Actinic Keratosis (AK)
Conditions
Brief summary
The purpose of the study is to compare the risk of developing squamous skin cancer (SCC) or other types of cancer after treatment of AKs with ingenol mebutate gel or imiquimod cream. Subjects will be randomised to treatment with ingenol mebutate or imiquimod and will receive a second treatment cycle with the same treatment if the first treatment does not clear all AKs. Subjects will be followed over a period of three year (36 months) after first treatment
Interventions
Ingenol mebutate gel 0.015 % (Picato®) applied on the selected treatment area. Retreatment if the treatment field is not completely cleared of AKs.
DRUGImiquimod Cream, 5%
Imiquimod 5% cream applied to the selected treatment area. Retreatment if the treatment field is not completely cleared of AKs
Sponsors
LEO Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed Informed Consent Form (ICF) prior to any trial-related procedures 2. Subjects with 5 to 9 clinically typical, visible and discrete AKs within a contiguous 25 cm² treatment area on the face or scalp. 3. Subject at least 18 years of age 4. Female subjects must be of either: 1. Non-childbearing potential, or, 2. Childbearing potential, provided there is a confirmed negative urine pregnancy test 5. Female subjects of childbearing potential must be willing to use highly effective methods of contraception (Pearl index \< 1%)
Exclusion criteria
1. Location of the selected treatment area: * on the periorbital skin * on the perioral skin/around the nostrils * within 5 cm of an incompletely healed wound * within 10 cm of a suspected BCC or SCC or other neoplasia 2. Selected treatment area lesions that have atypical clinical appearance (e.g., hypertrophic, hyperkeratotic or cutaneous horn). 3. History of SCC, BCC, malignant melanoma or other neoplasia in the selected treatment area. 4. History or evidence of skin conditions other than the trial indication that would interfere with evaluation of the trial medication in the selected treatment area 5. Use of ingenol mebutate and/or imiquimod in and within 5 cm of the selected treatment area within 2 years prior to Screening (Visit 1) 6. Organ transplant recipients 7. Immunosuppressed subjects (for example HIV patients) 8. Female subjects who are breastfeeding. 9. Subjects who are institutionalised by court order or by the local authority 10. 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 |
|---|---|---|
| Incidence of SCC | 3 years | Cumulative incidence of SCC after treatment with ingenol mebutate gel and imiquimod cream.\> The primary response criterion is diagnosis of SCC (defined as invasive SCC i.e. excludes SCC in situ) in the treatment field across the 3-year trial period.\> Kaplan-Meier estimate based on time to SCC or censoring. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of SCC and Other Neoplasia | 3 years | Cumulative incidence of SCC and other neoplasia after treatment with ingenol mebutate gel and imiquimod cream.\> The secondary response criterion is diagnosis of SCC and other neoplasia in the treatment field across the 3-year trial period.\> Kaplan-Meier estimate based on time to SCC and other neoplasia, or censoring. |
| Number of Participants With Complete Clearance of AK Lesions After Last Treatment | 8-16 weeks | To compare the complete clearance of AK lesions in the selected treatment area after the last treatment cycle (at Week 8 or 16) |
| Number of Participants With Partial Clearance of AK Lesions | 8-16 weeks | To compare the partial (at least 75%) clearance of AK lesions in the selected treatment area after the last treatment cycle (at Week 8 or 16) |
| Number of Participants With Complete Clearance of AK Lesions at 12 Months | 1 year | To compare the complete clearance of AK lesions at 12 months, defined as no AK lesions in the selected treatment area at any time from the last treatment cycle at Week 8 or 16 through to Month 12. |
Countries
France, Germany, United Kingdom
Participant flow
Recruitment details
The clinical trial was performed at 44 sites in 3 countries: France, 11 sites; Germany, 15 sites; and United Kingdom, 18 sites
Participants by arm
| Arm | Count |
|---|---|
| Ingenol Mebutate Arm A: Ingenol mebutate gel 0.015% applied daily for 3 consecutive days to the selected treatment area followed by 8 weeks' rest. Retreatment for another 3 consecutive days if the treatment field is not completely cleared of AKs at Week 8\>
\> Ingenol Mebutate Gel, 0.015%: Ingenol mebutate gel 0.015 % (Picato®) applied on the selected treatment area. Retreatment if the treatment field is not completely cleared of AKs. | 240 |
| Imiquimod Arm B: Imiquimod 5% cream applied 3 days per week for 4 weeks to the selected\> treatment area followed by 4 weeks' rest. Retreatment for another 4 weeks if the treatment field is not completely cleared of AKs at Week 8\>
