A new aqueous-based tretinoin gel 0.05% (Atralin) from Coria Laboratories has been formulated and studied for treatment of acne vulgaris, including Phase III trials. The major objectives were to:
1. develop a tretinoin formulation that exhibited efficacy comparable or superior to other topical retinoid formulations.
2. produce a formulation of tretinoin with a highly favorable tolerability profile.
In addition to purified water, the tretinoin gel 0.05% also contains specific excipients such as glycerin and sodium hyaluronate to assist in minimizing irritation.
Multicenter, investigator-blinded, randomized, vehicle-controlled Phase III trials have been completed evaluating the efficacy and safety of the tretinoin aqueous gel 0.05% applied once daily in patients with mild to moderate facial acne vulgaris, including non-inferiority comparison evaluations with tretinoin microsphere gel 0.1%. The following review highlights results from two studies — the first, a Phase III trial comparing the safety and efficacy of tretinoin gel 0.05% vs. tretinoin gel vehicle, and the second, a study of the efficacy and safety of tretinoin gel 0.05% vs. tretinoin microsphere gel 0.1% vs. tretinoin gel vehicle.
Phase III Trials with Tretinoin Aqueous Gel 0.05% in Acne Vulgaris
Tretinoin Gel 0.05% vs. Tretinoin Gel Vehicle: Efficacy and Safety
Overview. The efficacy and safety of tretinoin gel 0.05% was compared to its gel vehicle in a multicenter, investigator-blinded, randomized, two-arm, 12-week trial in study participants who had mild to moderate facial acne vulgaris. The participants were randomized 1:1 to receive either active study drug (n=299) or vehicle (n=302). The age range of subjects was 10 years to 65 years, with an average of 18.7 years and 19.1 years in the active and vehicle arms, respectively. Distributions of gender and skin phototype (~60% types III or IV in both arms) were approximately equal. The study drug was applied once daily at bedtime, and patients were evaluated at baseline and at weeks 1, 2, 4, 8, and 12 (endpoint).
A study analysis for superiority was conducted on both intent-to-treat (ITT) and per-protocol subject populations. A significance level (p value) of 0.05 was used during two-sided hypothesis testing for statistical evaluation. Last observation carried forward methodology was used to extrapolate missing lesion count and Global Severity evaluation data for subjects who prematurely discontinued the study. Recognized methods for informed consent with patients and parents/legal guardians (for minors) were utilized.
Study Criteria. Male and female participants who were ≥10 years of age were required to present with mild to moderate facial acne vulgaris based on an investigator Global Severity rating of 3 (mildly moderate) or 4 (moderate) at baseline. All study participants exhibited a baseline non-inflammatory acne lesion count (open and/or closed comedones) involving the face (including the nose) ranging from 30 to 125 lesions. The required baseline inflammatory (papules and/or pustules) lesion count range involving the face (including the nose) was 15 to 40 lesions. Patients were not included in the study if they demonstrated >3 nodules and/or cysts.
Conventional exclusion criteria for Phase III acne vulgaris trials were utilized, including pregnancy, nursing, and established washout periods for other specific medications such as other acne drugs or agents that could potentially influence study outcomes.
Study Endpoints. The primary efficacy parameters were absolute reduction from baseline in inflammatory and non-inflammatory lesion counts at week 12, and intergroup differences in the dichotomized Global Severity rating at week 12, although data were captured for all evaluations at each follow-up visit. The investigator Global Severity ratings were dichotomized into treatment “success” or “failure,” with “success” defined as a rating of 0 (clear) or 1 (almost clear) at week 12 plus at least a 2-grade decrease in Global Severity at week 12, as compared to baseline. Secondary efficacy variables included the mean percent change from baseline to week 12 in inflammatory and non-inflammatory lesion counts.
Safety Variables. Safety evaluations were carried out on all randomized study participants and were based on evaluation of adverse events, review of concomitant medications over the course of the study, and extent of drug exposure.
Efficacy Results. The primary and secondary efficacy results at week 12 are depicted in Table 1.
