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Long-term intermittent use of tacrolimus ointment for flare prevention and disease control in pediatric patients with stabilized atopic dermatitis
P603
P605
Cost-effectiveness of tacrolimus ointment versus pimecrolimus cream in pediatric patients with atopic dermatitis Charu Taneja, MPH, Policy Analysis Inc., Brookline, MA, United States; Richard Antaya, MD, Yale University School of Medicine, New Haven, CT, United States; Ariel Berger, MPH, Policy Analysis Inc., Brookline, MA, United States; Thomas Marshall, PharmD, Astellas Pharma Inc., Deerfield, IL, United States
The immune modulating effect of pimecrolimus (pimecrolimus SDZ ASM 981) in atopic dermatitis Richard Shimonkevitz, PhD, Institute for Molecular Medicine, Aurora, CO, United States; David Bar-Or, MD, Institute for Molecular Medicine, Aurora, CO, United States; Isaac Melamed, MD, 1st International Clinical Research Centers, Centennial, CO, United States
Background: The efficacy and safety of tacrolimus ointment (0.1%; T) versus pimecrolimus cream (1%; P) in pediatric patients with moderate or severe (78% and 21%, respectively) atopic dermatitis (AD) were assessed in a multicenter, randomized, investigator-blinded, 6-week clinical trial. T was more effective, and had faster onset of action, than P; safety profiles of T and P were similar. The objective of this study was to evaluate the cost-effectiveness of T versus P in this patient population, based on data from this trial.
Introduction: Cytotoxic T cells may play a role in the pathogenesis of atopic dermatitis (AD) via the role of perforin and granzyme B. On activation, perforin and granzyme B are released through exocytosis and cooperatively trigger cell death. Because T cells are thought to be involved in the pathogenesis of AD, we hypothesize that the cytotoxic granules released by skin infiltrating T-lymphocytes may be central to apoptosis failure seen in AD. Pimecrolimus (Pcms) selectively inhibits the activation of T cells and mast cells, two key events in the pathogenesis of AD. This study focused on the selective inhibition by Pcms and its influence on perforin and granzyme B. Methods: CD4-, CD8-, and CD56-positive lymphocyte cells lines were preincubated 6 various doses of Pcms (1-1000 nM), then stimulated with anti-CD3 plus anti-CD28. NK cells were stimulated with IFN gamma and IL-18. Activated lymphocyte secretion of granzyme, IFN gamma, IL-8, IL-16, perforin, and TNF alpha were measured by ELISA. Cellular apoptosis and intracellular cytokine expression were measured by flow cytometry.
Methods: We developed a Markov cohort model with daily periodicity to project clinical outcomes and costs over a 42-day period for children with AD, aged 2 to 15 years. Patients entering the model were assumed to have moderate to severe ‘‘active AD’’ (defined as Investigator Global Atopic Dermatitis Assessment [IGADA] score of moderate, severe, or very severe) and to receive either T or P. Probabilities of AD resolution were derived based on data reported from the clinical trial. Patients with resolved AD were assumed to remain resolved for the remainder of follow-up (ie, maximum, 42 days). Patients with active AD were assumed to apply T or P twice daily (;2.7 g daily). All patients were assumed to have an AD-related outpatient visit at model entry; those with active AD at weeks 3 and 6 were assumed to require additional visits at these times. Costs of AD-related care (2007 US$) were assumed to consist of drug therapy (ie, T or P) and AD-related outpatient visits. Cost-effectiveness of T versus P was assessed in terms of the ratio of the expected cost of ADrelated care to the number of days with resolved AD over 42 days. Results: Patients receiving T were estimated to experience, on average, 2.8 additional days with resolved AD over 42 days (vs P; 6.5 for T vs. 3.8 for P). Expected costs (per patient) of AD-related care over 42 days were $21.53 lower for T than P ($625.74 vs. $647.27, respectively), primarily because of a reduced need for follow-up visits. T therefore resulted in better outcomes at a lower cost than P. Findings were robust in sensitivity analyses. Limitations: T ointment 0.03%, but not 0.1%, is indicated for children younger than the age of 16 years. P cream is indicated for mild to moderate, but not severe, AD. Conclusion: In pediatric patients with moderate to severe AD, T (0.1%) results in better outcomes and lower costs than P over a 6-week period. Supported by Astellas Pharma Inc.
