- Email: [email protected]
Efficacy of montelukast during allergy season in patients with chronic asthma and seasonal aeroallergen sensitivity
S150 Abstracts
Formoterol 24 g Provides Effective Bronchodilation and Is Well Tolerated in Patients With Persistent Stable Asthma R. J. Lapidus1, J. Wolfe2, L. S. Greos3, B. Friedman4, C. Orevillo5, B. Ziehmer5, D. Till6, S. Stenglein6; 1Rocky Mountain Center for Clinical Research, Wheat Ridge, CO, 2Allergy and Asthma Associates, San Jose, CA, 3Colorado Allergy and Asthma Centers, Englewood, CO, 4Allergy, Asthma, Bronchitis and Immunology Associates, Fountain Valley, CA, 5Novartis Pharmaceuticals Corporation, East Hanover, NJ, 6Novartis Horsham Research Centre, Horsham, UNITED KINGDOM. RATIONALE: This 2085-patient, randomized, placebo-controlled study investigated the safety/efficacy of double-blind formoterol 12 g b.i.d. (F12), formoterol 24 g b.i.d. (F24) and placebo (P), and open-label formoterol 12 g b.i.d. with up to 2 additional doses/day as rescue (F12OL+rescue) in adolescents/adults aged 12 years or older with persistent asthma. METHODS: Patients received F12 (n=527), F24 (n=527), P (n=514), or F12-OL+rescue (n=517) for 16 weeks. Baseline mean FEV1 was 68-70% predicted in the 4 groups. Fixed combinations with long-acting ß2-agonists (LABA) and inhaled corticosteroids required LABA washout ≥24 hours before Visit 1. Efficacy was assessed as FEV1 pre-dose and 2 h post-dose; overall safety as frequency of treatment-emergent adverse events (AEs). RESULTS: F12, F24, and F12-OL+rescue treatment groups were significantly better (p<0.002) than P in pre-dose FEV1 at all post-baseline observations. No statistically significant/clinically relevant differences were detected between F12, F24, or F12-OL+rescue in any pre-dose FEV1 measurement. F12, F24, and F12-OL+rescue patients experienced significant improvement (p<0.0001) in 2 h post-dose FEV1 after the first dose and at all time points vs P (estimated treatment differences: 240-320 mL overall). Differences between F12, F24, or F12-OL+rescue in any 2h post-dose FEV1 measurement were small (≤60 mL) and not considered clinically relevant. Overall rates of AEs were 53% (n=279, F12), 61% (n=321, F24), 57% (n=291, P), and 55% (n=285, F12-OL+rescue). Most AEs were mild or moderate in severity. CONCLUSIONS: In each treatment regimen studied, formoterol demonstrated a clinically significant bronchodilator effect compared to placebo and was well tolerated, with an overall adverse event rate comparable to placebo. Funding: Novartis Pharma AG
597
MONDAY
Formoterol 24 g Is Not Associated With an Increase in Serious Asthma Exacerbations in Patients With Persistent Asthma J. Wolfe1, C. LaForce2, N. K. Ostrom3, P. Korenblat4, C. Orevillo5, B. Ziehmer5, D. Till6, S. Stenglein6; 1Allergy and Asthma Associates, San Jose, CA, 2North Carolina Clinical Research, Raleigh, NC, 3Allergy and Asthma Medical Group and Research Center, San Diego, CA, 4Clinical Research Center, St Louis, MO, 5Novartis Pharmaceuticals Corporation, East Hanover, NJ, 6Novartis Horsham Research Centre, Horsham, UNITED KINGDOM. RATIONALE: This 2085-patient, multicenter, randomized, parallelgroup, double-blind, placebo-controlled study investigated the safety and efficacy of regularly administered formoterol 12 g b.i.d. (F12) or 24 g b.i.d. (F24), placebo (P), and open-label formoterol 12 g b.i.d. plus up to 2 additional doses/day as rescue (F12-OL+rescue) in adolescents/adults aged 12 years or older with persistent asthma. The primary variable was percentage of patients reporting serious (e.g. requiring hospitalization) asthma-related adverse events (AEs). METHODS: Patients (mean FEV1 68-70% predicted) received F12 (n=527), F24 (n=527), P (n=514), or F12-OL+rescue (n=517) for 16 weeks. Fixed combinations with long-acting ß2-agonists (LABA) and inhaled corticosteroids (ICS) required LABA washout ≥24 hours before Visit 1. RESULTS: 97% of patients were receiving ≥1 asthma-related treatment before study start. Nearly two-thirds received regular anti-inflammatory medication, including ICS, during study. 9 patients had serious asthmarelated AEs: 5 for F12, 2 for F24, 1 for P, 1 for F12-OL+rescue. Only 2 of these events (F12, P) were considered study-drug related. P-treated