Safety Results. The majority of adverse events reported by study participants were related to the skin, and most were mild to moderate in severity and resolved. In the tretinoin gel arm, 24% of patients reported cutaneous adverse events; in the vehicle arm, 3% of subjects reported cutaneous adverse events. Regarding specific cutaneous reactions, dry skin, burning sensation, and peeling (exfoliation) were more common in the active therapy arm, with statistically significant differences noted (p<0.001 for all three adverse events). These findings were consistent with what would be expected with application of a topical retinoid. Out of 84 anticipated doses, patients in the tretinoin gel 0.05% group and vehicle group applied an average of 78.4 and 79.1 doses, respectively, suggesting favorable compliance.
Tretinoin Gel 0.05% vs. Tretinoin Microsphere Gel 0.1% vs. Tretinoin Gel Vehicle: Efficacy and Safety
Overview. The efficacy and safety of tretinoin gel 0.05% was compared to its gel vehicle and to tretinoin microsphere gel 0.1% in a multicenter, investigator-blinded, randomized, three-arm, 12-week trial in patients with mild to moderate facial acne vulgaris. Study participants were randomized 2:2:1 to receive either tretinoin gel 0.05% (n=375), its gel vehicle (n=185), or tretinoin microsphere gel 0.1% (n=376). The age range of subjects was 10 to 53 years, with an average of 18.5 years across all three study arms.
Distributions of gender and skin phototype (predominantly types III and IV) were approximately equal in both study groups, with 70% of patients being Caucasian. No significant differences were noted overall in demographics between groups for mean age, gender, race, and skin phototype. The study drug was applied once daily at bedtime, and patients were evaluated at baseline and weeks 1, 2, 4, 8, and 12 (endpoint).
A study analysis for superiority was conducted for comparison with vehicle and for non-inferiority between both actively treated study arms. Primary analyses of non-inferiority testing were conducted on both ITT and per-protocol (PP) populations, and superiority testing on the ITT population. Non-inferiority testing used the one-sided 97.5% confidence interval approach with a non-inferiority margin of 10% for percent change in lesion counts and dichotomized Global Severity grading. Recognized methods for informed consent with patients and parents (for minors) were utilized.
Study Criteria. Male and female patients ≥10 years of age were required to present with mild to moderate facial acne vulgaris based on an investigator Global Severity grade of 2 through 4. The protocol mandated that subjects exhibit a baseline non-inflammatory acne lesion count (open and/or closed comedones) involving the face (including the nose) ranging from 30 to 125 lesions. The required baseline inflammatory (papules and/or pustules) lesion count range involving the face (including the nose) was 15 to 40 lesions. Subjects were not allowed to enroll in the study if they demonstrated >3 nodules and/or cysts, which were excluded from lesion counts. At baseline, the majority of enrolled subjects in each arm (53% to 55%), demonstrated a severity grade of 3 (mildly-moderate severity), an average of 50 non-inflammatory lesions, 24 inflammatory lesions, and 74 total acne lesions. Conventional exclusion criteria for Phase III acne vulgaris trials were utilized, including pregnancy, nursing, and established washout periods for other specific medications such as other acne drugs or agents which could potentially influence study outcome.
Efficacy Endpoints. The primary efficacy parameters were median percent reduction from baseline in at least two of the following three variables: inflammatory lesion count, non-inflammatory lesion count, and total lesion count, at week 12, and dichotomized Global Severity rating at week 12, although data was captured for all evaluations at each follow-up visit. Investigator Global Severity grading was static using a 6-point scale (0 to 5) with results divided into “success” or “failure.” “Success” was defined as a rating of 0 (clear) or 1 (almost clear) at week 12 (end of study).
Safety Variables. Safety analysis included evaluation of plasma concentrations of tretinoin and its metabolites, 13-cis-retinoic acid and 4-oxo-13-cis-retinoic acid at week 12, performed in a subset of subjects (105 blood samples from three centers). Safety evaluations were carried out on all randomized subjects inclusive of adverse events observed by the investigator or reported by the patient, regardless of suspected causality. Assessments of severity and causality were based on specific definitions.