Results: In a dose-dependent response, Pcms significantly inhibited IFN gamma, IL-8, and TNF alpha release on CD4 and CD8 cells. In Pcms had an effect on CD4 cells: as a result the stimulation index (SI) of IFN gamma was reduced from 403 to 10 with 1000nM. IL-8 from 83 to 3.8 and TNF alpha from 233 to 1.5. No effect was seen on IL16, perforin, or granzyme B release in CD4 cells. In CD8 cells, 1000nM Pcms reduced S.I of IFN gamma from 313 to 3.7, TNF alpha from 717 to 16, IL-8 from 4.4 S.I to 2.2. In CD8 cells, Pcms suppressed perforin and granzyme B release; granzyme B S.I reduction from 74 to 54; perforin S.I reduction of 8 to 4. No significant effect of Pcms on CD56-positive NK line was noted. Conclusion: Our results indicate that Pcms has a selective effect both on various cytokine release and lymphocyte populations. Pcms may inhibit cytokines whose expression is dependent upon membrane signal transduction involving calcium influx, but not significantly affect preformed cytokine release apparently independent of calcineurin activity. Various populations of T cells, specifically, cytotoxic T cells may have a different signaling with a different response to Pcms. The selective suppressive effect of Pcms on perforin and granzyme B release suggests that various T cells, via perforin and granzyme B release, may play a specific role in the pathogenesis of AD. We will further explore the pathogenesis of AD via the immunomodulating effect of Pcms on various T cells and on perforin and granzyme B release. Novartis Pharmaceuticals Corporation supported this investigator-initiated study.
P604 Tacrolimus for the early relief from itching in adults and children with atopic dermatitis Jon Hanifin, MD, Oregon Health and Science University, Portland, OR, United States; Mark Boguniewicz, MD, National Jewish Medical and Research Center, University of Colorado School of Medicine, Denver, CO, United States; Sewon Kang, MHS, University of Michigan Medical Center, Ann Arbor, MI, United States; Sakari Reitamo, MD, Helsinki University Central Hospital, Helsinki, Finland Background: Pruritus is a primary symptom of atopic dermatitis (AD) and is one of the first signs of an impending AD flare. Pruritus provokes scratching, which aggravates skin inflammation and worsens the AD flare. Tacrolimus ointment has been shown to relieve the itch associated with AD within the first week and throughout treatment. The purpose of this analysis was to investigate the reduction of itch before 1 week with tacrolimus ointment. Methods: The timing of itch relief afforded by tacrolimus ointment was assessed in several phase II studies. These early studies in children and in adults with moderate to severe AD compared tacrolimus ointment at concentrations of 0.03%, 0.1%, and 0.3% with vehicle. Another study in children with moderate to severe AD assessed the effectiveness of tacrolimus ointment 0.03% and 0.1% versus vehicle depending on the proportion of body surface area (% BSA) affected by AD. The timing of itch relief with tacrolimus versus hydrocortisone acetate 1% once or twice daily or hydrocortisone butyrate 0.1% twice daily was separately assessed in three phase III studies. Two of these studies enrolled children with moderate to severe AD, while the other enrolled adults with moderate to severe AD. Additionally, two phase IV studies assessed the effectiveness of tacrolimus ointment 0.03% compared with vehicle for itch relief in children and adult patients with mild to moderate AD. Itch relief in all studies was recorded by patients according to a visual analog scale (VAS), based on a continuum ranging from 0 cm or ‘‘no itch’’ to 10 cm or ‘‘worst itch imaginable.’’ Results: In the phase II studies, itch relief assessed by reductions in VAS score was observed as early as 4 days after initiation of treatment with tacrolimus ointment. By comparison, VAS scores at day 4 with vehicle either increased or were reduced to a lesser extent. In the phase III studies, reductions of a similar magnitude in VAS score were observed after 4 days with both tacrolimus- and hydrocortisone-based regimens. Combined analysis of the two phase IV studies showed that VAS score at day 4 decreased from baseline by 1.6 and 0.9 for tacrolimus ointment and vehicle respectively (LS means; P \.0001). Conclusions: These findings demonstrate that tacrolimus ointment can provide comparable itch relief to topical corticosteroids and greater itch relief than vehicle or emollients as early as 4 days after starting therapy. This study and poster was sponsored by Astellas Pharma Inc. Dr. Hanifin received financial support from Astellas Pharma Inc. as an investigator on tacrolimus (Protopic) clinical trials.