\> Imiquimod Cream, 5%: Imiquimod 5% cream applied to the selected treatment area. Retreatment if the treatment field is not completely cleared of AKs | 244 |
| Total | 484 |
Baseline characteristics
| Characteristic | Ingenol Mebutate | Imiquimod | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 206 Participants | 202 Participants | 408 Participants |
| Age, Categorical Between 18 and 65 years | 34 Participants | 42 Participants | 76 Participants |
| Age, Continuous | 72.5 years STANDARD_DEVIATION 7.1 | 72.0 years STANDARD_DEVIATION 8 | 72.3 years STANDARD_DEVIATION 7.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants | 12 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 226 Participants | 232 Participants | 458 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 240 Participants | 244 Participants | 484 Participants |
| Region of Enrollment France | 60 Participants | 63 Participants | 123 Participants |
| Region of Enrollment Germany | 100 Participants | 100 Participants | 200 Participants |
| Region of Enrollment United Kingdom | 80 Participants | 81 Participants | 161 Participants |
| Sex: Female, Male Female | 10 Participants | 15 Participants | 25 Participants |
| Sex: Female, Male Male | 230 Participants | 229 Participants | 459 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 / 240 | 1 / 244 | 8 / 240 | 5 / 244 |
| other Total, other adverse events | 67 / 240 | 70 / 244 | 51 / 240 | 50 / 244 |
| serious Total, serious adverse events | 21 / 240 | 14 / 244 | 11 / 240 | 2 / 244 |
Outcome results
Primary
Incidence of SCC
Cumulative incidence of SCC after treatment with ingenol mebutate gel and imiquimod cream.\> The primary response criterion is diagnosis of SCC (defined as invasive SCC i.e. excludes SCC in situ) in the treatment field across the 3-year trial period.\> Kaplan-Meier estimate based on time to SCC or censoring.
Time frame: 3 years
Population: Safety analysis set: all treated subjects
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ingenol Mebutate | Incidence of SCC | 3.1 percentage of subjects |
| Imiquimod | Incidence of SCC | 0.4 percentage of subjects |
Secondary
Incidence of SCC and Other Neoplasia
Cumulative incidence of SCC and other neoplasia after treatment with ingenol mebutate gel and imiquimod cream.\> The secondary response criterion is diagnosis of SCC and other neoplasia in the treatment field across the 3-year trial period.\> Kaplan-Meier estimate based on time to SCC and other neoplasia, or censoring.
Time frame: 3 years
Population: Safety analysis set: all treated subjects
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ingenol Mebutate | Incidence of SCC and Other Neoplasia | 6.2 percentage of subjects |
| Imiquimod | Incidence of SCC and Other Neoplasia | 2.3 percentage of subjects |
Secondary
Number of Participants With Complete Clearance of AK Lesions After Last Treatment
To compare the complete clearance of AK lesions in the selected treatment area after the last treatment cycle (at Week 8 or 16)
Time frame: 8-16 weeks
Population: Full analysis set: all randomised subjects
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ingenol Mebutate | Number of Participants With Complete Clearance of AK Lesions After Last Treatment | 168 Participants |
| Imiquimod | Number of Participants With Complete Clearance of AK Lesions After Last Treatment | 192 Participants |
p-value: 0.0395% CI: [0.8, 0.99]Cochran-Mantel-Haenszel
Secondary
Number of Participants With Complete Clearance of AK Lesions at 12 Months
To compare the complete clearance of AK lesions at 12 months, defined as no AK lesions in the selected treatment area at any time from the last treatment cycle at Week 8 or 16 through to Month 12.
Time frame: 1 year
Population: Full analysis set: all randomised subjects.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ingenol Mebutate | Number of Participants With Complete Clearance of AK Lesions at 12 Months | 70 Participants |
| Imiquimod | Number of Participants With Complete Clearance of AK Lesions at 12 Months | 108 Participants |
p-value: <0.00195% CI: [0.52, 0.84]Cochran-Mantel-Haenszel
Secondary
Number of Participants With Partial Clearance of AK Lesions
To compare the partial (at least 75%) clearance of AK lesions in the selected treatment area after the last treatment cycle (at Week 8 or 16)
Time frame: 8-16 weeks
Population: Full analysis set: all randomised subjects
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ingenol Mebutate | Number of Participants With Partial Clearance of AK Lesions | 195 Participants |
| Imiquimod | Number of Participants With Partial Clearance of AK Lesions | 210 Participants |
p-value: 0.1895% CI: [0.87, 1.03]Cochran-Mantel-Haenszel