Efficacy Results. Efficacy results are shown in Table 2 for both the non-inferiority and superiority analyses based on the ITT population data. Results were similar for both the ITT and PP populations. Figure 1 graphically demonstrates total acne lesion count reduction for both tretinoin gel 0.05% and tretinoin microsphere gel 0.1% over a 12-week duration.
Safety Results. The observed plasma concentration levels for tretinoin and its metabolites determined before and after study drug application were in the range reported for endogenous levels of these compounds. Change from baselines was not statistically significant for any of the study arms for comparison of tretinoin (p=0.792), 13-cis-retinoic acid (p=0.827), or 4-oxo-13-cis-retinoic acid (p=0.666).
The most common adverse events were cutaneous, with 36% observed in the tretinoin gel 0.05% group, 52% reported in the tretinoin microsphere gel 0.1% group and 9% noted in the vehicle gel group. Reported skin reactions included dry skin, erythema, burning sensation and peeling (exfoliation), consistent with those reported overall with topical retinoid use. Few subjects in any of the study arms (<0.01%) withdrew from the trial demonstrating that cutaneous adverse events were manageable without need to discontinue the study medication.
Summary
• In a large Phase III trial, tretinoin gel 0.05% formulated in a novel aqueous-base proved to be superior to its vehicle in absolute inflammatory lesion count reduction (p=0.001), mean percent inflammatory lesion count reduction (p=0.001), absolute non-inflammatory lesion count reduction (p=0.001), mean percent non-inflammatory lesion count reduction (p=0.001), and static assessment of dichotomized Global Severity at the end of the 12 week study (p=0.002). A second Phase III trial further confirmed the superiority of tretinoin gel 0.05% over its vehicle.
• The majority of subjects utilizing either tretinoin gel 0.05% or its vehicle were compliant with dosing.
• Adverse events associated with either tretinoin gel 0.05% or its vehicle were primarily cutaneous in nature, mild to moderate in severity, and generally reversible without need for discontinuation from clinical trials.
• Tretinoin gel 0.05%, in a comparison trial with tretinoin microsphere gel 0.1%, demonstrated a more favorable skin tolerability profile. The trial did not confirm non-inferiority of tretinoin gel 0.05% to tretinoin microsphere gel 0.1%; however, the differences in median percent change in inflammatory lesion count reduction and non-inflammatory lesion count reduction were 8.3% and 10.7%, respectively. The time course trend of the changes in total acne lesion reduction between tretinoin gel 0.05% and tretinoin microsphere gel 0.1% were similar at all time points over the 12-week course of the trial.
Presented as a poster at Fall Clinical Dermatology in Las Vegas, October 2007.
A new aqueous-based tretinoin gel 0.05% (Atralin) from Coria Laboratories has been formulated and studied for treatment of acne vulgaris, including Phase III trials. The major objectives were to:
1. develop a tretinoin formulation that exhibited efficacy comparable or superior to other topical retinoid formulations.
2. produce a formulation of tretinoin with a highly favorable tolerability profile.
In addition to purified water, the tretinoin gel 0.05% also contains specific excipients such as glycerin and sodium hyaluronate to assist in minimizing irritation.
Multicenter, investigator-blinded, randomized, vehicle-controlled Phase III trials have been completed evaluating the efficacy and safety of the tretinoin aqueous gel 0.05% applied once daily in patients with mild to moderate facial acne vulgaris, including non-inferiority comparison evaluations with tretinoin microsphere gel 0.1%. The following review highlights results from two studies — the first, a Phase III trial comparing the safety and efficacy of tretinoin gel 0.05% vs. tretinoin gel vehicle, and the second, a study of the efficacy and safety of tretinoin gel 0.05% vs. tretinoin microsphere gel 0.1% vs. tretinoin gel vehicle.
