Actinic Keratosis
Conditions
Brief summary
Part 1: To identify Maximum Tolerated Dose (MTD) levels of two formulations of LEO 43204 after once daily treatment for two consecutive days Part 2: To evaluate efficacy of two formulations of LEO 43204 in two doses after once daily treatment for two consecutive days compared to vehicle formulations
Interventions
DRUGLEO 43204 Formulation 1
DRUGLEO 43204 Formulation 2
DRUGLEO 43204 Formulation 1 Dose X
DRUGLEO 43204 Formulation 1 Dose Y
DRUGLEO 43204 Formulation 2 Dose XX
DRUGLEO 43204 Formulation 2 Dose YY
DRUGPlacebo Formulation 1
DRUGPlacebo Formulation 2
Sponsors
LEO Pharma
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
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
1. Following verbal and written information about the trial, subject must provide informed consent documented by signing the Informed Consent Form (ICF) prior to any trial-related procedures. 2. Part 1: Subjects with 5 to 20 clinically typical, visible and discrete AKs on the face 3. Part 2: Subjects with 5 to 20 clinically typical, visible and discrete AKs on either the face or within a contiguous area of approximately 250 cm2 (40 in2) on the chest 4. Subject at least 18 years of age. 5. Female subjects must be of either: 1. Non-childbearing potential, i.e., have a confirmed clinical history of sterility (e.g., the subject is without a uterus or have tubal ligation), or, 2. Childbearing potential, provided there is a confirmed negative urine pregnancy test prior to trial treatment. 6. Female subjects of childbearing potential must use effective contraception throughout the study.
Exclusion criteria
1. Location of the treatment area within 5 cm (2 inches) of: 1. an incompletely healed wound, 2. a suspected basal or squamous cell carcinoma. 2. Prior treatment with ingenol mebutate gel on the treatment area. 3. Lesions in the treatment areas that have: 1. atypical clinical appearance (e.g., hypertrophic, hyperkeratotic or cutaneous horns) and/or 2. recalcitrant disease (e.g., did not respond to cryotherapy on two previous occasions). 4. 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, Rosacea), at the investigator's discretion. 5. Use of cosmetic or therapeutic products and procedures which could interfere with the assessments of the treatment areas. 6. Any other disease or medical condition such as history or presence of cancer, cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunological, or neurological disease or disorder, that, in the opinion of the investigator, makes the subject unsuitable to participate in the trial. 7. Any abnormal laboratory or ECG findings that are clinically significant and would impact the safety of the subjects or the interpretation of the study results, as determined by the investigator. 8. 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. 9. Known sensitivity or allergy to any of the ingredients in the LEO 43204. 10. Presence of acute sunburn within the treatment areas. 11. Current enrolment or participation in an investigational clinical trial within 30 days of entry into this trial. 12. Subjects previously randomised in the trial (Part 1 or 2). 13. Female subjects who are breastfeeding. 14. 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: Number of Participants Experiencing a Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | From Day 1 up to and including Day 8 | The number of participants experiencing DLTs are tabulated by treatment group. This was used to identify the maximum tolerated dose (MTD) of LEO 43204 after once daily treatment for 2 consecutive days.The MTD was defined as the highest dose level with less than 4 out of 12 participants(cohorts 1 to 4) or less than 6 out of 18 participants(cohorts 5 and 6) experiencing a DLT DLT was defined as one or more of the following 3 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 Local Skin Responses consists of the following 6 categories: Erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, erosion/ulceration. Each individual LSR category are given a numeric grade of severity from 0-4. Grade 0 being no presence and 4 being the highest grade of severity. |