598
J ALLERGY CLIN IMMUNOL FEBRUARY 2005
patients experienced more (9%, n=45) significant asthma exacerbations (requiring systemic corticosteroid) than F12 (6%, n=31, p=0.095 vs P) or F24 (6%, n=33, p=0.157 vs P) or F12-OL+rescue (4%, n=23, p<0.006 vs P) patients. Rescue albuterol (in 8h before final study visit) was used by 10% of F12, 12% of F24, 16% of P, and 10% of F12-OL+rescue patients. 40% of F12-OL+rescue patients used rescue formoterol in final 4 weeks (5 capsules/4 weeks). CONCLUSIONS: Few asthma-related serious/significant events occurred, with no clinically meaningful differences among the formoterol-treated groups. Funding: Novartis Pharma AG
599
Design and Characteristics of an MDI Counter Device
M. Hailey1, P. Rand1, J. Godfrey1, I. Cude1, M. Cox1, J. Carranza Rosenzweig2; 1GlaxoSmithKline, Ware, UNITED KINGDOM, 2GlaxoSmithKline, Research Triangle Park, NC. RATIONALE: The need for an MDI counter device has been identified by manufacturers, regulatory and patient groups. We identified concerns of MDI users and described the attributes of a newly developed MDI Counter. METHODS: Questionnaire data was collected from patients with previous MDI experiences. Counter reliability data were generated from in vitro testing conducted on an MDI with counter. RESULTS: In a survey of 237 Asthma and COPD patients, 63% felt anxious not knowing the number of doses remaining in their MDI. 41% said they sometimes waited until the MDI was completely empty and about 20% said they could never tell when the MDI was out of medication. To reliably inform patients of remaining doses, an MDI with counter has been developed. This counter is a numerical design, counting down to zero. This counter has been designed to continue to display 000 when the product has delivered the labeled number of actuations, but will allow continued use by not locking out additional actuations. This counter is permanently attached to the canister ensuring that the count is associated with a single canister. In vitro testing showed count accuracy in excess of 99%. Actuation forces for MDI with counter are similar to MDI without counter (both in the range 33-40N). Inhaler size and weight are similar to standard product without a counter such that patients routinely using MDIs will experience no handling differences. CONCLUSIONS: The design and function of this MDI counter addresses patients’ concerns and regulatory standards for these types of devices. Funding: GlaxoSmithKline Efficacy of Montelukast During Allergy Season in Patients With Chronic Asthma and Seasonal Aeroallergen Sensitivity W. W. Busse1, T. B. Casale2, M. S. Dykewicz3, E. O. Meltzer4, S. R. Bird5, C. M. Hustad5, R. K. Zeldin5; 1University of Wisconsin Medical School, Madison, WI, 2Division of Allergy, Department of Medicine, Creighton University School of Medicine, Omaha, NE, 3Saint Louis University School of Medicine, St. Louis, MO, 4Allergy and Asthma Medical Group & Research Center AP, San Diego, CA, 5Merck & Co., Inc., West Point, PA. RATIONALE: To determine the effectiveness of montelukast (vs. placebo) in improving asthma symptoms during allergy season in patients with asthma and seasonal aeroallergen sensitivity. METHODS: Adult patients with a history of chronic asthma also active during allergy season and skin test sensitivity to seasonal aeroallergens were enrolled in a randomized, parallel-group, multicenter study with a 1week, single-blind, placebo run-in period followed by a 3-week, doubleblind treatment period during the spring of 2004. After the run-in period, eligible patients were randomly assigned to either oral montelukast (10 mg) or placebo. Daytime asthma symptom scores and inhaled beta-agonist use were captured using an electronic diary completed daily. The primary endpoint was the mean change from baseline to Week 3 in daytime asthma symptom score, as determined by averaging daily patient responses to four questions regarding symptoms and impact on activity. RESULTS: Four hundred fifty-five patients were randomized; 433 completed the study. Compared to placebo, treatment with montelukast result-
