound * within 5 cm of a suspected basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) * Prior treatment with ingenol mebutate gel on 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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Participants Experiencing Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | From Day 1 up to and including Day 8 | The number participants experiencing a DLT was used to identify the maximum tolerated dose(MTD) levels of LEO 43204 after once daily treatment for 2 consecutive days.The MTD was defined as the highest dose level at which less than 4 out of 12 participants experienced a DLT. A DLT was defined as one or more of the following three LSRs: * Crusting Grade 4 * Erosion/Ulceration Grade 4 * Vesiculation/Pustulation Grade 4 or two or more of the following five LSRs: * Crusting Grade 3 * Swelling Grade 4 * Erosion/Ulceration Grade 3 * Vesiculation/Pustulation Grade 3 or other clinically relevant signs or symptoms observed, which the Investigator judged to be counted as a DLT. The LSRs consists of the following 6 categories: Erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, erosion/ulceration. Each individual LSR category was given a numeric grade of severity from 0-4. Grade 0 being no presence and Grade 4 being the highest grade of severity. |
| Part 2: Percent Reduction From Baseline in Actinic Keratosis (AK) Count | From baseline to Week 8 | Percent reduction from baseline in clinically visible actinic keratosis lesions (AKs) identified in the treatment area. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Participants With Complete Clearance of AKs (Last Observation Carried Forward [LOCF]) | From baseline to Week 8 | Complete clearance was defined as a 100% reduction from baseline in AK count. |
| Part 2: Participants With Partial Clearance of AKs (LOCF) | From baseline to Week 8 | Partial clearance was defined as at least 75% reduction from baseline in AK count. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part 1: LEO 43204 Gel 0.018% Once daily treatment for two consecutive days with LEO 43204 gel 0.018% | 12 |
| Part 1: LEO 43204 Gel 0.025% Once daily treatment for two consecutive days with LEO 43204 gel 0.025% | 12 |
| Part 1: LEO 43204 Gel 0.037% Once daily treatment for two consecutive days with LEO 43204 gel 0.037% | 12 |
| Part 1: LEO 43204 Gel 0.05% Once daily treatment for two consecutive days with LEO 43204 gel 0.05% | 12 |
| Part 1: LEO 43204 Gel 0.075% Once daily treatment for two consecutive days with LEO 43204 gel 0.075% | 12 |
| Part 1: LEO 43204 Gel 0.1% Once daily treatment for two consecutive days with LEO 43204 gel 0.1% | 9 |
| Part 2: LEO 43204 Vehicle Gel Once daily treatment for two consecutive days LEO 43204 vehicle gel | 32 |
| Part 2: LEO 43204 Gel 0.075% Once daily treatment for two consecutive days LEO 43204 gel 0.075% | 60 |
| Part 2: LEO 43204 Gel 0.1% Once daily treatment for two consecutive days LEO 43204 gel 0.1% | 63 |
| Total | 224 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Part 2 Double-blind Phase | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Part 2 Double-blind Phase | Unable to attend visit due to work | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Part 2 Double-blind Phase | Withdrawal of consent | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Part 1: LEO 43204 Gel 0.018% | Part 1: LEO 43204 Gel 0.025% | Part 1: LEO 43204 Gel 0.037% | Part 1: LEO 43204 Gel 0.05% | Part 1: LEO 43204 Gel 0.075% | Part 1: LEO 43204 Gel 0.1% | Part 2: LEO 43204 Vehicle Gel | Part 2: LEO 43204 Gel 0.075% | Part 2: LEO 43204 Gel 0.1% | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 10 Participants | 9 Participants | 8 Participants | 7 Participants | 6 Participants | 21 Participants | 38 Participants | 40 Participants | 142 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 2 Participants | 3 Participants | 4 Participants | 5 Participants | 3 Participants | 11 Participants | 22 Participants | 23 Participants | 82 Participants |
| Region of Enrollment Canada | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 11 participants | 20 participants | 21 participants | 52 participants |
| Region of Enrollment United States | 12 participants | 12 participants | 12 participants | 12 participants | 12 participants | 9 participants | 21 participants | 40 participants | 42 participants | 172 participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 15 Participants | 24 Participants | 26 Participants | 96 Participants |
| Sex: Female, Male Male | 8 Participants | 9 Participants | 6 Participants | 6 Participants | 6 Participants | 3 Participants | 17 Participants | 36 Participants | 37 Participants | 128 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 |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 12 | 3 / 12 | 5 / 12 | 9 / 12 | 10 / 12 | 7 / 9 | 6 / 32 | 36 / 60 | 39 / 63 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 9 | 0 / 32 | 1 / 60 | 2 / 63 |
Outcome results
Primary
Part 1: Participants Experiencing Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs)
The number participants experiencing a DLT was used to identify the maximum tolerated dose(MTD) levels of LEO 43204 after once daily treatment for 2 consecutive days.The MTD was defined as the highest dose level at which less than 4 out of 12 participants experienced a DLT. A DLT was defined as one or more of the following three LSRs: * Crusting Grade 4 * Erosion/Ulceration Grade 4 * Vesiculation/Pustulation Grade 4 or two or more of the following five LSRs: * Crusting Grade 3 * Swelling Grade 4 * Erosion/Ulceration Grade 3 * Vesiculation/Pustulation Grade 3 or other clinically relevant signs or symptoms observed, which the Investigator judged to be counted as a DLT. The LSRs consists of the following 6 categories: Erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, erosion/ulceration. Each individual LSR category was given a numeric grade of severity from 0-4. Grade 0 being no presence and Grade 4 being the highest grade of severity.