FEBRUARY 2008
P606 Long-term intermittent use of tacrolimus ointment for flare prevention and disease control in pediatric patients with stabilized atopic dermatitis Amy S. Paller, MD, Northwestern University Medical School/Children’s Memorial Hospital, Chicago, IL, United States; Lawrence F. Eichenfield, MD, University of California San Diego School of Medicine/Rady Children’s Hospital, San Diego, CA, United States; Robert S. Kirsner, MD, PhD, University of Miami Miller School of Medicine, Miami, FL, United States Objective: To compare the incidence of cutaneous adverse events (AEs) between tacrolimus ointment and corticosteroid ointment in the early treatment of atopic dermatitis (AD) (treatment phase). To evaluate the long-term efficacy and safety of tacrolimus ointment versus vehicle in preventing disease exacerbations (maintenance phase). Methods: In the treatment phase, pediatric patients with moderate to severe AD were randomized to 4 days of double-blind tacrolimus ointment 0.03% or alclometasone dipropionate ointment 0.05%; thereafter, all patients received open-label (OL) tacrolimus ointment until clear or almost clear (C/AC) of disease but for no more than 16 weeks. Key endpoints were incidence of cutaneous AEs at day 4 and week 2 (primary endpoint). Patients C/AC of disease were then eligible for double-blind randomization to tacrolimus ointment 0.03% or vehicle, applied once-a-day, 3 times/week for up to 40 weeks (maintenance phase). Primary endpoint was number of flare-free treatment days. Flares were treated with up to 8 weeks of twice daily OL tacrolimus ointment; corticosteroids were not permitted to treat flares. Results: A total of 152/206 randomized patients completed the treatment phase. The majority of discontinuations were for administrative reasons. Application-site AEs at day 4 were 14% for tacrolimus versus 13% for alclometasone (P ¼.76), and at week 2, 18% for tacrolimus versus 21% for the original alclometasone group (P ¼.60). A total of 104/152 patients were eligible and randomized (67 tacrolimus and 37 vehicle) into the maintenance phase. Tacrolimus ointment was more effective than vehicle in preventing disease exacerbations. The mean number of flare-free treatment days was 174 for tacrolimus and 107 for vehicle (P ¼ .0008). Median time to first exacerbation was 116 days for tacrolimus and 31 for vehicle (P ¼ .043), and mean number of exacerbation days was 47 for tacrolimus versus 76 for vehicle (P ¼.041). At most, 3 exacerbations occurred in the tacrolimus group compared with 6 in the vehicle group. There was no difference between tacrolimus and vehicle in the incidence of AEs. Conclusion: Tacrolimus and corticosteroid ointment have a similar safety profile in the initial treatment of pediatric patients with moderate to severe AD. Long-term, intermittent treatment with tacrolimus ointment in patients with stabilized disease results in significantly more disease-free days compared with vehicle, and a significantly longer time to first disease exacerbation. Sponsored by Astellas Pharma US, Inc.
