Quantifying monocyte infiltration in response to intradermal tetanus toxoid injection.

AIMS: To characterize monocyte response in a delayed-type hypersensitivity reaction to intradermal tetanus toxoid (TT) injection. MATERIALS & METHODS: Men with positive serum anti-tetanus titers were stratified by last TT vaccination. Subjects were administered three intradermal injections of TT and one saline control on the same side of the back. Skin biopsies were taken post-injection. After 2 weeks, the procedure was repeated on the contralateral side. RESULTS: Men who received TT booster vaccination 1 month before the study showed greater reproducibility and lower variability in monocyte responses than those who were not revaccinated. Monocyte concentration in subjects re-vaccinated within 1 month of study start appeared maximal at 48 h post-injection. CONCLUSION: This assay represents a novel approach that allows for quantification of dermal monocyte/macrophage influx. This clinical methodology has potential utility in the pharmacodynamic evaluation of therapies targeting inflammatory disorders, which involve monocyte tissue recruitment, like the delayed-type hypersensitivity response.

Rizatriptan for treatment of acute migraine in patients taking topiramate for migraine prophylaxis.

OBJECTIVE: To assess efficacy and tolerability of rizatriptan orally disintegrating tablet (ODT) for treatment of acute migraine in patients using topiramate for migraine prophylaxis. BACKGROUND: There are limited data from prospective controlled trials demonstrating the benefit of triptans in patients who experience migraine attacks while taking prophylactic medication. METHODS: This was a worldwide, randomized, placebo-controlled, double-blind, multiple-attack study in adults with a >1-year history of migraine taking a stable dose of topiramate for migraine prophylaxis and experiencing ≥2 moderate/severe attacks per month. Participants treated 3 moderate/severe attacks in crossover fashion (2 with rizatriptan 10-mg ODT, 1 with placebo) following random assignment to 1 of 3 treatment sequences. The primary end point was 2-hour pain relief. RESULTS: Two-hour pain relief was significantly greater with rizatriptan compared with placebo (55.0% vs 17.4%, P < .001). Response rates also favored rizatriptan for sustained pain relief from 2-24 hours (32.6% vs 11.1%, P < .001), 2-hour pain freedom (36.0% vs 6.5%, P < .001), normal functional ability at 2 hours (42.2% vs 12.7%, P < .001), and overall treatment satisfaction at 24 hours (60.8% vs 33.6%, P < .001). Few participants reported adverse experiences (16 [15.8%] with rizatriptan, 3 [3.2%] with placebo); none were serious. CONCLUSION: Rizatriptan 10-mg ODT was superior to placebo at all pain end points for treatment of acute migraine in patients using topiramate for migraine prophylaxis. Rizatriptan was generally well tolerated in this population. These results are comparable with those from clinical trials in patients not using prophylaxis, suggesting that the use of topiramate does not affect the efficacy or tolerability of rizatriptan for acute migraine treatment.

Efficacy and tolerability of rizatriptan for the treatment of acute migraine in sumatriptan non-responders.

OBJECTIVE: The study was carried out to assess the efficacy and tolerability of rizatriptan orally disintegrating tablet (ODT) for treating acute migraine in patients who are non-responders to sumatriptan. BACKGROUND: Many migraineurs report dissatisfaction with sumatriptan efficacy. It is unclear whether sumatriptan 100 mg non-responders will respond to other triptans. METHODS: This was a randomized, placebo-controlled, double-blind study in adults with >1-year history of ICHD-II (International Classification of Headache Disorders, second edition) migraine who reported that they generally do not respond to sumatriptan (≥50% unsatisfactory response). In the baseline phase, participants treated a single moderate/severe migraine attack with open-label generic sumatriptan 100 mg. Those who continued to experience moderate/severe pain at two hours post-dose were eligible to enter the double-blind treatment phase, during which participants treated three migraine attacks in crossover fashion (two with rizatriptan 10-mg ODT, one with placebo) after being randomly assigned to one of three treatment sequences (1 : 1 : 1 ratio). The primary endpoint was two-hour pain relief. RESULTS: A total of 102 (94%) participants treated at least one study migraine. Pain relief at two hours was significantly greater with rizatriptan compared with placebo (51% vs. 20%, p < .001). Response rates also favored rizatriptan on two-hour pain freedom (22% vs. 12%, p = .013) as well as 24-hour sustained pain relief (38% vs. 14%, p < .001) and sustained pain freedom (20% vs. 11%, p = .036). Treatment was generally well tolerated. CONCLUSION: Rizatriptan 10-mg ODT was superior to placebo at providing two-hour pain relief and two-hour pain freedom in the treatment of acute migraine in those who do not respond to sumatriptan 100 mg. Rizatriptan was generally well tolerated in this population.