Time frame: From Day 1 up to and including Day 8
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: LEO 43204 Gel 0.018% | Part 1: Participants Experiencing Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | Yes | 0 Participants |
| Part 1: LEO 43204 Gel 0.018% | Part 1: Participants Experiencing Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | No | 12 Participants |
| Part 1: LEO 43204 Gel 0.025% | Part 1: Participants Experiencing Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | No | 12 Participants |
| Part 1: LEO 43204 Gel 0.025% | Part 1: Participants Experiencing Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | Yes | 0 Participants |
| Part 1: LEO 43204 Gel 0.037% | Part 1: Participants Experiencing Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | Yes | 2 Participants |
| Part 1: LEO 43204 Gel 0.037% | Part 1: Participants Experiencing Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | No | 10 Participants |
| Part 1: LEO 43204 Gel 0.05% | Part 1: Participants Experiencing Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | No | 11 Participants |
| Part 1: LEO 43204 Gel 0.05% | Part 1: Participants Experiencing Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | Yes | 1 Participants |
| Part 1: LEO 43204 Gel 0.075% | Part 1: Participants Experiencing Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | No | 11 Participants |
| Part 1: LEO 43204 Gel 0.075% | Part 1: Participants Experiencing Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | Yes | 1 Participants |
| Part 1: LEO 43204 Gel 0.1% | Part 1: Participants Experiencing Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | Yes | 0 Participants |
| Part 1: LEO 43204 Gel 0.1% | Part 1: Participants Experiencing Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | No | 9 Participants |
Primary
Part 2: Percent Reduction From Baseline in Actinic Keratosis (AK) Count
Percent reduction from baseline in clinically visible actinic keratosis lesions (AKs) identified in the treatment area.
Time frame: From baseline to Week 8
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part 1: LEO 43204 Gel 0.018% | Part 2: Percent Reduction From Baseline in Actinic Keratosis (AK) Count | 32.7 percentage of reduction |
| Part 1: LEO 43204 Gel 0.025% | Part 2: Percent Reduction From Baseline in Actinic Keratosis (AK) Count | 70.0 percentage of reduction |
| Part 1: LEO 43204 Gel 0.037% | Part 2: Percent Reduction From Baseline in Actinic Keratosis (AK) Count | 62.2 percentage of reduction |
Comparison: Negative binominal regression with log baseline count as offset variable and treatment group and analysis site as factors.p-value: <0.00195% CI: [0.34, 0.58]Negative binominal regression
Comparison: Negative binominal regression with log baseline count as offset variable and treatment group and analysis site as factors.p-value: <0.00195% CI: [0.44, 0.73]Negative binominal regression
p-value: 0.05895% CI: [0.99, 1.6]Negative binominal regression
Secondary
Part 2: Participants With Complete Clearance of AKs (Last Observation Carried Forward [LOCF])
Complete clearance was defined as a 100% reduction from baseline in AK count.
Time frame: From baseline to Week 8
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: LEO 43204 Gel 0.018% | Part 2: Participants With Complete Clearance of AKs (Last Observation Carried Forward [LOCF]) | 3 Participants |
| Part 1: LEO 43204 Gel 0.025% | Part 2: Participants With Complete Clearance of AKs (Last Observation Carried Forward [LOCF]) | 6 Participants |
| Part 1: LEO 43204 Gel 0.037% | Part 2: Participants With Complete Clearance of AKs (Last Observation Carried Forward [LOCF]) | 6 Participants |
Comparison: Log binomial regression with factors treatment group and baseline AK count as a covariate.p-value: 0.9495% CI: [0.3, 4.73]Log binomial regression
Comparison: Log binomial regression with factors treatment group and baseline AK count as a covariate.p-value: 195% CI: [0.28, 4.51]Log binomial regression
Comparison: Log binomial regression with factors treatment group and baseline AK count as a covariate.p-value: 0.9395% CI: [0.31, 2.89]Log binomial regression
Secondary
Part 2: Participants With Partial Clearance of AKs (LOCF)
Partial clearance was defined as at least 75% reduction from baseline in AK count.
Time frame: From baseline to Week 8
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: LEO 43204 Gel 0.018% | Part 2: Participants With Partial Clearance of AKs (LOCF) | 5 Participants |
| Part 1: LEO 43204 Gel 0.025% | Part 2: Participants With Partial Clearance of AKs (LOCF) | 27 Participants |
| Part 1: LEO 43204 Gel 0.037% | Part 2: Participants With Partial Clearance of AKs (LOCF) | 28 Participants |
Comparison: Log binomial regression with factors treatment group and baseline AK count as a covariate.p-value: 0.00395% CI: [1.36, 7.85]Log binomial regression
Comparison: Log binomial regression with factors treatment group and baseline AK count as a covariate.p-value: 0.00495% CI: [1.35, 7.74]Log binomial regression
Comparison: Log binomial regression with factors treatment group and baseline AK count as a covariate.p-value: 0.9595% CI: [0.66, 1.47]Log binomial regression