600
Abstracts S151
J ALLERGY CLIN IMMUNOL VOLUME 115, NUMBER 2
Short-Term and Long-Term Asthma Control in Patients With Mild Persistent Asthma Receiving Montelukast or Fluticasone: A Randomized Controlled Trial R. S. Zeiger1, J. M. Edelman2, S. R. Bird2, M. S. Kaplan1, M. Schatz1, D. S. Pearlman3, E. J. Orav4, C. M. Hustad2; 1Kaiser Permanente, San Diego, CA, 2Merck & Co., Inc., West Point, PA, 3Colorado Allergy and Asthma Centers, PC, Denver, CO, 4Brigham and Women’s Hospital, Boston, MA. RATIONALE: To determine whether montelukast is as effective as fluticasone in controlling mild persistent asthma as determined by rescuefree days (RFD). METHODS: Participants 15 to 85 years old with mild persistent asthma (n=400) were randomized into a year-long, parallel-group, multicenter study with a 12-week, double-blind period of oral montelukast (10mg once nightly) or inhaled fluticasone (88g twice daily), followed by a 36week, open-label period. RESULTS: The mean percentage of RFD was similar between treatments after 12 weeks (fluticasone: 74.9%, montelukast: 73.1%; difference = 1.8%, 95% CI: 3.2%, 6.8%), but not during the open-label period (fluticasone: 77.3%, montelukast: 71.1%; difference = 6.2%, 95% CI: 0.8%, 11.7%). Both fluticasone and montelukast significantly improved symptoms, quality of life, and symptom-free days during both treatment periods, but greater improvements occurred with fluticasone in lung function (both periods) and asthma control (open-label period). Post-hoc analyses revealed a difference in RFD favoring fluticasone in participants in the quartiles for lowest lung function and greatest albuterol use at baseline. No differences were detected in the remaining quartiles. CONCLUSION: In individuals with mild persistent asthma, RFD and most other asthma control measures, except for lung function, improved similarly with both fluticasone and montelukast over the short-term. With more prolonged open-label treatment, asthma control improved more with fluticasone. Fluticasone appeared to be better for those with decreased lung function and greater albuterol use at baseline. In the remaining patients, the two treatments appeared to be comparable. These results suggest that the classification scheme for mild persistent asthma may need to be re-evaluated. Funding: Merck & Co., Inc.
601
A Randomized, Double-Blind Trial on the Effect of Treatment With Montelukast, Budesonide, Montelukast With Budesonide, Formoterol With Budesonide on Lung Function and Clinical Symptoms in Children With Asthma I. Stelmach1, T. Grzelewski1, J. Jerzynska1, P. Kuna2; 1Dep. of Pediatrics and Allergy, M Curie Hospital, Zgierz, POLAND, 2Dep. of Allergy and Pneumonology, Medical University of Lodz, Lodz, POLAND. RATIONALE: The purpose of this study was to define the effect of treatment with montelukast , budesonide, montelukast with budesonide, formoterol with budesonide on lung function (FEV1, specific airway resistance (sRaw), resistance measured by the interrupter technique (Rint)) and clinical symptoms (symptoms score ) in children with mild to moderate asthma. METHODS: An 4-week, randomized, double-blind trial was carried out. The subjects were 80 children 6-16 years old with mild-to-moderate atopic asthma, who were allergic to dust mite. Patients were randomly allocated to receive 5 or 10 mg (according to age) montelukast (M) (n =
602