Phase III Trials with Tretinoin Aqueous Gel 0.05% in Acne Vulgaris
Tretinoin Gel 0.05% vs. Tretinoin Gel Vehicle: Efficacy and Safety
Overview. The efficacy and safety of tretinoin gel 0.05% was compared to its gel vehicle in a multicenter, investigator-blinded, randomized, two-arm, 12-week trial in study participants who had mild to moderate facial acne vulgaris. The participants were randomized 1:1 to receive either active study drug (n=299) or vehicle (n=302). The age range of subjects was 10 years to 65 years, with an average of 18.7 years and 19.1 years in the active and vehicle arms, respectively. Distributions of gender and skin phototype (~60% types III or IV in both arms) were approximately equal. The study drug was applied once daily at bedtime, and patients were evaluated at baseline and at weeks 1, 2, 4, 8, and 12 (endpoint).
A study analysis for superiority was conducted on both intent-to-treat (ITT) and per-protocol subject populations. A significance level (p value) of 0.05 was used during two-sided hypothesis testing for statistical evaluation. Last observation carried forward methodology was used to extrapolate missing lesion count and Global Severity evaluation data for subjects who prematurely discontinued the study. Recognized methods for informed consent with patients and parents/legal guardians (for minors) were utilized.
Study Criteria. Male and female participants who were ≥10 years of age were required to present with mild to moderate facial acne vulgaris based on an investigator Global Severity rating of 3 (mildly moderate) or 4 (moderate) at baseline. All study participants exhibited a baseline non-inflammatory acne lesion count (open and/or closed comedones) involving the face (including the nose) ranging from 30 to 125 lesions. The required baseline inflammatory (papules and/or pustules) lesion count range involving the face (including the nose) was 15 to 40 lesions. Patients were not included in the study if they demonstrated >3 nodules and/or cysts.
Conventional exclusion criteria for Phase III acne vulgaris trials were utilized, including pregnancy, nursing, and established washout periods for other specific medications such as other acne drugs or agents that could potentially influence study outcomes.
Study Endpoints. The primary efficacy parameters were absolute reduction from baseline in inflammatory and non-inflammatory lesion counts at week 12, and intergroup differences in the dichotomized Global Severity rating at week 12, although data were captured for all evaluations at each follow-up visit. The investigator Global Severity ratings were dichotomized into treatment “success” or “failure,” with “success” defined as a rating of 0 (clear) or 1 (almost clear) at week 12 plus at least a 2-grade decrease in Global Severity at week 12, as compared to baseline. Secondary efficacy variables included the mean percent change from baseline to week 12 in inflammatory and non-inflammatory lesion counts.
Safety Variables. Safety evaluations were carried out on all randomized study participants and were based on evaluation of adverse events, review of concomitant medications over the course of the study, and extent of drug exposure.
Efficacy Results. The primary and secondary efficacy results at week 12 are depicted in Table 1.
Safety Results. The majority of adverse events reported by study participants were related to the skin, and most were mild to moderate in severity and resolved. In the tretinoin gel arm, 24% of patients reported cutaneous adverse events; in the vehicle arm, 3% of subjects reported cutaneous adverse events. Regarding specific cutaneous reactions, dry skin, burning sensation, and peeling (exfoliation) were more common in the active therapy arm, with statistically significant differences noted (p<0.001 for all three adverse events). These findings were consistent with what would be expected with application of a topical retinoid. Out of 84 anticipated doses, patients in the tretinoin gel 0.05% group and vehicle group applied an average of 78.4 and 79.1 doses, respectively, suggesting favorable compliance.
Tretinoin Gel 0.05% vs. Tretinoin Microsphere Gel 0.1% vs. Tretinoin Gel Vehicle: Efficacy and Safety
Overview. The efficacy and safety of tretinoin gel 0.05% was compared to its gel vehicle and to tretinoin microsphere gel 0.1% in a multicenter, investigator-blinded, randomized, three-arm, 12-week trial in patients with mild to moderate facial acne vulgaris. Study participants were randomized 2:2:1 to receive either tretinoin gel 0.05% (n=375), its gel vehicle (n=185), or tretinoin microsphere gel 0.1% (n=376). The age range of subjects was 10 to 53 years, with an average of 18.5 years across all three study arms.