Odanacatib in the treatment of postmenopausal women with low bone mineral density: three-year continued therapy and resolution of effect.

The selective cathepsin K inhibitor odanacatib (ODN) progressively increased bone mineral density (BMD) and decreased bone-resorption markers during 2 years of treatment in postmenopausal women with low BMD. A 1-year extension study further assessed ODN efficacy and safety and the effects of discontinuing therapy. In the base study, postmenopausal women with BMD T-scores between -2.0 and -3.5 at the lumbar spine or femur received placebo or ODN 3, 10, 25, or 50 mg weekly. After 2 years, patients (n = 189) were rerandomized to ODN 50 mg weekly or placebo for an additional year. Endpoints included BMD at the lumbar spine (primary), total hip, and hip subregions; levels of bone turnover markers; and safety assessments. Continued treatment with 50 mg of ODN for 3 years produced significant increases from baseline and from year 2 in BMD at the spine (7.9% and 2.3%) and total hip (5.8% and 2.4%). Urine cross-linked N-telopeptide of type I collagen (NTx) remained suppressed at year 3 (-50.5%), but bone-specific alkaline phosphatase (BSAP) was relatively unchanged from baseline. Treatment discontinuation resulted in bone loss at all sites, but BMD remained at or above baseline. After ODN discontinuation at month 24, bone turnover markers increased transiently above baseline, but this increase largely resolved by month 36. There were similar overall adverse-event rates in both treatment groups. It is concluded that 3 years of ODN treatment resulted in progressive increases in BMD and was generally well tolerated. Bone-resorption markers remained suppressed, whereas bone-formation markers returned to near baseline. ODN effects were reversible: bone resorption increased transiently and BMD decreased following treatment discontinuation.

Total migraine freedom, a potential primary endpoint to assess acute treatment in migraine: comparison to the current FDA requirement using the complete rizatriptan study database.

OBJECTIVE: To examine total migraine freedom (TMF), defined as pain freedom and absence of associated symptoms, using rizatriptan clinical trial data and to explore advantages of TMF as a single primary composite efficacy endpoint. BACKGROUND: The FDA has set a higher regulatory hurdle for registration of new migraine agents requiring both pain freedom (or relief) and absence of each associated symptom (phonophobia, photophobia, and nausea). METHODS: Twelve studies representing phase III + efficacy/safety studies of rizatriptan 10 mg in adults treating migraine were included in the meta-analysis. The percentage of patients achieving TMF at 2 hours by study and combined by treatment group was summarized by treatment paradigm (early/mild pain, moderate/severe, menstrual migraine). To demonstrate the impact of the strict migraine regulatory hurdle on clinical trial design and to compare it to TMF, simulation via bootstrap sampling was used. RESULTS: Odds ratios (rizatriptan vs placebo, all P < .001) for TMF were 6.2 (95% CI: [4.9, 7.7]) for moderate/severe, 2.7 (95% CI: [1.8, 4.0]) for menstrual, and 3.1 (95% CI: [2.4, 4.0]) for early/mild. Most with moderate/severe migraine reported photophobia and/or phonophobia at baseline, but only half had nausea. Simulation results showed a substantial loss of power analyzing absence of pain and each symptom compared with the composite TMF endpoint across all treatment paradigms. CONCLUSION: Rizatriptan 10 mg was superior to placebo in achieving TMF at 2 hours post-dose across all treatment paradigms. Given that the majority of patients with migraine do not exhibit all 3 associated symptoms, the TMF endpoint has significant advantages vs establishing efficacy on pain and each symptom individually.

