Actinic Keratosis
Conditions
Brief summary
This is a randomised, double-blind, parallel groups, vehicle controlled, 8-week phase 2 trial. The objective is to evaluate efficacy of ingenol mebutate gel 0.06 % after once daily treatment for 2, 3 or 4 consecutive days compared to vehicle gel
Interventions
DRUGingenol mebutate
OTHERPlacebo
Sponsors
LEO Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Subjects with 5 to 20 clinically typical, visible and discrete AKs within a contiguous area of approximately 250 cm² sun-damaged skin on either trunk (except chest), or extremities
Exclusion criteria
* Location of the treatment area (trunk (except chest) or extremities) * 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 within the selected treatment area * Lesions in the treatment area 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 |
|---|---|---|
| Percentage of Participants With Complete Clearance of Actinic Keratosis Lesions (AKs) | At Week 8 | Complete clearance of AKs at Week 8 was defined as a 100% reduction from baseline in number of AKs. The table presents the mean across 1000 multiple imputations. Missing values for AK count were imputed sequentially from a negative binomial regression model with treatment group, AK counts at the previous visit, and analysis site as covariates and log baseline AK count as offset. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Reduction in Actinic Keratosis (AK) Lesion Count From Baseline (Day 1) (Multiple Imputation) | At Week 8 | The number of clinically visible AK lesions identified in the treatment area was to be recorded at Visit 1(≤14 days prior to Day 1). The analysis was based on 1000 imputations of actinic keratosis lesion count at Week 8 using a negative binomial regression model with factors treatment and analysis site and with log of baseline actinic keratosis lesion count as offset. The table shows the adjusted percentage reduction from baseline. Values for the Ingenol 4 days arm were calculated separately based on observed cases. On the basis of the data monitoring committee's recommendation the 4-day active treatment group was closed, and this arm was excluded from statistical models and comparisons in the secondary efficacy analyses. |
| Percentage of Participants With Partial Clearance of AKs | At Week 8 | Partial clearance of AKs at Week 8, defined as at least 75% reduction from baseline in number of AKs, was analysed in the same way as the primary response criterion. The percent reduction at Week 8 from baseline was analyzed using a negative binomial regression for the AK count at Week 8 with treatment group and pooled sites as factors and baseline count as offset variable (using multiple imputations to account for missing values). The table presents the mean across 1000 multiple imputations. Missing values for AK count were imputed sequentially from a negative binomial regression model with treatment group, AK counts at the previous visit, and analysis site as covariates and log baseline AK count as offset. |
Countries
United States
Participant flow
Recruitment details
Participants were followed for 8 weeks following the first application of investigational medicinal product (IMP) at Day 1 (4-day treatment period including an 8-week follow-up period).
Pre-assignment details
266 participants were enrolled of which 224 participants were randomized to treatment
Participants by arm
| Arm | Count |
|---|---|
| Ingenol 2 Days 2 days treatment with ingenol mebutate 0.06% gel and 2 days treatment with vehicle gel | 55 |
| Ingenol 3 Days 3 days treatment with ingenol mebutate 0.06% gel and 1 day treatment with vehicle gel | 59 |
| Ingenol 4 Days 4 days treatment with ingenol mebutate 0.06% gel | 49 |
| Vehicle 4 days treatment with vehicle gel | 61 |
| Total | 224 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 | 1 |
| Overall Study | Other | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Ingenol 2 Days | Ingenol 3 Days | Ingenol 4 Days | Vehicle | Total |
|---|---|---|---|---|---|
| Age, Continuous | 67.7 years | 68.1 years | 68.8 years | 68.6 years | 68.3 years |
| Region of Enrollment Australia | 31 Participants | 33 Participants | 32 Participants | 36 Participants | 132 Participants |
| Region of Enrollment United States | 24 Participants | 26 Participants | 17 Participants | 25 Participants | 92 Participants |
| Sex: Female, Male Female | 20 Participants | 27 Participants | 13 Participants | 20 Participants | 80 Participants |
| Sex: Female, Male Male | 35 Participants | 32 Participants | 36 Participants | 41 Participants | 144 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 55 | 0 / 59 | 0 / 49 | 0 / 61 |
| other Total, other adverse events | 48 / 55 | 55 / 59 | 47 / 49 | 7 / 61 |
| serious Total, serious adverse events | 3 / 55 | 5 / 59 | 4 / 49 | 0 / 61 |
Outcome results
Primary
Percentage of Participants With Complete Clearance of Actinic Keratosis Lesions (AKs)
Complete clearance of AKs at Week 8 was defined as a 100% reduction from baseline in number of AKs. The table presents the mean across 1000 multiple imputations. Missing values for AK count were imputed sequentially from a negative binomial regression model with treatment group, AK counts at the previous visit, and analysis site as covariates and log baseline AK count as offset.