J AM ACAD DERMATOL
AB49
P605
Cost-effectiveness of tacrolimus ointment versus pimecrolimus cream in pediatric patients with atopic dermatitis Charu Taneja, MPH, Policy Analysis Inc., Brookline, MA, United States; Richard Antaya, MD, Yale University School of Medicine, New Haven, CT, United States; Ariel Berger, MPH, Policy Analysis Inc., Brookline, MA, United States; Thomas Marshall, PharmD, Astellas Pharma Inc., Deerfield, IL, United States
The immune modulating effect of pimecrolimus (pimecrolimus SDZ ASM 981) in atopic dermatitis Richard Shimonkevitz, PhD, Institute for Molecular Medicine, Aurora, CO, United States; David Bar-Or, MD, Institute for Molecular Medicine, Aurora, CO, United States; Isaac Melamed, MD, 1st International Clinical Research Centers, Centennial, CO, United States
Background: The efficacy and safety of tacrolimus ointment (0.1%; T) versus pimecrolimus cream (1%; P) in pediatric patients with moderate or severe (78% and 21%, respectively) atopic dermatitis (AD) were assessed in a multicenter, randomized, investigator-blinded, 6-week clinical trial. T was more effective, and had faster onset of action, than P; safety profiles of T and P were similar. The objective of this study was to evaluate the cost-effectiveness of T versus P in this patient population, based on data from this trial.
Introduction: Cytotoxic T cells may play a role in the pathogenesis of atopic dermatitis (AD) via the role of perforin and granzyme B. On activation, perforin and granzyme B are released through exocytosis and cooperatively trigger cell death. Because T cells are thought to be involved in the pathogenesis of AD, we hypothesize that the cytotoxic granules released by skin infiltrating T-lymphocytes may be central to apoptosis failure seen in AD. Pimecrolimus (Pcms) selectively inhibits the activation of T cells and mast cells, two key events in the pathogenesis of AD. This study focused on the selective inhibition by Pcms and its influence on perforin and granzyme B. Methods: CD4-, CD8-, and CD56-positive lymphocyte cells lines were preincubated 6 various doses of Pcms (1-1000 nM), then stimulated with anti-CD3 plus anti-CD28. NK cells were stimulated with IFN gamma and IL-18. Activated lymphocyte secretion of granzyme, IFN gamma, IL-8, IL-16, perforin, and TNF alpha were measured by ELISA. Cellular apoptosis and intracellular cytokine expression were measured by flow cytometry.
Methods: We developed a Markov cohort model with daily periodicity to project clinical outcomes and costs over a 42-day period for children with AD, aged 2 to 15 years. Patients entering the model were assumed to have moderate to severe ‘‘active AD’’ (defined as Investigator Global Atopic Dermatitis Assessment [IGADA] score of moderate, severe, or very severe) and to receive either T or P. Probabilities of AD resolution were derived based on data reported from the clinical trial. Patients with resolved AD were assumed to remain resolved for the remainder of follow-up (ie, maximum, 42 days). Patients with active AD were assumed to apply T or P twice daily (;2.7 g daily). All patients were assumed to have an AD-related outpatient visit at model entry; those with active AD at weeks 3 and 6 were assumed to require additional visits at these times. Costs of AD-related care (2007 US$) were assumed to consist of drug therapy (ie, T or P) and AD-related outpatient visits. Cost-effectiveness of T versus P was assessed in terms of the ratio of the expected cost of ADrelated care to the number of days with resolved AD over 42 days. Results: Patients receiving T were estimated to experience, on average, 2.8 additional days with resolved AD over 42 days (vs P; 6.5 for T vs. 3.8 for P). Expected costs (per patient) of AD-related care over 42 days were $21.53 lower for T than P ($625.74 vs. $647.27, respectively), primarily because of a reduced need for follow-up visits. T therefore resulted in better outcomes at a lower cost than P. Findings were robust in sensitivity analyses. Limitations: T ointment 0.03%, but not 0.1%, is indicated for children younger than the age of 16 years. P cream is indicated for mild to moderate, but not severe, AD. Conclusion: In pediatric patients with moderate to severe AD, T (0.1%) results in better outcomes and lower costs than P over a 6-week period. Supported by Astellas Pharma Inc.