Odanacatib, a cathepsin-K inhibitor for osteoporosis: a two-year study in postmenopausal women with low bone density.

Cathepsin K, a cysteine protease expressed in osteoclasts, degrades type 1 collagen. Odanacatib selectively and reversibly inhibited cathepsin K and rapidly decreased bone resorption in preclinical and phase I studies. A 1-year dose-finding trial with a 1-year extension on the same treatment assignment was performed in postmenopausal women with low bone mineral density (BMD) to evaluate the safety and efficacy of weekly doses of placebo or 3, 10, 25, or 50 mg of odanacatib on BMD and biomarkers of skeletal remodeling. Women with BMD T-scores of -2.0 or less but not less than -3.5 at the lumbar spine or femoral sites were randomly assigned to receive placebo or one of four doses of odanacatib; all received vitamin D with calcium supplementation as needed. The primary endpoint was percentage change from baseline lumbar spine BMD. Other endpoints included percentage change in BMD at hip and forearm sites, as well as changes in biomarkers of skeletal remodeling. Twenty-four months of treatment produced progressive dose-related increases in BMD. With the 50-mg dose of odanacatib, lumbar spine and total-hip BMD increased 5.5% and 3.2%, respectively, whereas BMD at these sites was essentially unchanged with placebo (-0.2% and -0.9%). Biochemical markers of bone turnover exhibited dose-related changes. The safety and tolerability of odanacatib generally were similar to those of placebo, with no dose-related trends in any adverse experiences. In summary, 2 years of weekly odanacatib treatment was generally well-tolerated and increased lumbar spine and total-hip BMD in a dose-related manner in postmenopausal women with low BMD.

Expanding access to triptans: assessment of clinical outcome.

OBJECTIVE: To evaluate whether access to more liberal quantities of rizatriptan improves clinical outcome in patients with episodic migraine. BACKGROUND: Currently many pharmacy benefit programs limit the number of triptan tablets/injections per month based on perceived cost savings and the belief that too-frequent use of triptans may lead to medication overuse headache and headache chronification. METHODS: This observer-blind, randomized, parallel-group study enrolled 197 subjects with migraine with or without aura. Subjects completed a 3-month baseline period to establish migraine frequency and then were randomly assigned to receive 9 (formulary limit [FL]) or 27 (clinical limit [CL]) tablets of 10 mg rizatriptan orally disintegrating tablet (ODT) per month for 3 months. The primary endpoint was change in the mean number of migraine days from the baseline to treatment period. RESULTS: There was no statistically significant difference between the FL and CL groups in mean number of migraine days (FL-CL LS mean: -0.08 [-0.39, 0.23]; P = .613). Subjects in the CL group treated attacks at lower headache severity. No CL subjects were reported to have developed chronic migraine despite utilization of greater than 10 rizatriptan ODT tablets per month. Rizatriptan was generally well tolerated by both groups. CONCLUSION: Providing a greater quantity of rizatriptan ODT 10 mg did not reduce the number of migraine days compared with providing 9 tablets per month for this population with episodic migraine with a frequency of 3-8 migraines per month. Regardless of quantity provided, rizatriptan was generally well tolerated.

Analysis of behavior-related adverse experiences in clinical trials of montelukast.

