Actinic Keratosis
Conditions
Brief summary
To identify the Maximum Tolerated Dose levels of LEO 43204 after once daily treatment for two consecutive days and to evaluate 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 full balding scalp. * Part 2: Subjects with 5 to 20 clinically typical, visible and discrete AKs on the full balding scalp
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: Number of Participants Experiencing a Dose-limiting Toxicity (DLT) | From Day 1 up to and including Day 8 | The number participants experiencing a DLT 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 experiencing a DLT. A DLT was defined as: * Erosion/ulceration Grade 4 on the Local Skin Response (LSR) scale * Other clinically relevant signs or symptoms observed, which the International Co-ordinating Investigator judges to be counted as a DLT. 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 Grade 4 being the highest grade of severity. |
| Part 2: Percent Reduction From Baseline in Actinic Keratosis (AK) Lesion Count | From baseline to Week 8 | Percent reduction from baseline in clinically visible actinic keratosis lesions (AKs) in the selected treatment area. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Participants With Complete Clearance of AKs | From baseline to Week 8 | Complete clearance of AKs at Week 8 was defined as a 100% reduction from baseline in AK count. |
| Part 2: Participants With Partial Clearance of AKs | From baseline to Week 8 | Partial clearance of AKs at Week 8 was defined as at least 75% reduction from baseline in AK count. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited in 7 centres in the US into Part 1 of the trial. First participant was enrolled on 14-05-14 and the last subject´s last visit (LSLV) was on 12-08-14. Participants were recruited in 11 centres in the US and 5 centres in Germany into Part 2 of trial. First participant was enrolled on 03-09-14 and LSLV was on 02-03-14.
Participants by arm
| Arm | Count |
|---|---|
| Part 1 - 0.018% Cohort Part 1 - Dose escalation
Once daily application with LEO 43204 gel 0.018% for two consecutive days on balding scalp. | 10 |
| Part 1 - 0.025% Cohort Part 1 - Dose escalation
Once daily application with LEO 43204 gel 0.025% for two consecutive days on balding scalp. | 11 |
| Part 1 - 0.037% Cohort Part 1 - Dose escalation
Once daily application with LEO 43204 gel 0.037% for two consecutive days on balding scalp. | 12 |
| Part 1 - 0.05% Cohort Part 1 - Dose escalation
Once daily application with LEO 43204 gel 0.05% for two consecutive days on balding scalp. | 12 |
| Part 1 - 0.075% Cohort Part 1 - Dose escalation
Once daily application with LEO 43204 gel 0.075% for two consecutive days on balding scalp. | 12 |
| Part 2 - Vehicle Part 2 - Dose finding
Once daily application with LEO 43204 gel vehicle for two consecutive days on balding scalp. | 32 |
| Part 2 - 0.037% Part 2 - Dose finding
Once daily application with LEO 43204 gel 0.037% for two consecutive days on balding scalp. | 64 |
| Part 2 - 0.05% Part 2 - Dose finding
Once daily application with LEO 43204 gel 0.05% for two consecutive days on balding scalp. | 67 |
| Total | 220 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Part 1 - 0.018% Cohort | Part 1 - 0.025% Cohort | Part 1 - 0.037% Cohort | Part 1 - 0.05% Cohort | Part 1 - 0.075% Cohort | Part 2 - Vehicle | Part 2 - 0.037% | Part 2 - 0.05% | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 8 Participants | 8 Participants | 8 Participants | 10 Participants | 23 Participants | 55 Participants | 53 Participants | 173 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 3 Participants | 4 Participants | 4 Participants | 2 Participants | 9 Participants | 9 Participants | 14 Participants | 47 Participants |
| Region of Enrollment Germany | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 8 participants | 15 participants | 16 participants | 39 participants |
| Region of Enrollment United States | 10 participants | 11 participants | 12 participants | 12 participants | 12 participants | 24 participants | 49 participants | 51 participants | 181 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 10 Participants | 11 Participants | 12 Participants | 12 Participants | 12 Participants | 32 Participants | 64 Participants | 67 Participants | 220 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 |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 10 | 7 / 11 | 12 / 12 | 10 / 12 | 12 / 12 | 4 / 32 | 47 / 64 | 50 / 67 |
| serious Total, serious adverse events | 0 / 10 | 0 / 11 | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 32 | 2 / 64 | 3 / 67 |
Outcome results
Primary
