Trial Outcomes & Findings for A 12-Day Randomized, Blinded, Vehicle and Active Comparator-Controlled Study to Determine the Efficacy and Safety of Six Concentrations of Topical E6201 Gel in Subjects With Psoriasis Vulgaris (NCT NCT01268527)

Results Overview

The AUC was based on the baseline-corrected thickness of the psoriatic infiltrate (20 megahertz (MHz) Sonographic measurement) at specified days for each treatment field calculated by applying the linear trapezoidal rule. Sonographic measurements were performed using a 20 MHz high-frequency sonograph. Serial A-scans were composed and represented on a monitor as a section of the skin. A lateral resolution of approximately 200 um and an axial resolution of 80 um were possible. Dependent on the echo patterns, components of the epidermis, dermis, and subcutis were represented. Therefore, exact measurement of skin thickness was possible. The inflammatory psoriatic infiltrate was seen as a clearly definable echo lucent band below the entrance echo. The thickness of the echo lucent psoriatic band was determined. The thickness was measured in micrometers (um) and was denoted as T.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

30 participants

Primary outcome timeframe

Day 0 (Baseline), Day 8 (Visit 10), and Day 12 (End of Treatment)

Results posted on

2021-06-11

Participant Flow

Participant milestones

Participant milestones
Measure	Cohort 1 Three concentrations of E6201 topical gel (0.03%, 0.1%, and 0.2%) and active comparator, calcipotriene cream (0.005%), were applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site using separate tuberculin syringes that were filled with approximately 200 uL of each concentration of study treatment and comparator. Prior to each new application, remaining preparation residues were removed by gently cleansing each test field with a separate soft tissue. The fields to be treated were done in an occlusive manner for a treatment period of 12 days. Application time was to be kept as close as possible to the baseline application time, and was not to differ by more than +/- 4 hours. The 3 concentrations of E6201 gel were dosed first in Cohort 1 to establish the safety and tolerability prior to dosing in Cohort 2.	Cohort 2 Three concentrations of E6201 topical gel (0.005%, 0.01%, and 0.05%) and active comparator, calcipotriene cream (0.005%), were applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described for Cohort 1. Cohort 2 participants were not dosed until all participants in Cohort 1 completed treatment and safety data were collected and evaluated.
Overall Study STARTED	15	15
Overall Study COMPLETED	15	15
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

A 12-Day Randomized, Blinded, Vehicle and Active Comparator-Controlled Study to Determine the Efficacy and Safety of Six Concentrations of Topical E6201 Gel in Subjects With Psoriasis Vulgaris

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort 1 n=15 Participants Three concentrations of E6201 topical gel (0.03%, 0.1%, and 0.2%) and active comparator, calcipotriene cream (0.005%), were applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site using separate tuberculin syringes that were filled with approximately 200 uL of each concentration of study treatment and comparator. Prior to each new application, remaining preparation residues were removed by gently cleansing each test field with a separate soft tissue. The fields to be treated were done in an occlusive manner for a treatment period of 12 days. Application time was to be kept as close as possible to the baseline application time, and was not to differ by more than +/- 4 hours. The 3 concentrations of E6201 gel were dosed first in Cohort 1 to establish the safety and tolerability prior to dosing in Cohort 2.	Cohort 2 n=15 Participants Three concentrations of E6201 topical gel (0.005%, 0.01%, and 0.05%) and active comparator, calcipotriene cream (0.005%), were applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described for Cohort 1. Cohort 2 participants were not dosed until all participants in Cohort 1 completed treatment and safety data were collected and evaluated.	Total n=30 Participants Total of all reporting groups
Age, Continuous	47.4 Years STANDARD_DEVIATION 12.44 • n=99 Participants	50.6 Years STANDARD_DEVIATION 7.01 • n=107 Participants	49.0 Years STANDARD_DEVIATION 10.05 • n=206 Participants
Sex: Female, Male Female	2 Participants n=99 Participants	3 Participants n=107 Participants	5 Participants n=206 Participants
Sex: Female, Male Male	13 Participants n=99 Participants	12 Participants n=107 Participants	25 Participants n=206 Participants

PRIMARY outcome

Timeframe: Day 0 (Baseline), Day 8 (Visit 10), and Day 12 (End of Treatment)

Population: Full analysis population (Intent-to-treat population) included all randomized participants who received at least one application of at least one study treatment and had at least one postbaseline efficacy assessment.