BACKGROUND: Frequencies of behavior-related adverse experiences (BRAEs) in controlled clinical studies of leukotriene modifier drugs have not been summarized. OBJECTIVE: We sought to compare the frequency of BRAEs in patients receiving montelukast or placebo in a retrospective analysis of Merck clinical trial data. METHODS: An adverse experience database was constructed to include all double-blind, placebo-controlled trials of montelukast meeting prespecified criteria. BRAEs (described using the Medical Dictionary for Regulatory Activities controlled vocabulary dictionary) were prespecified to include any term in the Psychiatric Disorders System Organ Class, selected terms related to general disorders, and terms related to akathisia. Frequencies of BRAEs (overall, leading to study discontinuation, and/or serious) were summarized. Analyses estimated the odds ratios (ORs) for montelukast versus placebo based on the frequency of patients with BRAEs in each study. RESULTS: In total 35 adult and 11 pediatric placebo-controlled trials were included; 11,673 patients received montelukast, 8,827 received placebo, and 4,724 received active control. The frequency of patients with 1 or more BRAEs was 2.73% and 2.27% in the montelukast and placebo groups, respectively; the OR for montelukast versus placebo was 1.12 (95% CI, 0.93-1.36). The frequency of patients with a BRAE leading to study discontinuation was 0.07% and 0.11% in the montelukast and placebo groups, respectively (OR, 0.52; 95% CI, 0.17-1.51). The frequency of patients with a BRAE considered serious was 0.03% in both treatment groups. CONCLUSION: Reports of BRAEs were infrequent in clinical trials of montelukast. Those leading to study discontinuation or considered serious were rare. Frequencies were similar regardless of treatment group.

Rizatriptan 10-mg ODT for early treatment of migraine and impact of migraine education on treatment response.

OBJECTIVE: To examine the efficacy of rizatriptan 10-mg orally disintegrating tablet (ODT) for treating migraines of mild intensity soon after onset, with or without patient-specific migraine education. BACKGROUND: Studies have shown rizatriptan tablet efficacy in early migraine treatment. METHODS: In this randomized, placebo-controlled, double-blind, factorial design study, adults with a history of migraine were assigned to rizatriptan 10-mg ODT patient education (personalized summary of early migraine signs and symptoms) or placebo patient education in a 1 : 1 : 1 : 1 ratio. Patients were instructed to treat 1 attack at the earliest time they knew that their headache was a migraine, while pain was mild. During the next 24 hours, patients assessed pain severity, associated symptoms, functional disability, use of rescue medication, and treatment satisfaction. The primary endpoint was pain freedom at 2 hours; a key secondary endpoint was 24-hour sustained pain freedom. RESULTS: Of 207 patients randomized to treatment, 188 (91%) treated a study migraine. Significantly more patients taking rizatriptan reported pain freedom at 2 hours compared with placebo (66.3% vs 28.1%, P < .001). Similarly, significantly more patients taking rizatriptan reported 24-hour sustained pain freedom (52.2% vs 17.7%, P < .001). A greater proportion of patients in the rizatriptan + education group reported pain freedom at 2 hours compared with those in the rizatriptan + no education group (71.7% vs 60.9%, P = .430). Few adverse events were reported. CONCLUSION: Rizatriptan 10-mg ODT, when taken early, while headache pain is mild, was superior to placebo at providing pain freedom at 2 hours and 24-hour sustained pain freedom.

Rizatriptan efficacy in ICHD-II pure menstrual migraine and menstrually related migraine.

OBJECTIVE: To examine the efficacy of rizatriptan for the treatment of pure menstrual migraine (PMM). BACKGROUND: In 2004, the International Headache Society proposed new research criteria for menstrual migraine (International Classification of Headache Disorders [ICHD-II]). Two subtypes were defined: PMM, in which attacks occur exclusively with menstruation, and menstrually related migraine (MRM), in which attacks may also occur at other times of the cycle. METHODS: The 2 protocols (MM1 and MM2) were identical randomized, double-blind studies. Adult patients with ICHD-II menstrual migraine were assigned to either rizatriptan 10-mg tablet or placebo (2:1). Patients were to treat a single menstrual migraine attack of moderate or severe pain intensity. This prospectively planned substudy pooled data from patients with a diagnosis of PMM from both studies. The primary substudy endpoint was 2-hour pain relief. Efficacy data were summarized for patients with a diagnosis of MRM. RESULTS: Of 707 (MM1: 357, MM2: 350) patients treated in the study, 146 patients (MM1: 81, MM2: 65) had a diagnosis of PMM. The percentage of patients reporting 2-hour pain relief was significantly greater for rizatriptan than for placebo for both PMM (73% vs 50%, P = .006) and MRM subgroups (71% vs 52%, P < .001). Most other efficacy endpoints favored rizatriptan compared with placebo in patients with either PMM or MRM. CONCLUSION: Rizatriptan 10 mg was superior to placebo for the treatment of PMM, as measured by 2-hour pain relief. Rizatriptan was also effective for the treatment of MRM and for relief of migraine-associated symptoms for both headache subtypes.