| Part 2: Percent Reduction From Baseline in Actinic Keratosis (AK) Counts (Multiple Imputation) | At Week 8 | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Percentage of Participants With Complete Clearance of Actinic Keratosis Lesions (AKs) (Multiple Imputation) | At Week 8 | Complete clearance was defined as a 100% reduction from baseline in AK count. For treatment groups Vehicle, 0.006 and 0.012 the table shows the percentage of mean number of participants across imputations with complete clearance. For treatment group 0.018 the table shows the percentage of mean number of participants with complete clearance in observed cases. |
| Part 2: Percentage of Participants With Partial Clearance of AKs (Multiple Imputation) | At Week 8 | Partial clearance was defined as at least 75% reduction from baseline in AK count. For treatment groups Vehicle, 0.006 and 0.012 the table shows the percentage of mean number of participants across imputations with partial clearance. For treatment group 0.018 the table shows the percentage of mean number of participants with partial clearance in observed cases. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part 1: LEO 43204 Gel 0.0015 Part 1: Open-Label, Dose-Escalation, Once-Daily, 2-Day Treatment | 3 |
| Part 1: LEO 43204 Gel 0.003 Part 1: Open-Label, Dose-Escalation, Once-Daily, 2-Day Treatment | 3 |
| Part 1: LEO 43204 Gel 0.006 Part 1: Open-Label, Dose-Escalation, Once-Daily, 2-Day Treatment | 6 |
| Part 1: LEO 43204 Gel 0.012 Part 1: Open-Label, Dose-Escalation, Once-Daily, 2-Day Treatment | 6 |
| Part 1: LEO 43204 Gel 0.018 Part 1: Open-Label, Dose-Escalation, Once-Daily, 2-Day Treatment | 17 |
| Part 1: LEO 43204 Gel 0.025 Part 1: Open-Label, Dose-Escalation, Once-Daily, 2-Day Treatment | 18 |
| Part 1: LEO 43204 Cream 0.0015 Part 1: Open-Label phase, Dose-Escalation, Once-Daily, 2-Day Treatment | 3 |
| Part 1: LEO 43204 Cream 0.003 Part 1: Open-Label phase, Dose-Escalation, Once-Daily, 2-Day Treatment | 3 |
| Part 1: LEO 43204 Cream 0.006 Part 1: Open-Label phase, Dose-Escalation, Once-Daily, 2-Day Treatment | 6 |
| Part 1: LEO 43204 Cream 0.012 Part 1: Open-Label phase, Dose-Escalation, Once-Daily, 2-Day Treatment | 12 |
| Part 2: LEO 43204 Gel Vehicle Part 2: Double-Blind, Once-Daily, 2-Day Treatment | 59 |
| Part 2: LEO 43204 Gel 0.006 Part 2: Double-Blind, Once-Daily, 2-Day Treatment | 62 |
| Part 2: LEO 43204 Gel 0.012 Part 2: Double-Blind, Once-Daily, 2-Day Treatment | 60 |
| Part 2: LEO 43204 Gel 0.018 Part 2: Double-Blind, Once-Daily, 2-Day Treatment | 62 |
| Total | 320 |
Baseline characteristics
| Characteristic | Part 1: LEO 43204 Gel 0.0015 | Part 1: LEO 43204 Gel 0.003 | Part 1: LEO 43204 Gel 0.006 | Part 1: LEO 43204 Gel 0.012 | Part 1: LEO 43204 Gel 0.018 | Part 1: LEO 43204 Gel 0.025 | Part 1: LEO 43204 Cream 0.0015 | Part 1: LEO 43204 Cream 0.003 | Part 1: LEO 43204 Cream 0.006 | Part 1: LEO 43204 Cream 0.012 | Part 2: LEO 43204 Gel Vehicle | Part 2: LEO 43204 Gel 0.006 | Part 2: LEO 43204 Gel 0.012 | Part 2: LEO 43204 Gel 0.018 | 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 3 Participants | 5 Participants | 7 Participants | 12 Participants | 1 Participants | 3 Participants | 2 Participants | 7 Participants | 41 Participants | 45 Participants | 39 Participants | 41 Participants | 210 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants | 3 Participants | 1 Participants | 10 Participants | 6 Participants | 2 Participants | 0 Participants | 4 Participants | 5 Participants | 18 Participants | 17 Participants | 21 Participants | 21 Participants | 110 Participants |