The AUC was based on the baseline-corrected thickness of the psoriatic infiltrate (20 megahertz (MHz) Sonographic measurement) at specified days for each treatment field calculated by applying the linear trapezoidal rule. Sonographic measurements were performed using a 20 MHz high-frequency sonograph. Serial A-scans were composed and represented on a monitor as a section of the skin. A lateral resolution of approximately 200 um and an axial resolution of 80 um were possible. Dependent on the echo patterns, components of the epidermis, dermis, and subcutis were represented. Therefore, exact measurement of skin thickness was possible. The inflammatory psoriatic infiltrate was seen as a clearly definable echo lucent band below the entrance echo. The thickness of the echo lucent psoriatic band was determined. The thickness was measured in micrometers (um) and was denoted as T.

Outcome measures

Outcome measures
Measure	Daivonex (Calcipotriene Cream) n=30 Participants Daivonex (calcipotriene cream) at 0.005% was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site using a tuberculin syringe that was filled with approximately 200 uL of Daivonex. Prior to each new application, remaining preparation residues were removed by gently cleansing each test field with a separate soft tissue. The fields to be treated were done in an occlusive manner for a treatment period of 12 days. Application time was to be kept as close as possible to the baseline application time, and was not to differ by more than +/- 4 hours.	E6201 Vehicle n=30 Participants E6201 vehicle was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.005% E6201 Gel n=15 Participants E6201 gel (0.005%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.01% E6201 Gel n=15 Participants E6201 gel (0.01%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.03% E6201 Gel n=15 Participants E6201 gel (0.03%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.05% E6201 Gel n=15 Participants E6201 gel (0.05%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.1% E6201 Gel n=6 Participants E6201 gel (0.1%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.2% E6201 Gel n=6 Participants E6201 gel (0.2%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.
Summary Statistics and Primary Pairwise Comparison (Vehicle-E6201) of Area Under the Curve (AUC) for the Baseline-Corrected Thickness of the Psoriatic Infiltrate	-1449.2 um.day Interval -1660.0 to -1238.4	17.0 um.day Interval -64.3 to 98.3	-694.4 um.day Interval -1108.0 to -280.8	-1102.8 um.day Interval -1351.8 to -853.8	-763.1 um.day Interval -1548.2 to 22.1	-1758.2 um.day Interval -2134.3 to -1382.1	-904.4 um.day Interval -1303.4 to -505.4	-920.8 um.day Interval -1588.3 to -253.3

SECONDARY outcome

Timeframe: Day 12/Discontinuation (Visit 14/End of Treatment)

Population: Full analysis population (Intent-to-treat population) included all randomized participants who received at least one application of at least one study treatment and had at least one postbaseline efficacy assessment.

Psoriatic infiltrate thickness was determined by 20 MHz Sonographic measurements using a 20 MHz high-frequency sonograph. Serial-A scans were composed and represented on a monitor as a section of the skin. A lateral resolution of approximately 200 um and an axial resolution of 80 um were possible. Dependent on the echo patterns, components of the epidermis, dermis, and subcutis were represented. Therefore exact measurement of the skin thickness was possible. The inflammatory psoriatic infiltrate was seen as a clearly definable echo lucent back below the entrance echo. The thickness of the echo lucent psoriatic band was determined. Comparisons were made with the untreated plaque(s) beneath the hydrocolloid dressing. Baseline was defined as Visit 2 (Day 0). Least Squares Means (LSM) and Confidence Intervals (CI) were obtained from ANCOVA model with factors for treatment and baseline psoriatic infiltrate thickness as a continuous covariate.