Distributions of gender and skin phototype (predominantly types III and IV) were approximately equal in both study groups, with 70% of patients being Caucasian. No significant differences were noted overall in demographics between groups for mean age, gender, race, and skin phototype. The study drug was applied once daily at bedtime, and patients were evaluated at baseline and weeks 1, 2, 4, 8, and 12 (endpoint).
A study analysis for superiority was conducted for comparison with vehicle and for non-inferiority between both actively treated study arms. Primary analyses of non-inferiority testing were conducted on both ITT and per-protocol (PP) populations, and superiority testing on the ITT population. Non-inferiority testing used the one-sided 97.5% confidence interval approach with a non-inferiority margin of 10% for percent change in lesion counts and dichotomized Global Severity grading. Recognized methods for informed consent with patients and parents (for minors) were utilized.
Study Criteria. Male and female patients ≥10 years of age were required to present with mild to moderate facial acne vulgaris based on an investigator Global Severity grade of 2 through 4. The protocol mandated that subjects exhibit a baseline non-inflammatory acne lesion count (open and/or closed comedones) involving the face (including the nose) ranging from 30 to 125 lesions. The required baseline inflammatory (papules and/or pustules) lesion count range involving the face (including the nose) was 15 to 40 lesions. Subjects were not allowed to enroll in the study if they demonstrated >3 nodules and/or cysts, which were excluded from lesion counts. At baseline, the majority of enrolled subjects in each arm (53% to 55%), demonstrated a severity grade of 3 (mildly-moderate severity), an average of 50 non-inflammatory lesions, 24 inflammatory lesions, and 74 total acne lesions. Conventional exclusion criteria for Phase III acne vulgaris trials were utilized, including pregnancy, nursing, and established washout periods for other specific medications such as other acne drugs or agents which could potentially influence study outcome.
Efficacy Endpoints. The primary efficacy parameters were median percent reduction from baseline in at least two of the following three variables: inflammatory lesion count, non-inflammatory lesion count, and total lesion count, at week 12, and dichotomized Global Severity rating at week 12, although data was captured for all evaluations at each follow-up visit. Investigator Global Severity grading was static using a 6-point scale (0 to 5) with results divided into “success” or “failure.” “Success” was defined as a rating of 0 (clear) or 1 (almost clear) at week 12 (end of study).
Safety Variables. Safety analysis included evaluation of plasma concentrations of tretinoin and its metabolites, 13-cis-retinoic acid and 4-oxo-13-cis-retinoic acid at week 12, performed in a subset of subjects (105 blood samples from three centers). Safety evaluations were carried out on all randomized subjects inclusive of adverse events observed by the investigator or reported by the patient, regardless of suspected causality. Assessments of severity and causality were based on specific definitions.
Efficacy Results. Efficacy results are shown in Table 2 for both the non-inferiority and superiority analyses based on the ITT population data. Results were similar for both the ITT and PP populations. Figure 1 graphically demonstrates total acne lesion count reduction for both tretinoin gel 0.05% and tretinoin microsphere gel 0.1% over a 12-week duration.
Safety Results. The observed plasma concentration levels for tretinoin and its metabolites determined before and after study drug application were in the range reported for endogenous levels of these compounds. Change from baselines was not statistically significant for any of the study arms for comparison of tretinoin (p=0.792), 13-cis-retinoic acid (p=0.827), or 4-oxo-13-cis-retinoic acid (p=0.666).
The most common adverse events were cutaneous, with 36% observed in the tretinoin gel 0.05% group, 52% reported in the tretinoin microsphere gel 0.1% group and 9% noted in the vehicle gel group. Reported skin reactions included dry skin, erythema, burning sensation and peeling (exfoliation), consistent with those reported overall with topical retinoid use. Few subjects in any of the study arms (<0.01%) withdrew from the trial demonstrating that cutaneous adverse events were manageable without need to discontinue the study medication.