| Region of Enrollment Canada | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 32 Participants | 31 Participants | 31 Participants | 32 Participants | 126 Participants |
| Region of Enrollment United States | 3 Participants | 3 Participants | 6 Participants | 6 Participants | 17 Participants | 18 Participants | 3 Participants | 3 Participants | 6 Participants | 12 Participants | 27 Participants | 31 Participants | 29 Participants | 30 Participants | 194 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 4 Participants | 2 Participants | 6 Participants | 6 Participants | 0 Participants | 0 Participants | 1 Participants | 5 Participants | 17 Participants | 20 Participants | 19 Participants | 21 Participants | 103 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 2 Participants | 4 Participants | 11 Participants | 12 Participants | 3 Participants | 3 Participants | 5 Participants | 7 Participants | 42 Participants | 42 Participants | 41 Participants | 41 Participants | 217 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 | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 1 / 3 | 5 / 6 | 5 / 6 | 10 / 17 | 11 / 18 | 1 / 3 | 1 / 3 | 2 / 6 | 8 / 12 | 11 / 58 | 38 / 62 | 40 / 60 | 47 / 62 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 1 / 6 | 0 / 6 | 1 / 17 | 0 / 18 | 0 / 3 | 0 / 3 | 0 / 6 | 0 / 12 | 0 / 58 | 5 / 62 | 2 / 60 | 0 / 62 |
Outcome results
Primary
Part 1: Number of Participants Experiencing a Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs)
The number of participants experiencing DLTs are tabulated by treatment group. This was used to identify the maximum tolerated dose (MTD) of LEO 43204 after once daily treatment for 2 consecutive days.The MTD was defined as the highest dose level with less than 4 out of 12 participants(cohorts 1 to 4) or less than 6 out of 18 participants(cohorts 5 and 6) experiencing a DLT DLT was defined as one or more of the following 3 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 Local Skin Responses consists of the following 6 categories: Erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, erosion/ulceration. Each individual LSR category are given a numeric grade of severity from 0-4. Grade 0 being no presence and 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: Cohort 1: LEO 43204 Gel 0.0015 | Part 1: Number of Participants Experiencing a Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | No | 3 Participants |
| Part 1: Cohort 1: LEO 43204 Gel 0.0015 | Part 1: Number of Participants Experiencing a Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | Yes | 0 Participants |
| Part 1: Cohort 2: LEO 43204 Gel 0.003 | Part 1: Number of Participants Experiencing a Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | No | 3 Participants |
| Part 1: Cohort 2: LEO 43204 Gel 0.003 | Part 1: Number of Participants Experiencing a Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | Yes | 0 Participants |
| Part 1: Cohort 3: LEO 43204 Gel 0.006 | Part 1: Number of Participants Experiencing a Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | No | 6 Participants |
| Part 1: Cohort 3: LEO 43204 Gel 0.006 | Part 1: Number of Participants Experiencing a Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | Yes | 0 Participants |
| Part 1: Cohort 4: LEO 43204 Gel 0.012 | Part 1: Number of Participants Experiencing a Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | No | 6 Participants |
| Part 1: Cohort 4: LEO 43204 Gel 0.012 | Part 1: Number of Participants Experiencing a Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | Yes | 0 Participants |
| Part 1: Cohort 5: LEO 43204 Gel 0.018 | Part 1: Number of Participants Experiencing a Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | Yes | 0 Participants |