Efficacy of rizatriptan for menstrual migraine in an early intervention model: a prospective subgroup analysis of the rizatriptan TAME (Treat A Migraine Early) studies.

OBJECTIVE: A prospective subgroup analysis of the TAME (Treat A Migraine Early) studies examined the efficacy of rizatriptan in patients treating a menstrual migraine attack. METHODS: Both TAME studies were randomized, placebo-controlled, and double-blind. Adults with migraine were assigned (2:1) to either rizatriptan 10-mg tablet or placebo. Patients were instructed to treat within 1 hour of migraine onset and when the pain was mild. The primary endpoint was 2-hour pain freedom. The diagnosis of menstrual migraine was established according to the revised 2004 International Headache Society (IHS) diagnostic criteria. Data from both studies were pooled for logistic regression analyses. A test for interaction was performed to compare rates of 2-hour pain freedom between patients treating a menstrual and non-menstrual attack. RESULTS: A total of 94 patients (63 in the rizatriptan group and 31 in the placebo group) met IHS criteria for menstrual migraine and treated a menstrual attack. The percentage of patients reporting 2-hour pain freedom was significantly greater for rizatriptan than for placebo (63.5% vs 29.0%; odds ratio = 4.5; 95% confidence interval: 1.7, 11.9; P = .002) in those treating a menstrual attack. In those treating with rizatriptan, the percentage of patients with 2-hour pain freedom did not statistically differ between those treating a menstrual or non-menstrual migraine attack (63.5% vs 57.5%; P = .454). CONCLUSION: Rizatriptan 10 mg was effective for the treatment of menstrual migraine in an early intervention model, as measured by 2-hour pain freedom. Rates of 2-hour pain freedom were comparable for patients treating menstrual and non-menstrual migraine attacks with rizatriptan.

Elimination of migraine-associated nausea in patients treated with rizatriptan orally disintegrating tablet (ODT): a randomized, double-blind, placebo-controlled study.

OBJECTIVE: To confirm the efficacy of rizatriptan 10 mg orally disintegrating tablet (ODT) for the elimination of migraine-associated nausea. BACKGROUND: Pooled studies of rizatriptan analyzing elimination of nausea as a secondary endpoint showed that 65% of rizatriptan patients reported elimination of nausea at 2 hours compared with 41% of patients taking placebo. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled single-attack trial enrolling adult patients with at least a 6-month history of migraine who typically experience migraine-associated nausea. Patients treated a moderate or severe migraine headache at the earliest sign of nausea with either rizatriptan 10 mg ODT or placebo (2 : 1). The primary endpoint was elimination of nausea at 2 hours postdose, and the secondary endpoint was pain relief at 2 hours postdose. RESULTS: Although not statistically significant, a greater percentage of patients had elimination of nausea at 2 hours with rizatriptan compared with placebo (70.3% vs 62.0%, P = .165, odds ratio [95% CI] = 1.45 [0.86, 2.46]). When patients were grouped by baseline headache severity, rizatriptan showed a greater advantage than placebo for patients with moderate pain (rizatriptan 72.8% vs placebo 57.4%), but no difference for patients with severe pain (rizatriptan 67.7% vs placebo 66.7%). There were significantly more patients who achieved 2-hour pain relief with rizatriptan (69.7% vs 54.3%, P = .012, odds ratio [95% CI] = 1.94 [1.16, 3.25]). CONCLUSION: Although the efficacy of rizatriptan 10 mg ODT for the elimination of migraine-associated nausea was comparable to that seen in previous rizatriptan trials, the higher-than-usual placebo response prevented a finding of a statistically significant difference. There was a sizable difference in placebo response between patients who treated moderate vs severe migraine. Rizatriptan was effective for 2-hour pain relief.