Outcome measures

Outcome measures
Measure	Daivonex (Calcipotriene Cream) n=30 Participants Daivonex (calcipotriene cream) at 0.005% was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site using a tuberculin syringe that was filled with approximately 200 uL of Daivonex. Prior to each new application, remaining preparation residues were removed by gently cleansing each test field with a separate soft tissue. The fields to be treated were done in an occlusive manner for a treatment period of 12 days. Application time was to be kept as close as possible to the baseline application time, and was not to differ by more than +/- 4 hours.	E6201 Vehicle n=30 Participants E6201 vehicle was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.005% E6201 Gel n=15 Participants E6201 gel (0.005%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.01% E6201 Gel n=15 Participants E6201 gel (0.01%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.03% E6201 Gel n=15 Participants E6201 gel (0.03%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.05% E6201 Gel n=15 Participants E6201 gel (0.05%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.1% E6201 Gel n=6 Participants E6201 gel (0.1%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.2% E6201 Gel n=6 Participants E6201 gel (0.2%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.
Change in Thickness of the Psoriatic Infiltrate From Baseline to End of Treatment (Day 12/Discontinuation)	-205.3 um Interval -239.2 to -171.4	7.1 um Interval -32.2 to 46.3	-94.4 um Interval -154.5 to -34.3	-175.3 um Interval -206.5 to -144.1	-162.4 um Interval -194.1 to -130.7	-239.5 um Interval -295.8 to -183.2	-125.2 um Interval -202.3 to -48.2	-137.9 um Interval -218.3 to -57.6

SECONDARY outcome

Timeframe: Day 8 (Visit 10)

Population: Full analysis population (Intent-to-treat population) included all randomized participants who received at least one application of at least one study treatment and had at least one postbaseline efficacy assessment.

Psoriatic infiltrate thickness was determined by 20 MHz Sonographic measurements using a 20 MHz high-frequency sonograph. Serial-A scans were composed and represented on a monitor as a section of the skin. A lateral resolution of approximately 200 um and an axial resolution of 80 um were possible. Dependent on the echo patterns, components of the epidermis, dermis, and subcutis were represented. Therefore exact measurement of the skin thickness was possible. The inflammatory psoriatic infiltrate was seen as a clearly definable echo lucent back below the entrance echo. The thickness of the echo lucent psoriatic band was determined. Comparisons were made with the untreated plaque(s) beneath the hydrocolloid dressing. Baseline was defined as Visit 2 (Day 0). LSM and CI were obtained from ANCOVA model with factors for treatment and baseline psoriatic infiltrate thickness as a continuous covariate.

Outcome measures

Outcome measures
Measure	Daivonex (Calcipotriene Cream) n=30 Participants Daivonex (calcipotriene cream) at 0.005% was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site using a tuberculin syringe that was filled with approximately 200 uL of Daivonex. Prior to each new application, remaining preparation residues were removed by gently cleansing each test field with a separate soft tissue. The fields to be treated were done in an occlusive manner for a treatment period of 12 days. Application time was to be kept as close as possible to the baseline application time, and was not to differ by more than +/- 4 hours.	E6201 Vehicle n=30 Participants E6201 vehicle was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.005% E6201 Gel n=15 Participants E6201 gel (0.005%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.01% E6201 Gel n=15 Participants E6201 gel (0.01%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.03% E6201 Gel n=15 Participants E6201 gel (0.03%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.05% E6201 Gel n=15 Participants E6201 gel (0.05%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.1% E6201 Gel n=6 Participants E6201 gel (0.1%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.2% E6201 Gel n=6 Participants E6201 gel (0.2%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.
Change in Thickness of the Psoriatic Infiltrate From Baseline to Day 8	-151.7 um Interval -215.1 to -88.3	17.3 um Interval -20.2 to 54.8	-63.4 um Interval -110.3 to -16.5	-110.7 um Interval -147.3 to -74.0	-92.9 um Interval -200.1 to 14.3	-190.3 um Interval -243.6 to -136.9	-108.0 um Interval -162.9 to -53.1	-102.7 um Interval -172.6 to -32.9

SECONDARY outcome

Timeframe: Day 12/Discontinuation (Visit 14/End of Treatment)

Population: Full analysis population (Intent-to-treat population) included all randomized participants who received at least one application of at least one study treatment and had at least one postbaseline efficacy assessment.