| Part 1: Cohort 5: LEO 43204 Gel 0.018 | Part 1: Number of Participants Experiencing a Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | No | 17 Participants |
| Part 1: Cohort 6: LEO 43204 Gel 0.025 | Part 1: Number of Participants Experiencing a Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | Yes | 6 Participants |
| Part 1: Cohort 6: LEO 43204 Gel 0.025 | Part 1: Number of Participants Experiencing a Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | No | 12 Participants |
| Part 1: Cohort 1: LEO 43204 Cream 0.0015 | Part 1: Number of Participants Experiencing a Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | Yes | 0 Participants |
| Part 1: Cohort 1: LEO 43204 Cream 0.0015 | Part 1: Number of Participants Experiencing a Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | No | 3 Participants |
| Part 1: Cohort 2: LEO 43204 Cream 0.003 | Part 1: Number of Participants Experiencing a Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | No | 3 Participants |
| Part 1: Cohort 2: LEO 43204 Cream 0.003 | Part 1: Number of Participants Experiencing a Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | Yes | 0 Participants |
| Part 1: Cohort 3: LEO 43204 Cream 0.006 | Part 1: Number of Participants Experiencing a Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | No | 6 Participants |
| Part 1: Cohort 3: LEO 43204 Cream 0.006 | Part 1: Number of Participants Experiencing a Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | Yes | 0 Participants |
| Part 1: Cohort 4: LEO 43204 Cream 0.012 | Part 1: Number of Participants Experiencing a Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | No | 9 Participants |
| Part 1: Cohort 4: LEO 43204 Cream 0.012 | Part 1: Number of Participants Experiencing a Dose Limiting Toxicity (DLT) Based on Local Skin Responses (LSRs) | Yes | 3 Participants |
Primary
Part 2: Percent Reduction From Baseline in Actinic Keratosis (AK) Counts (Multiple Imputation)
Time frame: At Week 8
Population: The analysis was based on the Full Analysis Set, which was defined as all randomized participants who applied investigation product. One participant from the LEO 43204 gel vehicle arm did not apply investigation product, and thus was excluded from the efficacy analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part 1: Cohort 1: LEO 43204 Gel 0.0015 | Part 2: Percent Reduction From Baseline in Actinic Keratosis (AK) Counts (Multiple Imputation) | 42.3 percentage of reduction |
| Part 1: Cohort 2: LEO 43204 Gel 0.003 | Part 2: Percent Reduction From Baseline in Actinic Keratosis (AK) Counts (Multiple Imputation) | 69.7 percentage of reduction |
| Part 1: Cohort 3: LEO 43204 Gel 0.006 | Part 2: Percent Reduction From Baseline in Actinic Keratosis (AK) Counts (Multiple Imputation) | 73.4 percentage of reduction |
| Part 1: Cohort 4: LEO 43204 Gel 0.012 | Part 2: Percent Reduction From Baseline in Actinic Keratosis (AK) Counts (Multiple Imputation) | 79.0 percentage of reduction |
p-value: <0.00195% CI: [0.4, 0.69]Negative binominal regression
p-value: <0.00195% CI: [0.35, 0.61]Negative binominal regression
p-value: <0.00195% CI: [0.28, 0.48]Negative binominal regression
p-value: 0.3895% CI: [0.66, 1.17]Negative binominal regression
p-value: 0.01395% CI: [0.52, 0.93]Negative binominal regression
p-value: 0.1395% CI: [0.58, 1.07]Negative binominal regression
Secondary
Part 2: Percentage of Participants With Complete Clearance of Actinic Keratosis Lesions (AKs) (Multiple Imputation)
Complete clearance was defined as a 100% reduction from baseline in AK count. For treatment groups Vehicle, 0.006 and 0.012 the table shows the percentage of mean number of participants across imputations with complete clearance. For treatment group 0.018 the table shows the percentage of mean number of participants with complete clearance in observed cases.
