Actinic Keratosis
Conditions
Keywords
actinic keratosis, skin disease
Brief summary
The objective of this study is to evaluate the efficacy and safety of imiquimod cream versus placebo cream when used after cryosurgery in the treatment of actinic keratoses (AKs).
Detailed description
In this multicenter, randomized, double-blind, placebo-controlled study, the efficacy and safety of imiquimod 3.75% cream following cryosurgery to treat clinically typical visible or palpable AK lesions on the face was compared with that of placebo cream. Based on a 1:1 randomization, approximately 120 subjects applied imiquimod 3.75% cream daily (up to 500 mg cream daily \[18.75 mg imiquimod\]) and approximately 120 subjects applied placebo cream daily during two 2-week periods (Cycle 1 and Cycle 2) separated by 2 weeks of no treatment. Subjects visited the clinic 9 times-1 screening/cryosurgery visit (additional visits might be needed during the screening period to assess healing from the cryosurgery), 4 treatment visits(treatment initiation at Weeks 0 and 4 and treatment follow-up at the end of Weeks 2 and 6), and 4 posttreatment visits (4, 8, 14, and 20 weeks after the last administration of study treatment at the end of Week 6). The total study duration for a subject, including a 2-week screening period, was up to 28 weeks. Prior to cryosurgery, subjects had to have ≥10 clinically typical visible or palpable AK lesions in an area that exceeded 25 cm\^2 on the face to be eligible for participation in the study. At screening, a minimum of 5 visible lesions were not treated with cryosurgery, and 5 to 14 visible lesions were treated with cryosurgery. Subjects had to have at least 5 AK lesions after the skin healed sufficiently from the cryosurgery to be eligible for randomization to either imiquimod 3.75% or placebo cream. Subjects applied up to 2 packets of study cream (500 mg total) as a thin layer to the entire face, avoiding the periocular areas, lips, and nares; ears were excluded from both assessment and treatment. Study cream was applied prior to normal sleeping hours and removed approximately 8 hours later with mild soap and water. Rest periods from daily treatment could be approved by the investigator as needed, with treatment resumption at the investigator's discretion.
Interventions
DRUGimiquimod cream
Imiquimod 3.75% cream (250 mg/packet) up to 2 packets applied daily Two 2-week treatment periods (Cycle 1 and Cycle 2) separated by a 2-week no-treatment period
DRUGplacebo cream
cream applied once daily for two 2-week treatment periods (Cycle 1 and Cycle 2) separated by a 2-week no-treatment period
Sponsors
Graceway Pharmaceuticals, LLC
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
* In good general health * Negative urine pregnancy test (for women of child-bearing potential) and agree to use an approved method of birth control while enrolled in the study. * Prior to cryosurgery, have ≥ 10 clinically typical (visible or palpable) AKs in an area that exceeds 25 cm2 on the face. * Must have had cryosurgery on 5 to 14 AKs on the face after giving informed consent and prior to receiving study medication. Lesions previously treated with cryosurgery must be healed sufficiently prior to randomization to study cream. * Following cryosurgery, have ≥ 5 clinically typical (visible or palpable) AKs in an area that exceeds 25 cm2 on the face that are suitable for treatment with the study cream.
Exclusion criteria
* Women who are pregnant, lactating, or planning to become pregnant during the study * Had a medical event within 90 days of the visit (e.g., stroke, heart attack, etc.). * Have any skin condition in the treatment area that may be made worse by treatment with imiquimod (e.g., rosacea, psoriasis, atopic dermatitis, eczema). * Have received specific treatments/medications in the treatment area within the designated time period prior to study treatment initiation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Percentage of Lesion Count | Week 26 | The primary efficacy endpoint was a comparison between the active and placebo treatment groups of percent change from baseline in the total AK lesion count at Week 26. All AK lesions on the face were included in the analysis-treated and untreated AK lesions at baseline (defined as the AK lesion count just prior to cryosurgery) and new lesions that appeared post-baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Subjects With Complete Clearance | Week 26 | Proportion of subjects who achieved complete clearance of all AK lesions, cryosurgery-treated AK lesions, and non cryosurgery-treated AK lesions from baseline to Week 26/EOS in the ITT population. |
| Number of Participants With Any Post-baseline Local Skin Reactions (LSRs) | Weeks 2, 4, 6, 10, 14, 20, and 26 | LSRs were assessed independently from AEs. The frequency and percentage of subjects, as well as the mean (SD) and median score for severity (none=0, mild=1, moderate=2, and severe=3), were summarized by treatment group and by visit for the following LSRs: erythema, edema, weeping/exudates, flaking/ scaling/dryness, and scabbing/crusting. Erosion and ulceration were also evaluated (none=0, erosion=1, and ulceration=2). A score of greater than 0 for the specified LSR was considered a treatment site reaction. |
Countries
Canada, United States
Participant flow
Recruitment details
Subjects were screened in 20 sites-16 in the United States of America (U.S.A.) and 4 in Canada. Screening began on 01 Jun 2009 and the last subject was enrolled on 03 Aug 2009.