20), 200 mcg budesonide (B) (n=20), 5 or 10 mg (according to age) M with 200 mcg B (n=20), 4,5 mcg formoterol (F) with 200 mcg B (n=20) for 4 weeks. RESULTS: Symptoms score improved significantly after treatment in all groups: M (p<0,0001), B (p=0,011), M with B (p<0,001), F with B (p<0,0001). FEV1 and sRaw values did not differ significantly after treatment in any group. Mean values of Rint (% of predicted value) before and after treatment in M with B group were 138,2±21,8 and 123,2±19,9 respectively (p=0,02). Rint values did not differ significantly after treatment in any other group. CONCLUSIONS: Clinical symptoms improved significantly in all treatment groups. Additionaly montelukast in combination with budesonide significantly decreased Rint which is important parameter of airway obstruction. This observation raises the possibility that montelukast, combined with budesonide, may be optimal treatment combination reducing airway obstruction in children with asthma. Phase I Study of MN-001, an Oral Anti-inflammatory Agent for the Treatment of Asthma K. W. Locke; MediciNova, Inc., San Diego, CA. RATIONALE: A variety of inflammatory mechanisms are involved in the pathogenesis of asthma. MN-001 blocks a number of these mechanisms in vitro, including leukotriene receptors, phosphodiesterases III and IV, 5-lipoxygenase, phospholipase C and thromboxane A2. MN-001 is also active in a variety of in vivo preclinical asthma models. Extensive preclinical toxicology testing has demonstrated that MN-001 has a relatively low toxicity. Therefore, it was essential to evaluate the clinical safety and pharmacokinetics of MN-001 to guide design of efficacy trials. METHODS: MN-001 (250, 500, 750 or 1000 mg BID) was evaluated in a multiple-dose, double-blind, placebo-controlled, ascending-dose tolerance study in 32 healthy human volunteers. RESULTS: MN-001 was well tolerated at oral doses up to 1000 mg BID for 7 days. The adverse effects (e.g., upper abdominal pain, loose stools and nausea) of MN-001 were mild in intensity and short in duration. There were no dose-related toxicities identified in this study. MN-001 was rapidly absorbed and exhibited linear pharmacokinetics following singleand multiple-dose administrations of the same dose level from 250 to 1000 mg BID. CONCLUSIONS: MN-001 was well tolerated when administered orally to human volunteers at doses up to 1000 mg BID for 7 days.
603
Ketokonazol Treatment Prevents the Progress of “Allergic March” in Children With Atopic Dermatitis—Prospective Studies A. M. Hofman, T. Hofman; Center of Allergology, Poznan, POLAND. RATIONALE: The aim of this study was to estimate the influence of ketokonazol treatment on evolution of “atopic march” in children with atopic dermatitis (AD). METHODS: 97 children aged up to 24 months of life with AD were examined. They were on constant observation up to 12 year of life. In 4th year of life patients were devided into 2 groups: one-53 children had additional treatment by ketokonazol (taken periodically) and diet without sugar ( K+ group), and second- 36 children without this treatment ( Kgroup). RESULTS: In 1st year of life 9,3 % of children suffered also from bronchial asthma (BA), and 4,1 % had inhalant allergy. In 4th year of life BA occurred in 16,8% children from K+ group, and 13,8 % from Kgroup. And inhalant allergy was observed in 7,5% K+ and 8,4% K-. In children aged 8 in K+ group BA occurred in 26,4%, however in K- in 33,3%. And inhalant allergy similar in 26,4% K+ and 33,3% K-. In 12 year of life BA decreased to 11,3% in K+ group, but increased to 41,6% in K- group. The same percent was noted due to inhalant allergy- 11,3% in K+ and 44,4% in K- group. Moreover, in K- group also venom allergy occurred, which was not met in K+ group. CONCLUSIONS: Ketokonazol treatment in children with AD prevents development of “ allergic march”, BA and inhalant allergy.
604
MONDAY
ed in a significant improvement from baseline in daytime asthma symptom score (0.54 vs. 0.34, p=0.002; least-squares mean difference: 0.20 [0.34, 0.07]) and a reduction in daily puffs of -agonist (0.83 vs. 0.42, p = 0.003; least-squares mean difference: 0.41 [0.67, 0.14]). Few patients discontinued the study due to asthma (M:1.3% vs. P:3.1%), and there was no significant difference between treatment groups in the number of patients experiencing an asthma attack. CONCLUSIONS: In patients with chronic asthma and seasonal aeroallergen sensitivity, montelukast provided significant asthma symptom relief over a 3-week treatment period during allergy season when compared to placebo. Funding: Merck & Co., Inc.