Results: In a dose-dependent response, Pcms significantly inhibited IFN gamma, IL-8, and TNF alpha release on CD4 and CD8 cells. In Pcms had an effect on CD4 cells: as a result the stimulation index (SI) of IFN gamma was reduced from 403 to 10 with 1000nM. IL-8 from 83 to 3.8 and TNF alpha from 233 to 1.5. No effect was seen on IL16, perforin, or granzyme B release in CD4 cells. In CD8 cells, 1000nM Pcms reduced S.I of IFN gamma from 313 to 3.7, TNF alpha from 717 to 16, IL-8 from 4.4 S.I to 2.2. In CD8 cells, Pcms suppressed perforin and granzyme B release; granzyme B S.I reduction from 74 to 54; perforin S.I reduction of 8 to 4. No significant effect of Pcms on CD56-positive NK line was noted. Conclusion: Our results indicate that Pcms has a selective effect both on various cytokine release and lymphocyte populations. Pcms may inhibit cytokines whose expression is dependent upon membrane signal transduction involving calcium influx, but not significantly affect preformed cytokine release apparently independent of calcineurin activity. Various populations of T cells, specifically, cytotoxic T cells may have a different signaling with a different response to Pcms. The selective suppressive effect of Pcms on perforin and granzyme B release suggests that various T cells, via perforin and granzyme B release, may play a specific role in the pathogenesis of AD. We will further explore the pathogenesis of AD via the immunomodulating effect of Pcms on various T cells and on perforin and granzyme B release. Novartis Pharmaceuticals Corporation supported this investigator-initiated study.
P604 Tacrolimus for the early relief from itching in adults and children with atopic dermatitis Jon Hanifin, MD, Oregon Health and Science University, Portland, OR, United States; Mark Boguniewicz, MD, National Jewish Medical and Research Center, University of Colorado School of Medicine, Denver, CO, United States; Sewon Kang, MHS, University of Michigan Medical Center, Ann Arbor, MI, United States; Sakari Reitamo, MD, Helsinki University Central Hospital, Helsinki, Finland Background: Pruritus is a primary symptom of atopic dermatitis (AD) and is one of the first signs of an impending AD flare. Pruritus provokes scratching, which aggravates skin inflammation and worsens the AD flare. Tacrolimus ointment has been shown to relieve the itch associated with AD within the first week and throughout treatment. The purpose of this analysis was to investigate the reduction of itch before 1 week with tacrolimus ointment. Methods: The timing of itch relief afforded by tacrolimus ointment was assessed in several phase II studies. These early studies in children and in adults with moderate to severe AD compared tacrolimus ointment at concentrations of 0.03%, 0.1%, and 0.3% with vehicle. Another study in children with moderate to severe AD assessed the effectiveness of tacrolimus ointment 0.03% and 0.1% versus vehicle depending on the proportion of body surface area (% BSA) affected by AD. The timing of itch relief with tacrolimus versus hydrocortisone acetate 1% once or twice daily or hydrocortisone butyrate 0.1% twice daily was separately assessed in three phase III studies. Two of these studies enrolled children with moderate to severe AD, while the other enrolled adults with moderate to severe AD. Additionally, two phase IV studies assessed the effectiveness of tacrolimus ointment 0.03% compared with vehicle for itch relief in children and adult patients with mild to moderate AD. Itch relief in all studies was recorded by patients according to a visual analog scale (VAS), based on a continuum ranging from 0 cm or ‘‘no itch’’ to 10 cm or ‘‘worst itch imaginable.’’ Results: In the phase II studies, itch relief assessed by reductions in VAS score was observed as early as 4 days after initiation of treatment with tacrolimus ointment. By comparison, VAS scores at day 4 with vehicle either increased or were reduced to a lesser extent. In the phase III studies, reductions of a similar magnitude in VAS score were observed after 4 days with both tacrolimus- and hydrocortisone-based regimens. Combined analysis of the two phase IV studies showed that VAS score at day 4 decreased from baseline by 1.6 and 0.9 for tacrolimus ointment and vehicle respectively (LS means; P \.0001). Conclusions: These findings demonstrate that tacrolimus ointment can provide comparable itch relief to topical corticosteroids and greater itch relief than vehicle or emollients as early as 4 days after starting therapy. This study and poster was sponsored by Astellas Pharma Inc. Dr. Hanifin received financial support from Astellas Pharma Inc. as an investigator on tacrolimus (Protopic) clinical trials.