Time frame: At Week 8
Population: The analysis was based on the Full Analysis Set, which was defined as all randomized participants who applied investigation product. One participant from the LEO 43204 gel vehicle arm did not apply investigation product, and thus was excluded from the efficacy analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Cohort 1: LEO 43204 Gel 0.0015 | Part 2: Percentage of Participants With Complete Clearance of Actinic Keratosis Lesions (AKs) (Multiple Imputation) | 12.2 percentage of participants |
| Part 1: Cohort 2: LEO 43204 Gel 0.003 | Part 2: Percentage of Participants With Complete Clearance of Actinic Keratosis Lesions (AKs) (Multiple Imputation) | 9.9 percentage of participants |
| Part 1: Cohort 3: LEO 43204 Gel 0.006 | Part 2: Percentage of Participants With Complete Clearance of Actinic Keratosis Lesions (AKs) (Multiple Imputation) | 18.8 percentage of participants |
| Part 1: Cohort 4: LEO 43204 Gel 0.012 | Part 2: Percentage of Participants With Complete Clearance of Actinic Keratosis Lesions (AKs) (Multiple Imputation) | 24.2 percentage of participants |
Comparison: Log binomial regression with treatment group as factor and baseline AK count included as covariate.p-value: 0.5795% CI: [0.27, 2.04]Log binomial regression
Comparison: Log binomial regression with treatment group as factor and baseline AK count included as covariate.p-value: 0.5195% CI: [0.56, 3.13]Log binomial regression
Comparison: Log binomial regression with treatment group as factor and baseline AK count included as covariate.p-value: 0.1195% CI: [0.86, 4.21]Log binomial regression
Comparison: Log binomial regression with treatment group as factor and baseline AK count included as covariate.p-value: 0.2195% CI: [0.72, 4.43]Log binomial regression
Comparison: Log binomial regression with treatment group as factor and baseline AK count included as covariate.p-value: 0.03195% CI: [1.09, 5.98]Log binomial regression
Comparison: Log binomial regression with treatment group as factor and baseline AK count included as covariate.p-value: 0.2995% CI: [0.74, 2.75]Log binomial regression
Secondary
Part 2: Percentage of Participants With Partial Clearance of AKs (Multiple Imputation)
Partial clearance was defined as at least 75% reduction from baseline in AK count. For treatment groups Vehicle, 0.006 and 0.012 the table shows the percentage of mean number of participants across imputations with partial clearance. For treatment group 0.018 the table shows the percentage of mean number of participants with partial clearance in observed cases.
Time frame: At Week 8
Population: The analysis was based on the Full Analysis Set, which was defined as all randomized participants who applied investigation product. One participant from the LEO 43204 gel vehicle arm did not apply investigation product, and thus was excluded from the efficacy analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Cohort 1: LEO 43204 Gel 0.0015 | Part 2: Percentage of Participants With Partial Clearance of AKs (Multiple Imputation) | 29.9 percentage of participants |
| Part 1: Cohort 2: LEO 43204 Gel 0.003 | Part 2: Percentage of Participants With Partial Clearance of AKs (Multiple Imputation) | 52.4 percentage of participants |
| Part 1: Cohort 3: LEO 43204 Gel 0.006 | Part 2: Percentage of Participants With Partial Clearance of AKs (Multiple Imputation) | 54.5 percentage of participants |
| Part 1: Cohort 4: LEO 43204 Gel 0.012 | Part 2: Percentage of Participants With Partial Clearance of AKs (Multiple Imputation) | 62.9 percentage of participants |
Comparison: Log binomial regression with treatment group as factor and baseline AK count included as covariate.p-value: 0.02695% CI: [1.06, 2.69]Log binomial regression
Comparison: Log binomial regression with treatment group as factor and baseline AK count included as covariate.p-value: 0.01395% CI: [1.13, 2.84]Log binomial regression
p-value: <0.00195% CI: [1.35, 3.25]Log binomial regression
p-value: 0.7395% CI: [0.76, 1.47]Log binomial regression
p-value: 0.1695% CI: [0.92, 1.67]Log binomial regression
Comparison: Log binomial regression with treatment group as factor and baseline AK count included as covariate.p-value: 0.395% CI: [0.87, 1.57]Log binomial regression