Formoterol 24 g Provides Effective Bronchodilation and Is Well Tolerated in Patients With Persistent Stable Asthma R. J. Lapidus1, J. Wolfe2, L. S. Greos3, B. Friedman4, C. Orevillo5, B. Ziehmer5, D. Till6, S. Stenglein6; 1Rocky Mountain Center for Clinical Research, Wheat Ridge, CO, 2Allergy and Asthma Associates, San Jose, CA, 3Colorado Allergy and Asthma Centers, Englewood, CO, 4Allergy, Asthma, Bronchitis and Immunology Associates, Fountain Valley, CA, 5Novartis Pharmaceuticals Corporation, East Hanover, NJ, 6Novartis Horsham Research Centre, Horsham, UNITED KINGDOM. RATIONALE: This 2085-patient, randomized, placebo-controlled study investigated the safety/efficacy of double-blind formoterol 12 g b.i.d. (F12), formoterol 24 g b.i.d. (F24) and placebo (P), and open-label formoterol 12 g b.i.d. with up to 2 additional doses/day as rescue (F12OL+rescue) in adolescents/adults aged 12 years or older with persistent asthma. METHODS: Patients received F12 (n=527), F24 (n=527), P (n=514), or F12-OL+rescue (n=517) for 16 weeks. Baseline mean FEV1 was 68-70% predicted in the 4 groups. Fixed combinations with long-acting ß2-agonists (LABA) and inhaled corticosteroids required LABA washout ≥24 hours before Visit 1. Efficacy was assessed as FEV1 pre-dose and 2 h post-dose; overall safety as frequency of treatment-emergent adverse events (AEs). RESULTS: F12, F24, and F12-OL+rescue treatment groups were significantly better (p<0.002) than P in pre-dose FEV1 at all post-baseline observations. No statistically significant/clinically relevant differences were detected between F12, F24, or F12-OL+rescue in any pre-dose FEV1 measurement. F12, F24, and F12-OL+rescue patients experienced significant improvement (p<0.0001) in 2 h post-dose FEV1 after the first dose and at all time points vs P (estimated treatment differences: 240-320 mL overall). Differences between F12, F24, or F12-OL+rescue in any 2h post-dose FEV1 measurement were small (≤60 mL) and not considered clinically relevant. Overall rates of AEs were 53% (n=279, F12), 61% (n=321, F24), 57% (n=291, P), and 55% (n=285, F12-OL+rescue). Most AEs were mild or moderate in severity. CONCLUSIONS: In each treatment regimen studied, formoterol demonstrated a clinically significant bronchodilator effect compared to placebo and was well tolerated, with an overall adverse event rate comparable to placebo. Funding: Novartis Pharma AG
597
MONDAY
Formoterol 24 g Is Not Associated With an Increase in Serious Asthma Exacerbations in Patients With Persistent Asthma J. Wolfe1, C. LaForce2, N. K. Ostrom3, P. Korenblat4, C. Orevillo5, B. Ziehmer5, D. Till6, S. Stenglein6; 1Allergy and Asthma Associates, San Jose, CA, 2North Carolina Clinical Research, Raleigh, NC, 3Allergy and Asthma Medical Group and Research Center, San Diego, CA, 4Clinical Research Center, St Louis, MO, 5Novartis Pharmaceuticals Corporation, East Hanover, NJ, 6Novartis Horsham Research Centre, Horsham, UNITED KINGDOM. RATIONALE: This 2085-patient, multicenter, randomized, parallelgroup, double-blind, placebo-controlled study investigated the safety and efficacy of regularly administered formoterol 12 g b.i.d. (F12) or 24 g b.i.d. (F24), placebo (P), and open-label formoterol 12 g b.i.d. plus up to 2 additional doses/day as rescue (F12-OL+rescue) in adolescents/adults aged 12 years or older with persistent asthma. The primary variable was percentage of patients reporting serious (e.g. requiring hospitalization) asthma-related adverse events (AEs). METHODS: Patients (mean FEV1 68-70% predicted) received F12 (n=527), F24 (n=527), P (n=514), or F12-OL+rescue (n=517) for 16 weeks. Fixed combinations with long-acting ß2-agonists (LABA) and inhaled corticosteroids (ICS) required LABA washout ≥24 hours before Visit 1. RESULTS: 97% of patients were receiving ≥1 asthma-related treatment before study start. Nearly two-thirds received regular anti-inflammatory medication, including ICS, during study. 9 patients had serious asthmarelated AEs: 5 for F12, 2 for F24, 1 for P, 1 for F12-OL+rescue. Only 2 of these events (F12, P) were considered study-drug related. P-treated