Summary
• In a large Phase III trial, tretinoin gel 0.05% formulated in a novel aqueous-base proved to be superior to its vehicle in absolute inflammatory lesion count reduction (p=0.001), mean percent inflammatory lesion count reduction (p=0.001), absolute non-inflammatory lesion count reduction (p=0.001), mean percent non-inflammatory lesion count reduction (p=0.001), and static assessment of dichotomized Global Severity at the end of the 12 week study (p=0.002). A second Phase III trial further confirmed the superiority of tretinoin gel 0.05% over its vehicle.
• The majority of subjects utilizing either tretinoin gel 0.05% or its vehicle were compliant with dosing.
• Adverse events associated with either tretinoin gel 0.05% or its vehicle were primarily cutaneous in nature, mild to moderate in severity, and generally reversible without need for discontinuation from clinical trials.
• Tretinoin gel 0.05%, in a comparison trial with tretinoin microsphere gel 0.1%, demonstrated a more favorable skin tolerability profile. The trial did not confirm non-inferiority of tretinoin gel 0.05% to tretinoin microsphere gel 0.1%; however, the differences in median percent change in inflammatory lesion count reduction and non-inflammatory lesion count reduction were 8.3% and 10.7%, respectively. The time course trend of the changes in total acne lesion reduction between tretinoin gel 0.05% and tretinoin microsphere gel 0.1% were similar at all time points over the 12-week course of the trial.
Presented as a poster at Fall Clinical Dermatology in Las Vegas, October 2007.
A new aqueous-based tretinoin gel 0.05% (Atralin) from Coria Laboratories has been formulated and studied for treatment of acne vulgaris, including Phase III trials. The major objectives were to:
1. develop a tretinoin formulation that exhibited efficacy comparable or superior to other topical retinoid formulations.
2. produce a formulation of tretinoin with a highly favorable tolerability profile.
In addition to purified water, the tretinoin gel 0.05% also contains specific excipients such as glycerin and sodium hyaluronate to assist in minimizing irritation.
Multicenter, investigator-blinded, randomized, vehicle-controlled Phase III trials have been completed evaluating the efficacy and safety of the tretinoin aqueous gel 0.05% applied once daily in patients with mild to moderate facial acne vulgaris, including non-inferiority comparison evaluations with tretinoin microsphere gel 0.1%. The following review highlights results from two studies — the first, a Phase III trial comparing the safety and efficacy of tretinoin gel 0.05% vs. tretinoin gel vehicle, and the second, a study of the efficacy and safety of tretinoin gel 0.05% vs. tretinoin microsphere gel 0.1% vs. tretinoin gel vehicle.
Phase III Trials with Tretinoin Aqueous Gel 0.05% in Acne Vulgaris
Tretinoin Gel 0.05% vs. Tretinoin Gel Vehicle: Efficacy and Safety
Overview. The efficacy and safety of tretinoin gel 0.05% was compared to its gel vehicle in a multicenter, investigator-blinded, randomized, two-arm, 12-week trial in study participants who had mild to moderate facial acne vulgaris. The participants were randomized 1:1 to receive either active study drug (n=299) or vehicle (n=302). The age range of subjects was 10 years to 65 years, with an average of 18.7 years and 19.1 years in the active and vehicle arms, respectively. Distributions of gender and skin phototype (~60% types III or IV in both arms) were approximately equal. The study drug was applied once daily at bedtime, and patients were evaluated at baseline and at weeks 1, 2, 4, 8, and 12 (endpoint).
A study analysis for superiority was conducted on both intent-to-treat (ITT) and per-protocol subject populations. A significance level (p value) of 0.05 was used during two-sided hypothesis testing for statistical evaluation. Last observation carried forward methodology was used to extrapolate missing lesion count and Global Severity evaluation data for subjects who prematurely discontinued the study. Recognized methods for informed consent with patients and parents/legal guardians (for minors) were utilized.
Study Criteria. Male and female participants who were ≥10 years of age were required to present with mild to moderate facial acne vulgaris based on an investigator Global Severity rating of 3 (mildly moderate) or 4 (moderate) at baseline. All study participants exhibited a baseline non-inflammatory acne lesion count (open and/or closed comedones) involving the face (including the nose) ranging from 30 to 125 lesions. The required baseline inflammatory (papules and/or pustules) lesion count range involving the face (including the nose) was 15 to 40 lesions. Patients were not included in the study if they demonstrated >3 nodules and/or cysts.