Adherence with montelukast or fluticasone in a long-term clinical trial: results from the mild asthma montelukast versus inhaled corticosteroid trial.

BACKGROUND: Nonadherence with asthma therapy is common and may contribute to poor clinical outcomes. OBJECTIVE: To examine the effect of dosing frequency and mode of delivery of therapy on adherence and clinical outcomes. METHODS: We examined adherence in patients with mild persistent asthma (15-85 years) enrolled in a randomized study of montelukast (10 mg once daily) or fluticasone (88 microg, 2 puffs twice daily) during a 12-week double-blind treatment period (DB), followed by a 36-week open-label trial (OL). Adherence was monitored using eDEM for montelukast/placebo and MDILog devices for fluticasone/placebo. RESULTS: Participants used at least 1 puff of inhaled therapy on 83.3% DB/76.8% OL of days and at least 1 dose of oral therapy on 77.5%/71.4% of days (P < .0001). Subjects used inhaled therapy less than prescribed on 49.5%/57.5% of days, compared with 22.5%/28.6% of days for oral therapy (P < .0001). In the DB, a dose-response relationship was observed with fluticasone and asthma rescue-free days (P = .02) and FEV(1) percent predicted (P < .01) only for patients with FEV(1) < or = 86%. In the OL period, a dose-response relationship was observed with fluticasone and FEV(1) percent predicted (P < .001). CONCLUSION: Whereas subjects were more likely to use inhaled fluticasone/placebo at least once a day, subjects were more likely to take once-daily oral montelukast/placebo as prescribed. Clinical outcomes were inconsistently associated with adherence levels. CLINICAL IMPLICATIONS: Patients were less likely to be fully adherent with twice-daily therapy than with once-daily therapy, but most still achieved adequate asthma control.

Efficacy of Rizatriptan 10 mg administered early in a migraine attack.

OBJECTIVE: To determine if administration of rizatriptan 10 mg is superior to placebo for the early treatment of acute migraine, while the pain is mild. BACKGROUND: Past studies have suggested that treatment outcomes can be improved if a triptan is administered early in the time course of a migraine attack. METHODS: Two randomized, parallel, placebo-controlled, double-blind studies. TAME (Treat A Migraine Early)1 was conducted at 46 centers in the United States; TAME2, at 48 centers in the United States. Totally, 1030 adult patients with at least a 6-month history of migraine were studied. Patients were instructed to treat within 1 hour of migraine onset, while pain was mild. Patients maintained a headache diary in which they rated their levels of pain and disability, and recorded other symptoms of migraine. Primary endpoints were pain freedom at 2 hours and sustained pain freedom at 24 hours post-dose. RESULTS: In TAME1, 57.3% versus 31.1% of patients reported pain freedom at 2 hours post-dose and 42.6% versus 23.2% reported 24-hour sustained pain freedom with rizatriptan versus placebo, respectively (P < .001 for both). In TAME2, 58.9% versus 31.1% of patients reported pain freedom at 2 hours post-dose and 48.0% versus 24.6% reported 24-hour sustained pain freedom with rizatriptan versus placebo, respectively (P < .001 for both). All other efficacy endpoints favored rizatriptan. Repeat doses of the medicine were not allowed; patients may have delayed treatment; non-migraine headaches may have been treated. CONCLUSIONS: Rizatriptan 10 mg was superior to placebo when treating migraine early, while pain is mild, as measured by pain freedom at 2 hours and 24-hour sustained pain freedom.

Pharmacokinetic profile of rizatriptan 10-mg tablet and 10-mg orally disintegrating tablet administered with or without water in healthy subjects: an open-label, randomized, single-dose, 3-period crossover study.