598
J ALLERGY CLIN IMMUNOL FEBRUARY 2005
patients experienced more (9%, n=45) significant asthma exacerbations (requiring systemic corticosteroid) than F12 (6%, n=31, p=0.095 vs P) or F24 (6%, n=33, p=0.157 vs P) or F12-OL+rescue (4%, n=23, p<0.006 vs P) patients. Rescue albuterol (in 8h before final study visit) was used by 10% of F12, 12% of F24, 16% of P, and 10% of F12-OL+rescue patients. 40% of F12-OL+rescue patients used rescue formoterol in final 4 weeks (5 capsules/4 weeks). CONCLUSIONS: Few asthma-related serious/significant events occurred, with no clinically meaningful differences among the formoterol-treated groups. Funding: Novartis Pharma AG
599
Design and Characteristics of an MDI Counter Device
M. Hailey1, P. Rand1, J. Godfrey1, I. Cude1, M. Cox1, J. Carranza Rosenzweig2; 1GlaxoSmithKline, Ware, UNITED KINGDOM, 2GlaxoSmithKline, Research Triangle Park, NC. RATIONALE: The need for an MDI counter device has been identified by manufacturers, regulatory and patient groups. We identified concerns of MDI users and described the attributes of a newly developed MDI Counter. METHODS: Questionnaire data was collected from patients with previous MDI experiences. Counter reliability data were generated from in vitro testing conducted on an MDI with counter. RESULTS: In a survey of 237 Asthma and COPD patients, 63% felt anxious not knowing the number of doses remaining in their MDI. 41% said they sometimes waited until the MDI was completely empty and about 20% said they could never tell when the MDI was out of medication. To reliably inform patients of remaining doses, an MDI with counter has been developed. This counter is a numerical design, counting down to zero. This counter has been designed to continue to display 000 when the product has delivered the labeled number of actuations, but will allow continued use by not locking out additional actuations. This counter is permanently attached to the canister ensuring that the count is associated with a single canister. In vitro testing showed count accuracy in excess of 99%. Actuation forces for MDI with counter are similar to MDI without counter (both in the range 33-40N). Inhaler size and weight are similar to standard product without a counter such that patients routinely using MDIs will experience no handling differences. CONCLUSIONS: The design and function of this MDI counter addresses patients’ concerns and regulatory standards for these types of devices. Funding: GlaxoSmithKline Efficacy of Montelukast During Allergy Season in Patients With Chronic Asthma and Seasonal Aeroallergen Sensitivity W. W. Busse1, T. B. Casale2, M. S. Dykewicz3, E. O. Meltzer4, S. R. Bird5, C. M. Hustad5, R. K. Zeldin5; 1University of Wisconsin Medical School, Madison, WI, 2Division of Allergy, Department of Medicine, Creighton University School of Medicine, Omaha, NE, 3Saint Louis University School of Medicine, St. Louis, MO, 4Allergy and Asthma Medical Group & Research Center AP, San Diego, CA, 5Merck & Co., Inc., West Point, PA. RATIONALE: To determine the effectiveness of montelukast (vs. placebo) in improving asthma symptoms during allergy season in patients with asthma and seasonal aeroallergen sensitivity. METHODS: Adult patients with a history of chronic asthma also active during allergy season and skin test sensitivity to seasonal aeroallergens were enrolled in a randomized, parallel-group, multicenter study with a 1week, single-blind, placebo run-in period followed by a 3-week, doubleblind treatment period during the spring of 2004. After the run-in period, eligible patients were randomly assigned to either oral montelukast (10 mg) or placebo. Daytime asthma symptom scores and inhaled beta-agonist use were captured using an electronic diary completed daily. The primary endpoint was the mean change from baseline to Week 3 in daytime asthma symptom score, as determined by averaging daily patient responses to four questions regarding symptoms and impact on activity. RESULTS: Four hundred fifty-five patients were randomized; 433 completed the study. Compared to placebo, treatment with montelukast result-