FEBRUARY 2008
P606 Long-term intermittent use of tacrolimus ointment for flare prevention and disease control in pediatric patients with stabilized atopic dermatitis Amy S. Paller, MD, Northwestern University Medical School/Children’s Memorial Hospital, Chicago, IL, United States; Lawrence F. Eichenfield, MD, University of California San Diego School of Medicine/Rady Children’s Hospital, San Diego, CA, United States; Robert S. Kirsner, MD, PhD, University of Miami Miller School of Medicine, Miami, FL, United States Objective: To compare the incidence of cutaneous adverse events (AEs) between tacrolimus ointment and corticosteroid ointment in the early treatment of atopic dermatitis (AD) (treatment phase). To evaluate the long-term efficacy and safety of tacrolimus ointment versus vehicle in preventing disease exacerbations (maintenance phase). Methods: In the treatment phase, pediatric patients with moderate to severe AD were randomized to 4 days of double-blind tacrolimus ointment 0.03% or alclometasone dipropionate ointment 0.05%; thereafter, all patients received open-label (OL) tacrolimus ointment until clear or almost clear (C/AC) of disease but for no more than 16 weeks. Key endpoints were incidence of cutaneous AEs at day 4 and week 2 (primary endpoint). Patients C/AC of disease were then eligible for double-blind randomization to tacrolimus ointment 0.03% or vehicle, applied once-a-day, 3 times/week for up to 40 weeks (maintenance phase). Primary endpoint was number of flare-free treatment days. Flares were treated with up to 8 weeks of twice daily OL tacrolimus ointment; corticosteroids were not permitted to treat flares. Results: A total of 152/206 randomized patients completed the treatment phase. The majority of discontinuations were for administrative reasons. Application-site AEs at day 4 were 14% for tacrolimus versus 13% for alclometasone (P ¼.76), and at week 2, 18% for tacrolimus versus 21% for the original alclometasone group (P ¼.60). A total of 104/152 patients were eligible and randomized (67 tacrolimus and 37 vehicle) into the maintenance phase. Tacrolimus ointment was more effective than vehicle in preventing disease exacerbations. The mean number of flare-free treatment days was 174 for tacrolimus and 107 for vehicle (P ¼ .0008). Median time to first exacerbation was 116 days for tacrolimus and 31 for vehicle (P ¼ .043), and mean number of exacerbation days was 47 for tacrolimus versus 76 for vehicle (P ¼.041). At most, 3 exacerbations occurred in the tacrolimus group compared with 6 in the vehicle group. There was no difference between tacrolimus and vehicle in the incidence of AEs. Conclusion: Tacrolimus and corticosteroid ointment have a similar safety profile in the initial treatment of pediatric patients with moderate to severe AD. Long-term, intermittent treatment with tacrolimus ointment in patients with stabilized disease results in significantly more disease-free days compared with vehicle, and a significantly longer time to first disease exacerbation. Sponsored by Astellas Pharma US, Inc.
J AM ACAD DERMATOL
AB49