Conventional exclusion criteria for Phase III acne vulgaris trials were utilized, including pregnancy, nursing, and established washout periods for other specific medications such as other acne drugs or agents that could potentially influence study outcomes.
Study Endpoints. The primary efficacy parameters were absolute reduction from baseline in inflammatory and non-inflammatory lesion counts at week 12, and intergroup differences in the dichotomized Global Severity rating at week 12, although data were captured for all evaluations at each follow-up visit. The investigator Global Severity ratings were dichotomized into treatment “success” or “failure,” with “success” defined as a rating of 0 (clear) or 1 (almost clear) at week 12 plus at least a 2-grade decrease in Global Severity at week 12, as compared to baseline. Secondary efficacy variables included the mean percent change from baseline to week 12 in inflammatory and non-inflammatory lesion counts.
Safety Variables. Safety evaluations were carried out on all randomized study participants and were based on evaluation of adverse events, review of concomitant medications over the course of the study, and extent of drug exposure.
Efficacy Results. The primary and secondary efficacy results at week 12 are depicted in Table 1.
Safety Results. The majority of adverse events reported by study participants were related to the skin, and most were mild to moderate in severity and resolved. In the tretinoin gel arm, 24% of patients reported cutaneous adverse events; in the vehicle arm, 3% of subjects reported cutaneous adverse events. Regarding specific cutaneous reactions, dry skin, burning sensation, and peeling (exfoliation) were more common in the active therapy arm, with statistically significant differences noted (p<0.001 for all three adverse events). These findings were consistent with what would be expected with application of a topical retinoid. Out of 84 anticipated doses, patients in the tretinoin gel 0.05% group and vehicle group applied an average of 78.4 and 79.1 doses, respectively, suggesting favorable compliance.
Tretinoin Gel 0.05% vs. Tretinoin Microsphere Gel 0.1% vs. Tretinoin Gel Vehicle: Efficacy and Safety
Overview. The efficacy and safety of tretinoin gel 0.05% was compared to its gel vehicle and to tretinoin microsphere gel 0.1% in a multicenter, investigator-blinded, randomized, three-arm, 12-week trial in patients with mild to moderate facial acne vulgaris. Study participants were randomized 2:2:1 to receive either tretinoin gel 0.05% (n=375), its gel vehicle (n=185), or tretinoin microsphere gel 0.1% (n=376). The age range of subjects was 10 to 53 years, with an average of 18.5 years across all three study arms.
Distributions of gender and skin phototype (predominantly types III and IV) were approximately equal in both study groups, with 70% of patients being Caucasian. No significant differences were noted overall in demographics between groups for mean age, gender, race, and skin phototype. The study drug was applied once daily at bedtime, and patients were evaluated at baseline and weeks 1, 2, 4, 8, and 12 (endpoint).
A study analysis for superiority was conducted for comparison with vehicle and for non-inferiority between both actively treated study arms. Primary analyses of non-inferiority testing were conducted on both ITT and per-protocol (PP) populations, and superiority testing on the ITT population. Non-inferiority testing used the one-sided 97.5% confidence interval approach with a non-inferiority margin of 10% for percent change in lesion counts and dichotomized Global Severity grading. Recognized methods for informed consent with patients and parents (for minors) were utilized.
Study Criteria. Male and female patients ≥10 years of age were required to present with mild to moderate facial acne vulgaris based on an investigator Global Severity grade of 2 through 4. The protocol mandated that subjects exhibit a baseline non-inflammatory acne lesion count (open and/or closed comedones) involving the face (including the nose) ranging from 30 to 125 lesions. The required baseline inflammatory (papules and/or pustules) lesion count range involving the face (including the nose) was 15 to 40 lesions. Subjects were not allowed to enroll in the study if they demonstrated >3 nodules and/or cysts, which were excluded from lesion counts. At baseline, the majority of enrolled subjects in each arm (53% to 55%), demonstrated a severity grade of 3 (mildly-moderate severity), an average of 50 non-inflammatory lesions, 24 inflammatory lesions, and 74 total acne lesions. Conventional exclusion criteria for Phase III acne vulgaris trials were utilized, including pregnancy, nursing, and established washout periods for other specific medications such as other acne drugs or agents which could potentially influence study outcome.