600
Abstracts S151
J ALLERGY CLIN IMMUNOL VOLUME 115, NUMBER 2
Short-Term and Long-Term Asthma Control in Patients With Mild Persistent Asthma Receiving Montelukast or Fluticasone: A Randomized Controlled Trial R. S. Zeiger1, J. M. Edelman2, S. R. Bird2, M. S. Kaplan1, M. Schatz1, D. S. Pearlman3, E. J. Orav4, C. M. Hustad2; 1Kaiser Permanente, San Diego, CA, 2Merck & Co., Inc., West Point, PA, 3Colorado Allergy and Asthma Centers, PC, Denver, CO, 4Brigham and Women’s Hospital, Boston, MA. RATIONALE: To determine whether montelukast is as effective as fluticasone in controlling mild persistent asthma as determined by rescuefree days (RFD). METHODS: Participants 15 to 85 years old with mild persistent asthma (n=400) were randomized into a year-long, parallel-group, multicenter study with a 12-week, double-blind period of oral montelukast (10mg once nightly) or inhaled fluticasone (88g twice daily), followed by a 36week, open-label period. RESULTS: The mean percentage of RFD was similar between treatments after 12 weeks (fluticasone: 74.9%, montelukast: 73.1%; difference = 1.8%, 95% CI: 3.2%, 6.8%), but not during the open-label period (fluticasone: 77.3%, montelukast: 71.1%; difference = 6.2%, 95% CI: 0.8%, 11.7%). Both fluticasone and montelukast significantly improved symptoms, quality of life, and symptom-free days during both treatment periods, but greater improvements occurred with fluticasone in lung function (both periods) and asthma control (open-label period). Post-hoc analyses revealed a difference in RFD favoring fluticasone in participants in the quartiles for lowest lung function and greatest albuterol use at baseline. No differences were detected in the remaining quartiles. CONCLUSION: In individuals with mild persistent asthma, RFD and most other asthma control measures, except for lung function, improved similarly with both fluticasone and montelukast over the short-term. With more prolonged open-label treatment, asthma control improved more with fluticasone. Fluticasone appeared to be better for those with decreased lung function and greater albuterol use at baseline. In the remaining patients, the two treatments appeared to be comparable. These results suggest that the classification scheme for mild persistent asthma may need to be re-evaluated. Funding: Merck & Co., Inc.
601
A Randomized, Double-Blind Trial on the Effect of Treatment With Montelukast, Budesonide, Montelukast With Budesonide, Formoterol With Budesonide on Lung Function and Clinical Symptoms in Children With Asthma I. Stelmach1, T. Grzelewski1, J. Jerzynska1, P. Kuna2; 1Dep. of Pediatrics and Allergy, M Curie Hospital, Zgierz, POLAND, 2Dep. of Allergy and Pneumonology, Medical University of Lodz, Lodz, POLAND. RATIONALE: The purpose of this study was to define the effect of treatment with montelukast , budesonide, montelukast with budesonide, formoterol with budesonide on lung function (FEV1, specific airway resistance (sRaw), resistance measured by the interrupter technique (Rint)) and clinical symptoms (symptoms score ) in children with mild to moderate asthma. METHODS: An 4-week, randomized, double-blind trial was carried out. The subjects were 80 children 6-16 years old with mild-to-moderate atopic asthma, who were allergic to dust mite. Patients were randomly allocated to receive 5 or 10 mg (according to age) montelukast (M) (n =
602