This open-label, 3-period crossover study compared the plasma concentration profiles of rizatriptan tablet, orally disintegrating tablet with water (ODTc), and ODT without water (ODTs) in 24 healthy volunteers aged 18 to 45 years. At each period, subjects received a single dose of either 10-mg rizatriptan tablet, 10-mg rizatriptan ODTs, or 10-mg rizatriptan ODTc. The authors hypothesized that ODTc has a greater geometric mean AUC(0-2h) than ODTs and that ODTc has a greater geometric mean AUC(0-1h) than tablet. A secondary end point was to compare the time of occurrence of the maximum rizatriptan plasma concentration (t(max)) of each dosing method. ODTc had a statistically significantly greater geometric mean AUC(0-2h) compared with ODTs (33.84 h x ng/mL vs 18.83 h x ng/mL; P < .001). ODTc had a slightly, but not statistically significantly, greater geometric mean AUC(0-1h) compared with rizatriptan tablet (17.07 h x ng/mL vs 13.32 h x ng/mL). The median t(max) was 0.67 hours for ODTc and tablet and 1.33 hours for ODTs. ODTc showed a slightly, but not significantly, faster rate of absorption compared with tablet. ODTs with water had a faster rate of absorption than ODTc. Future studies are needed to determine whether this pharmacokinetic difference produces differential efficacy in a clinical setting.

Efficacy of montelukast during the allergy season in patients with chronic asthma and seasonal aeroallergen sensitivity.

BACKGROUND: Montelukast has proven efficacy in the treatment of chronic asthma and seasonal allergic rhinitis, but it has not been evaluated in the subpopulation of asthmatic patients with seasonal asthma symptoms. OBJECTIVE: To determine the effectiveness of montelukast treatment in improving the control of asthma symptoms during the allergy season in patients with active asthma and seasonal aeroallergen sensitivity. METHODS: Adults with a history of chronic asthma who are also symptomatic during the allergy season and with skin test sensitivity to seasonal aeroallergens were enrolled in a randomized, parallel-group, multicenter study with a 1-week, single-blind, placebo run-in period followed by 3 weeks of double-blind treatment during the spring of 2004. After the run-in period, eligible patients were randomly assigned to receive either oral montelukast (10 mg) or placebo. Daytime and nighttime asthma symptom scores, beta-agonist use, and morning and evening peak expiratory flow rates were recorded daily using an electronic diary. The primary end point was mean change from baseline to week 3 in the daytime asthma symptom score. RESULTS: Of 455 randomized patients, 433 completed the study. Compared with placebo, treatment with montelukast resulted in a significant improvement from baseline in the daytime asthma symptom score (-0.54 vs -0.34; P = .002) and in beta-agonist use, nighttime symptoms, and peak expiratory flow rates. Few patients in the montelukast and placebo groups discontinued study participation because of asthma (1.3% and 3.0%, respectively). CONCLUSION: In patients with chronic asthma and seasonal aeroallergen sensitivity, montelukast treatment provided significant asthma control during the allergy season compared with placebo.

Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and emesis over multiple cycles of moderately emetogenic chemotherapy.

BACKGROUND: An aprepitant (APR) regimen was evaluated for prevention of nausea and emesis due to moderately emetogenic chemotherapy (MEC) over multiple cycles. METHODS: The authors performed a randomized, double-blind study. Eligible patients with breast carcinoma were naïve to emetogenic chemotherapy and treated with cyclophosphamide alone or with doxorubicin or epirubicin. Patients were randomized to receive either an APR regimen (Day 1: APR 125 mg, ondansetron [OND] 8 mg, and dexamethasone [DEX] 12 mg before chemotherapy and OND 8 mg 8 hrs later; Days 2-3: APR 80 mg every day) or a control regimen (Day 1: OND 8 mg and DEX 20 mg before chemotherapy and OND 8 mg 8 hrs later; Days 2-3: OND 8 mg twice per day). Data on nausea, emesis, and use of rescue medication were collected. The primary end point was the proportion of patients with a complete response (CR; no emesis or use of rescue therapy) in Cycle 1. Efficacy end points for the multiple-cycle extension were the probabilities of a CR in Cycles 2-4 and a sustained CR rate across multiple cycles. RESULTS: Of 866 patients randomized, 744 (85.9%) entered the multiple-cycle extension, and 650 (75.1%) completed all 4 cycles. Overall, the CR was greater with the APR regimen over the 4 cycles: 53.8% versus 39.4% for Cycle 2, 54.1% versus 39.3% for Cycle 3, and 55.0% versus 38.4% for Cycle 4. The cumulative percentage of patients with a sustained CR over all 4 cycles was greater with the APR regimen (P = 0.017). CONCLUSIONS: The APR regimen was more effective than a control regimen for the prevention of nausea and emesis induced by MEC over multiple chemotherapy cycles.