Clinical (global) assessment of the test fields was performed using a 5-point score: -1 = worsened, 0 = unchanged (no effect), 1 = slight improvement, 2 = clear improvement but not completely healed, and 3 = completely healed. Comparisons were made with the untreated plaque(s) beneath the hydrocolloid dressing. Clinically apparent differences in erythema and infiltration contributed to the global assessment. Baseline was defined as Visit 2 (Day 0).

Outcome measures

Outcome measures
Measure	Daivonex (Calcipotriene Cream) n=30 Participants Daivonex (calcipotriene cream) at 0.005% was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site using a tuberculin syringe that was filled with approximately 200 uL of Daivonex. Prior to each new application, remaining preparation residues were removed by gently cleansing each test field with a separate soft tissue. The fields to be treated were done in an occlusive manner for a treatment period of 12 days. Application time was to be kept as close as possible to the baseline application time, and was not to differ by more than +/- 4 hours.	E6201 Vehicle n=30 Participants E6201 vehicle was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.005% E6201 Gel n=15 Participants E6201 gel (0.005%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.01% E6201 Gel n=15 Participants E6201 gel (0.01%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.03% E6201 Gel n=15 Participants E6201 gel (0.03%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.05% E6201 Gel n=15 Participants E6201 gel (0.05%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.1% E6201 Gel n=6 Participants E6201 gel (0.1%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.2% E6201 Gel n=6 Participants E6201 gel (0.2%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.
Clinical (Global) Assessment of Efficacy at Day 12/Discontinuation Worsened	0 Percentage of participants	0 Percentage of participants	0 Percentage of participants	0 Percentage of participants	0 Percentage of participants	0 Percentage of participants	0 Percentage of participants	0 Percentage of participants
Clinical (Global) Assessment of Efficacy at Day 12/Discontinuation Unchanged (no effect)	6.7 Percentage of participants	90.0 Percentage of participants	20.0 Percentage of participants	0 Percentage of participants	6.7 Percentage of participants	0 Percentage of participants	0 Percentage of participants	0 Percentage of participants
Clinical (Global) Assessment of Efficacy at Day 12/Discontinuation Slight improvement	56.7 Percentage of participants	10.0 Percentage of participants	66.7 Percentage of participants	33.3 Percentage of participants	46.7 Percentage of participants	13.3 Percentage of participants	83.3 Percentage of participants	83.3 Percentage of participants
Clinical (Global) Assessment of Efficacy at Day 12/Discontinuation Clear improvement but not completely healed	33.3 Percentage of participants	0 Percentage of participants	13.3 Percentage of participants	66.7 Percentage of participants	46.7 Percentage of participants	86.7 Percentage of participants	16.7 Percentage of participants	0 Percentage of participants
Clinical (Global) Assessment of Efficacy at Day 12/Discontinuation Completely healed	3.3 Percentage of participants	0 Percentage of participants	0 Percentage of participants	0 Percentage of participants	0 Percentage of participants	0 Percentage of participants	0 Percentage of participants	16.7 Percentage of participants

SECONDARY outcome

Timeframe: Day 8 (Visit 10)

Population: Full analysis population (Intent-to-treat population) included all randomized participants who received at least one application of at least one study treatment and had at least one postbaseline efficacy assessment.