20), 200 mcg budesonide (B) (n=20), 5 or 10 mg (according to age) M with 200 mcg B (n=20), 4,5 mcg formoterol (F) with 200 mcg B (n=20) for 4 weeks. RESULTS: Symptoms score improved significantly after treatment in all groups: M (p<0,0001), B (p=0,011), M with B (p<0,001), F with B (p<0,0001). FEV1 and sRaw values did not differ significantly after treatment in any group. Mean values of Rint (% of predicted value) before and after treatment in M with B group were 138,2±21,8 and 123,2±19,9 respectively (p=0,02). Rint values did not differ significantly after treatment in any other group. CONCLUSIONS: Clinical symptoms improved significantly in all treatment groups. Additionaly montelukast in combination with budesonide significantly decreased Rint which is important parameter of airway obstruction. This observation raises the possibility that montelukast, combined with budesonide, may be optimal treatment combination reducing airway obstruction in children with asthma. Phase I Study of MN-001, an Oral Anti-inflammatory Agent for the Treatment of Asthma K. W. Locke; MediciNova, Inc., San Diego, CA. RATIONALE: A variety of inflammatory mechanisms are involved in the pathogenesis of asthma. MN-001 blocks a number of these mechanisms in vitro, including leukotriene receptors, phosphodiesterases III and IV, 5-lipoxygenase, phospholipase C and thromboxane A2. MN-001 is also active in a variety of in vivo preclinical asthma models. Extensive preclinical toxicology testing has demonstrated that MN-001 has a relatively low toxicity. Therefore, it was essential to evaluate the clinical safety and pharmacokinetics of MN-001 to guide design of efficacy trials. METHODS: MN-001 (250, 500, 750 or 1000 mg BID) was evaluated in a multiple-dose, double-blind, placebo-controlled, ascending-dose tolerance study in 32 healthy human volunteers. RESULTS: MN-001 was well tolerated at oral doses up to 1000 mg BID for 7 days. The adverse effects (e.g., upper abdominal pain, loose stools and nausea) of MN-001 were mild in intensity and short in duration. There were no dose-related toxicities identified in this study. MN-001 was rapidly absorbed and exhibited linear pharmacokinetics following singleand multiple-dose administrations of the same dose level from 250 to 1000 mg BID. CONCLUSIONS: MN-001 was well tolerated when administered orally to human volunteers at doses up to 1000 mg BID for 7 days.
603
Ketokonazol Treatment Prevents the Progress of “Allergic March” in Children With Atopic Dermatitis—Prospective Studies A. M. Hofman, T. Hofman; Center of Allergology, Poznan, POLAND. RATIONALE: The aim of this study was to estimate the influence of ketokonazol treatment on evolution of “atopic march” in children with atopic dermatitis (AD). METHODS: 97 children aged up to 24 months of life with AD were examined. They were on constant observation up to 12 year of life. In 4th year of life patients were devided into 2 groups: one-53 children had additional treatment by ketokonazol (taken periodically) and diet without sugar ( K+ group), and second- 36 children without this treatment ( Kgroup). RESULTS: In 1st year of life 9,3 % of children suffered also from bronchial asthma (BA), and 4,1 % had inhalant allergy. In 4th year of life BA occurred in 16,8% children from K+ group, and 13,8 % from Kgroup. And inhalant allergy was observed in 7,5% K+ and 8,4% K-. In children aged 8 in K+ group BA occurred in 26,4%, however in K- in 33,3%. And inhalant allergy similar in 26,4% K+ and 33,3% K-. In 12 year of life BA decreased to 11,3% in K+ group, but increased to 41,6% in K- group. The same percent was noted due to inhalant allergy- 11,3% in K+ and 44,4% in K- group. Moreover, in K- group also venom allergy occurred, which was not met in K+ group. CONCLUSIONS: Ketokonazol treatment in children with AD prevents development of “ allergic march”, BA and inhalant allergy.
604
MONDAY
ed in a significant improvement from baseline in daytime asthma symptom score (0.54 vs. 0.34, p=0.002; least-squares mean difference: 0.20 [0.34, 0.07]) and a reduction in daily puffs of -agonist (0.83 vs. 0.42, p = 0.003; least-squares mean difference: 0.41 [0.67, 0.14]). Few patients discontinued the study due to asthma (M:1.3% vs. P:3.1%), and there was no significant difference between treatment groups in the number of patients experiencing an asthma attack. CONCLUSIONS: In patients with chronic asthma and seasonal aeroallergen sensitivity, montelukast provided significant asthma symptom relief over a 3-week treatment period during allergy season when compared to placebo. Funding: Merck & Co., Inc.