Short-term and long-term asthma control in patients with mild persistent asthma receiving montelukast or fluticasone: a randomized controlled trial.

PURPOSE: To determine whether montelukast is as effective as fluticasone in controlling mild persistent asthma as determined by rescue-free days. SUBJECTS AND METHODS: Participants aged 15 to 85 years with mild persistent asthma (n = 400) were randomized to oral montelukast (10 mg once nightly) or inhaled fluticasone (88 mug twice daily) in a year-long, parallel-group, multicenter study with a 12-week, double-blind period, followed by a 36-week, open-label period. RESULTS: The mean percentage of rescue-free days was similar between treatments after 12 weeks (fluticasone: 74.9%, montelukast: 73.1%; difference = 1.8%, 95% confidence interval [CI]: -3.2% to 6.8%) but not during the open-label period (fluticasone: 77.3%, montelukast: 71.1%; difference = 6.2%, 95% CI: 0.8% to 11.7%). Although both fluticasone and montelukast significantly improved symptoms, quality of life, and symptom-free days during both treatment periods, greater improvements occurred with fluticasone in lung function during both periods and in asthma control during open-label treatment. Post hoc analyses revealed a difference in rescue-free days favoring fluticasone in participants in the quartiles for lowest lung function and greatest albuterol use at baseline. CONCLUSION: In patients with mild persistent asthma, rescue-free days and most asthma control measures improved similarly with fluticasone or montelukast over the short term, but with prolonged open-label treatment, asthma control improved more with fluticasone. Improved asthma control with fluticasone appeared to occur in 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 classification criteria for mild persistent asthma may need to be re-evaluated.

Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy.

PURPOSE: This is the first study in which the NK(1)-receptor antagonist, aprepitant (APR), was evaluated for the prevention of chemotherapy-induced nausea and vomiting (CINV) with moderately emetogenic chemotherapy. PATIENTS AND METHODS: Eligible breast cancer patients were naive to emetogenic chemotherapy and treated with cyclophosphamide +/- doxorubicin or epirubicin. Patients were randomly assigned to either an aprepitant regimen (day 1, APR 125 mg, ondansetron (OND) 8 mg, and dexamethasone 12 mg before chemotherapy and OND 8 mg 8 hours later; days 2 through 3, APR 80 qd) [DOSAGE ERROR CORRECTED] or a control regimen (day 1, OND 8 mg and dexamethasone 20 mg before chemotherapy and OND 8 mg 8 hours later; days 2 through 3, OND 8 mg bid). Data on nausea, vomiting, and use of rescue medication were collected with a self-report diary. The primary efficacy end point was the proportion of patients with complete response, defined as no vomiting and no use of rescue therapy, during 120 hours after initiation of chemotherapy in cycle 1. The secondary end point was the proportion of patients with an average item score higher than 6 of 7 on the Functional Living Index-Emesis questionnaire. RESULTS: Of 866 patients randomized, 857 patients (99%) were assessable. Overall complete response was greater with the aprepitant regimen than with the control regimen (50.8% v 42.5%; P = .015). More patients in the aprepitant group reported minimal or no impact of CINV on daily life (63.5% v 55.6%; P = .019). Both treatments were generally well tolerated. CONCLUSION: The aprepitant regimen was more effective than the control regimen for prevention of CINV in patients receiving both an anthracycline and cyclophosphamide.