Clinical (global) assessment of the test fields was performed using a 5-point score: -1 = worsened, 0 = unchanged (no effect), 1 = slight improvement, 2 = clear improvement but not completely healed, and 3 = completely healed. Comparisons were made with the untreated plaque(s) beneath the hydrocolloid dressing. Clinically apparent differences in erythema and infiltration contributed to the global assessment. Baseline was defined as Visit 2 (Day 0).

Outcome measures

Outcome measures
Measure	Daivonex (Calcipotriene Cream) n=30 Participants Daivonex (calcipotriene cream) at 0.005% was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site using a tuberculin syringe that was filled with approximately 200 uL of Daivonex. Prior to each new application, remaining preparation residues were removed by gently cleansing each test field with a separate soft tissue. The fields to be treated were done in an occlusive manner for a treatment period of 12 days. Application time was to be kept as close as possible to the baseline application time, and was not to differ by more than +/- 4 hours.	E6201 Vehicle n=30 Participants E6201 vehicle was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.005% E6201 Gel n=15 Participants E6201 gel (0.005%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.01% E6201 Gel n=15 Participants E6201 gel (0.01%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.03% E6201 Gel n=15 Participants E6201 gel (0.03%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.05% E6201 Gel n=15 Participants E6201 gel (0.05%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.1% E6201 Gel n=6 Participants E6201 gel (0.1%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.	0.2% E6201 Gel n=6 Participants E6201 gel (0.2%) was applied once daily for 12 days to specific test fields determined at Baseline. Study treatments were applied at the research unit by designated personnel of the investigational site in the same manner as described earlier.
Clinical (Global) Assessment of Efficacy on Day 8 Clear improvement but not completely healed	30.0 Percentage of participants	0 Percentage of participants	0 Percentage of participants	40.0 Percentage of participants	26.7 Percentage of participants	86.7 Percentage of participants	0 Percentage of participants	0 Percentage of participants
Clinical (Global) Assessment of Efficacy on Day 8 Unchanged (no effect)	20.0 Percentage of participants	90.0 Percentage of participants	33.3 Percentage of participants	6.7 Percentage of participants	6.7 Percentage of participants	0 Percentage of participants	16.7 Percentage of participants	0 Percentage of participants
Clinical (Global) Assessment of Efficacy on Day 8 Worsened	3.3 Percentage of participants	3.3 Percentage of participants	0 Percentage of participants	0 Percentage of participants	6.7 Percentage of participants	0 Percentage of participants	0 Percentage of participants	0 Percentage of participants
Clinical (Global) Assessment of Efficacy on Day 8 Slight improvement	46.7 Percentage of participants	6.7 Percentage of participants	66.7 Percentage of participants	53.3 Percentage of participants	60.0 Percentage of participants	13.3 Percentage of participants	83.3 Percentage of participants	100 Percentage of participants
Clinical (Global) Assessment of Efficacy on Day 8 Completely healed	0 Percentage of participants	0 Percentage of participants	0 Percentage of participants	0 Percentage of participants	0 Percentage of participants	0 Percentage of participants	0 Percentage of participants	0 Percentage of participants

SECONDARY outcome

Timeframe: From first dose of study treatment up to 30 days after the last dose, or until resolution, whichever came first, or up to approximately 10 months.

Population: Safety population included all participants who received at least one application of at least one study treatment and had at least one postdose safety assessment.

TEAEs were defined as an adverse event (AE) that emerged during treatment, having been absent at pretreatment (baseline), or re-emerged during treatment, having been present at baseline but stopped prior to treatment, or worsened in severity during treatment relative to the pretreatment state, when the AE was continuous. Safety variables included TEAEs including skin reactions, diascopy and biopsy findings, clinical laboratory parameters, vital signs, and physical examinations. For Cohort 2, special attention was given to a close, daily monitoring of the application site for signs of skin irritation. Any suspected ecchymoses or petechiae were to be followed up with a diascopy test that was to be documented with digital photographs. Any positive diascopy test was to be followed up by biopsy for skin ultrastructural analysis (if agreed to by the participant, sponsor, and investigator). Few adverse events occurred in more than one treatment group.