Time frame: At Week 8
Population: The analysis was based on the Full Analysis Set, which was defined as all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ingenol 2 Days | Percentage of Participants With Complete Clearance of Actinic Keratosis Lesions (AKs) | 12.7 percentage of participants |
| Ingenol 3 Days | Percentage of Participants With Complete Clearance of Actinic Keratosis Lesions (AKs) | 5.1 percentage of participants |
| Ingenol 4 Days | Percentage of Participants With Complete Clearance of Actinic Keratosis Lesions (AKs) | 26.8 percentage of participants |
| Vehicle | Percentage of Participants With Complete Clearance of Actinic Keratosis Lesions (AKs) | 0.0 percentage of participants |
Comparison: Treatment comparison based on 1000 imputations of AK count at week 8 using a negative binomial regression model with factors treatment and analysis site and with log of baseline AK count as offset.~Cochran-Mantel-Haenszel logit estimators were used for comparisons with vehicle due to absence of cleared participant in the vehicle group.p-value: 0.1895% CI: [0.6, 14.74]Cochran-Mantel-Haenszel
Comparison: Treatment comparison based on 1000 imputations of AK count at week 8 using a negative binomial regression model with factors treatment and analysis site and with log of baseline AK count as offset.~Cochran-Mantel-Haenszel logit estimators were used for comparisons with vehicle due to absence of cleared subject in the vehicle group.~Type I error not controlled.p-value: 0.05195% CI: [1, 12.41]Cochran-Mantel-Haenszel
Comparison: Treatment comparison based on 1000 imputations of AK count at week 8 using a negative binomial regression model with factors treatment and analysis site and with log of baseline AK count as offset.~Type I error not controlled. Mantel-Haenszel estimators were used.p-value: 0.2595% CI: [0.13, 1.68]Mantel Haenszel
Secondary
Percentage of Participants With Partial Clearance of AKs
Partial clearance of AKs at Week 8, defined as at least 75% reduction from baseline in number of AKs, was analysed in the same way as the primary response criterion. The percent reduction at Week 8 from baseline was analyzed using a negative binomial regression for the AK count at Week 8 with treatment group and pooled sites as factors and baseline count as offset variable (using multiple imputations to account for missing values). The table presents the mean across 1000 multiple imputations. Missing values for AK count were imputed sequentially from a negative binomial regression model with treatment group, AK counts at the previous visit, and analysis site as covariates and log baseline AK count as offset.
Time frame: At Week 8
Population: The analysis was based on the Full Analysis Set, which was defined as all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ingenol 2 Days | Percentage of Participants With Partial Clearance of AKs | 47.3 percentage of participants |
| Ingenol 3 Days | Percentage of Participants With Partial Clearance of AKs | 56.2 percentage of participants |
| Ingenol 4 Days | Percentage of Participants With Partial Clearance of AKs | 60.4 percentage of participants |
| Vehicle | Percentage of Participants With Partial Clearance of AKs | 2.0 percentage of participants |
Comparison: The treatment comparison was based on 1000 imputations of AK count at week 8 using a negative binomial regression model with factors treatment and analysis site and with log of baseline AK count as offset.p-value: <0.00195% CI: [4.39, 236.8]Cochran-Mantel-Haenszel
Comparison: The treatment comparison was based on 1000 imputations of AK count at week 8 using a negative binomial regression model with factors treatment and analysis site and with log of baseline AK count as offset.p-value: 0.00295% CI: [3.39, 187.4]Cochran-Mantel-Haenszel
Comparison: The treatment comparison was based on 1000 imputations of AK count at week 8 using a negative binomial regression model with factors treatment and analysis site and with log of baseline AK count as offset.p-value: 0.2895% CI: [0.86, 1.65]Cochran-Mantel-Haenszel
Secondary
Percentage of Reduction in Actinic Keratosis (AK) Lesion Count From Baseline (Day 1) (Multiple Imputation)
The number of clinically visible AK lesions identified in the treatment area was to be recorded at Visit 1(≤14 days prior to Day 1). The analysis was based on 1000 imputations of actinic keratosis lesion count at Week 8 using a negative binomial regression model with factors treatment and analysis site and with log of baseline actinic keratosis lesion count as offset. The table shows the adjusted percentage reduction from baseline. Values for the Ingenol 4 days arm were calculated separately based on observed cases. On the basis of the data monitoring committee's recommendation the 4-day active treatment group was closed, and this arm was excluded from statistical models and comparisons in the secondary efficacy analyses.
Time frame: At Week 8
Population: The analysis was based on the Full Analysis Set, which was defined as all randomized participants.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ingenol 2 Days | Percentage of Reduction in Actinic Keratosis (AK) Lesion Count From Baseline (Day 1) (Multiple Imputation) | 64.5 percentage of reduction |
| Ingenol 3 Days | Percentage of Reduction in Actinic Keratosis (AK) Lesion Count From Baseline (Day 1) (Multiple Imputation) | 68.3 percentage of reduction |
| Ingenol 4 Days | Percentage of Reduction in Actinic Keratosis (AK) Lesion Count From Baseline (Day 1) (Multiple Imputation) | 73.6 percentage of reduction |
| Vehicle | Percentage of Reduction in Actinic Keratosis (AK) Lesion Count From Baseline (Day 1) (Multiple Imputation) | 11.9 percentage of reduction |
p-value: 0.3695% CI: [0.7, 1.14]Negative binomial regression
p-value: <0.00195% CI: [0.32, 0.51]Negative binomial regression
p-value: <0.00195% CI: [0.29, 0.45]Negative binomial regression