Part 1: Number of Participants Experiencing a Dose-limiting Toxicity (DLT)
The number participants experiencing a DLT 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 experiencing a DLT. A DLT was defined as: * Erosion/ulceration Grade 4 on the Local Skin Response (LSR) scale * Other clinically relevant signs or symptoms observed, which the International Co-ordinating Investigator judges to be counted as a DLT. 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 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 - 0.018% Cohort | Part 1: Number of Participants Experiencing a Dose-limiting Toxicity (DLT) | Yes | 0 Participants |
| Part 1 - 0.018% Cohort | Part 1: Number of Participants Experiencing a Dose-limiting Toxicity (DLT) | No | 10 Participants |
| Part 1 - 0.025% Cohort | Part 1: Number of Participants Experiencing a Dose-limiting Toxicity (DLT) | No | 11 Participants |
| Part 1 - 0.025% Cohort | Part 1: Number of Participants Experiencing a Dose-limiting Toxicity (DLT) | Yes | 0 Participants |
| Part 1 - 0.037% Cohort | Part 1: Number of Participants Experiencing a Dose-limiting Toxicity (DLT) | No | 12 Participants |
| Part 1 - 0.037% Cohort | Part 1: Number of Participants Experiencing a Dose-limiting Toxicity (DLT) | Yes | 0 Participants |
| Part 1 - 0.05% Cohort | Part 1: Number of Participants Experiencing a Dose-limiting Toxicity (DLT) | Yes | 0 Participants |
| Part 1 - 0.05% Cohort | Part 1: Number of Participants Experiencing a Dose-limiting Toxicity (DLT) | No | 12 Participants |
| Part 1 - 0.075% Cohort | Part 1: Number of Participants Experiencing a Dose-limiting Toxicity (DLT) | No | 12 Participants |
| Part 1 - 0.075% Cohort | Part 1: Number of Participants Experiencing a Dose-limiting Toxicity (DLT) | Yes | 0 Participants |
Primary
Part 2: Percent Reduction From Baseline in Actinic Keratosis (AK) Lesion Count
Percent reduction from baseline in clinically visible actinic keratosis lesions (AKs) in the selected treatment area.
Time frame: From baseline to Week 8
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part 1 - 0.018% Cohort | Part 2: Percent Reduction From Baseline in Actinic Keratosis (AK) Lesion Count | 12.6 percentage of reduction |
| Part 1 - 0.025% Cohort | Part 2: Percent Reduction From Baseline in Actinic Keratosis (AK) Lesion Count | 72.7 percentage of reduction |
| Part 1 - 0.037% Cohort | Part 2: Percent Reduction From Baseline in Actinic Keratosis (AK) Lesion Count | 78.5 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: [0.23, 0.42]Negative binomial 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: [0.18, 0.33]Negative binomial regression
Comparison: Negative binominal regression with log baseline count as offset variable and treatment group and analysis site as factors.p-value: =0.09695% CI: [0.59, 1.04]Negative binomial regression
Secondary
Part 2: Participants With Complete Clearance of AKs
Complete clearance of AKs at Week 8 was defined as a 100% reduction from baseline in AK count.
Time frame: From baseline to Week 8
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 - 0.018% Cohort | Part 2: Participants With Complete Clearance of AKs | 3.1 percentage of participants |
| Part 1 - 0.025% Cohort | Part 2: Participants With Complete Clearance of AKs | 21.9 percentage of participants |
| Part 1 - 0.037% Cohort | Part 2: Participants With Complete Clearance of AKs | 29.9 percentage of participants |
Comparison: Log binomial regression with treatment group as factor and baseline AK count included as covariate.p-value: =0.00795% CI: [1.53, 124]Log binomial regression
Comparison: Log binomial regression with treatment group as factor and baseline AK count included as covariate.p-value: =0.00195% CI: [1.99, 154.5]Log binomial regression
Comparison: Log binomial regression with treatment group as factor and baseline AK count included as covariate.p-value: =0.4395% CI: [0.72, 2.31]Log binomial regression
Secondary
Part 2: Participants With Partial Clearance of AKs
Partial clearance of AKs at Week 8 was defined as at least 75% reduction from baseline in AK count.
Time frame: From baseline to Week 8
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 - 0.018% Cohort | Part 2: Participants With Partial Clearance of AKs | 6.3 percentage of participants |
| Part 1 - 0.025% Cohort | Part 2: Participants With Partial Clearance of AKs | 54.7 percentage of participants |
| Part 1 - 0.037% Cohort | Part 2: Participants With Partial Clearance of AKs | 59.7 percentage of participants |
p-value: <0.00195% CI: [2.93, 51.66]Log binomial regression
p-value: <0.00195% CI: [3.22, 56.4]Log binomial regression
p-value: =0.5595% CI: [0.81, 1.49]Log binomial regression