Pre-assignment details
Subjects had to have ≥10 AK lesions in an area the face to participate in the study. At screening, at least 5 visible lesions were not treated with cryosurgery, and 5 to 14 visible lesions were treated with cryosurgery. Subjects needed at least 5 AK lesions after the skin healed sufficiently from the cryosurgery to be eligible for randomization.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Cream placebo cream in 250 mg/packet, up to 2 packets applied daily | 121 |
| Imiquimod Cream Imiquimod 3.75% cream, 250 mg single-use packets, up to 2 packets applied daily | 126 |
| Total | 247 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 4 |
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | Non-compliance with study procedures | 0 | 2 |
| Overall Study | Other, not due to AE | 1 | 2 |
| Overall Study | Withdrawal by Subject | 4 | 4 |
Baseline characteristics
| Characteristic | Placebo Cream | Imiquimod Cream | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 73 Participants | 63 Participants | 136 Participants |
| Age, Categorical Between 18 and 65 years | 48 Participants | 63 Participants | 111 Participants |
| Age Continuous | 67.3 years STANDARD_DEVIATION 10.05 | 66.0 years STANDARD_DEVIATION 9.49 | 66.7 years STANDARD_DEVIATION 9.77 |
| Region of Enrollment Canada | 31 participants | 35 participants | 66 participants |
| Region of Enrollment United States | 90 participants | 91 participants | 181 participants |
| Sex: Female, Male Female | 15 Participants | 18 Participants | 33 Participants |
| Sex: Female, Male Male | 106 Participants | 108 Participants | 214 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 28 / 121 | 54 / 126 |
| serious Total, serious adverse events | 2 / 121 | 6 / 126 |
Outcome results
Primary
Change From Baseline in Percentage of Lesion Count
The primary efficacy endpoint was a comparison between the active and placebo treatment groups of percent change from baseline in the total AK lesion count at Week 26. All AK lesions on the face were included in the analysis-treated and untreated AK lesions at baseline (defined as the AK lesion count just prior to cryosurgery) and new lesions that appeared post-baseline.
Time frame: Week 26
Population: Intent to treat population, Last Observation Carried Forward (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Cream | Change From Baseline in Percentage of Lesion Count | -43.3 percentage of lesion count | Standard Deviation 30.66 |
| Imiquimod Cream | Change From Baseline in Percentage of Lesion Count | -77.4 percentage of lesion count | Standard Deviation 27.54 |
Secondary
Number of Participants With Any Post-baseline Local Skin Reactions (LSRs)
LSRs were assessed independently from AEs. The frequency and percentage of subjects, as well as the mean (SD) and median score for severity (none=0, mild=1, moderate=2, and severe=3), were summarized by treatment group and by visit for the following LSRs: erythema, edema, weeping/exudates, flaking/ scaling/dryness, and scabbing/crusting. Erosion and ulceration were also evaluated (none=0, erosion=1, and ulceration=2). A score of greater than 0 for the specified LSR was considered a treatment site reaction.
Time frame: Weeks 2, 4, 6, 10, 14, 20, and 26
Population: Safety population: all randomized subjects were presumed to have applied at least one application of study medication and were included in the safety population. This population was used for all safety analyses. Subjects were analyzed as treated.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo Cream | Number of Participants With Any Post-baseline Local Skin Reactions (LSRs) | Edema | 9 participants |
| Placebo Cream | Number of Participants With Any Post-baseline Local Skin Reactions (LSRs) | Erythema | 88 participants |
| Placebo Cream | Number of Participants With Any Post-baseline Local Skin Reactions (LSRs) | Weeping/Exudate | 9 participants |
| Placebo Cream | Number of Participants With Any Post-baseline Local Skin Reactions (LSRs) | Flaking/Scaling/Dryness | 3 participants |
| Placebo Cream | Number of Participants With Any Post-baseline Local Skin Reactions (LSRs) | Scabbing, crusting | 81 participants |
| Placebo Cream | Number of Participants With Any Post-baseline Local Skin Reactions (LSRs) | Erosion/Ulceration | 22 participants |
| Imiquimod Cream | Number of Participants With Any Post-baseline Local Skin Reactions (LSRs) | Scabbing, crusting | 112 participants |
| Imiquimod Cream | Number of Participants With Any Post-baseline Local Skin Reactions (LSRs) | Edema | 93 participants |
| Imiquimod Cream | Number of Participants With Any Post-baseline Local Skin Reactions (LSRs) | Flaking/Scaling/Dryness | 114 participants |
| Imiquimod Cream | Number of Participants With Any Post-baseline Local Skin Reactions (LSRs) | Erythema | 125 participants |
| Imiquimod Cream | Number of Participants With Any Post-baseline Local Skin Reactions (LSRs) | Erosion/Ulceration | 60 participants |
| Imiquimod Cream | Number of Participants With Any Post-baseline Local Skin Reactions (LSRs) | Weeping/Exudate | 64 participants |
Secondary
Percent of Subjects With Complete Clearance
Proportion of subjects who achieved complete clearance of all AK lesions, cryosurgery-treated AK lesions, and non cryosurgery-treated AK lesions from baseline to Week 26/EOS in the ITT population.
Time frame: Week 26
Population: Intent to treat (ITT) population, last observation carried forward (LOCF)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Cream | Percent of Subjects With Complete Clearance | 3 percentage of participants |
| Imiquimod Cream | Percent of Subjects With Complete Clearance | 30 percentage of participants |