Efficacy Endpoints. The primary efficacy parameters were median percent reduction from baseline in at least two of the following three variables: inflammatory lesion count, non-inflammatory lesion count, and total lesion count, at week 12, and dichotomized Global Severity rating at week 12, although data was captured for all evaluations at each follow-up visit. Investigator Global Severity grading was static using a 6-point scale (0 to 5) with results divided into “success” or “failure.” “Success” was defined as a rating of 0 (clear) or 1 (almost clear) at week 12 (end of study).
Safety Variables. Safety analysis included evaluation of plasma concentrations of tretinoin and its metabolites, 13-cis-retinoic acid and 4-oxo-13-cis-retinoic acid at week 12, performed in a subset of subjects (105 blood samples from three centers). Safety evaluations were carried out on all randomized subjects inclusive of adverse events observed by the investigator or reported by the patient, regardless of suspected causality. Assessments of severity and causality were based on specific definitions.
Efficacy Results. Efficacy results are shown in Table 2 for both the non-inferiority and superiority analyses based on the ITT population data. Results were similar for both the ITT and PP populations. Figure 1 graphically demonstrates total acne lesion count reduction for both tretinoin gel 0.05% and tretinoin microsphere gel 0.1% over a 12-week duration.
Safety Results. The observed plasma concentration levels for tretinoin and its metabolites determined before and after study drug application were in the range reported for endogenous levels of these compounds. Change from baselines was not statistically significant for any of the study arms for comparison of tretinoin (p=0.792), 13-cis-retinoic acid (p=0.827), or 4-oxo-13-cis-retinoic acid (p=0.666).
The most common adverse events were cutaneous, with 36% observed in the tretinoin gel 0.05% group, 52% reported in the tretinoin microsphere gel 0.1% group and 9% noted in the vehicle gel group. Reported skin reactions included dry skin, erythema, burning sensation and peeling (exfoliation), consistent with those reported overall with topical retinoid use. Few subjects in any of the study arms (<0.01%) withdrew from the trial demonstrating that cutaneous adverse events were manageable without need to discontinue the study medication.
Summary
• In a large Phase III trial, tretinoin gel 0.05% formulated in a novel aqueous-base proved to be superior to its vehicle in absolute inflammatory lesion count reduction (p=0.001), mean percent inflammatory lesion count reduction (p=0.001), absolute non-inflammatory lesion count reduction (p=0.001), mean percent non-inflammatory lesion count reduction (p=0.001), and static assessment of dichotomized Global Severity at the end of the 12 week study (p=0.002). A second Phase III trial further confirmed the superiority of tretinoin gel 0.05% over its vehicle.
• The majority of subjects utilizing either tretinoin gel 0.05% or its vehicle were compliant with dosing.
• Adverse events associated with either tretinoin gel 0.05% or its vehicle were primarily cutaneous in nature, mild to moderate in severity, and generally reversible without need for discontinuation from clinical trials.
• Tretinoin gel 0.05%, in a comparison trial with tretinoin microsphere gel 0.1%, demonstrated a more favorable skin tolerability profile. The trial did not confirm non-inferiority of tretinoin gel 0.05% to tretinoin microsphere gel 0.1%; however, the differences in median percent change in inflammatory lesion count reduction and non-inflammatory lesion count reduction were 8.3% and 10.7%, respectively. The time course trend of the changes in total acne lesion reduction between tretinoin gel 0.05% and tretinoin microsphere gel 0.1% were similar at all time points over the 12-week course of the trial.
Presented as a poster at Fall Clinical Dermatology in Las Vegas, October 2007.
