A secukinumab dose-escalation study in patients with ankylosing spondylitis not achieving inactive disease after 16 weeks of treatment.

OBJECTIVE: To investigate the clinical response at week 52 in patients with ankylosing spondylitis (AS) who received secukinumab 300 vs 150 mg after inadequate response to 150 mg at week 16. METHODS: ASLeap (NCT03350815) was a randomized, double-blind, parallel-group, multicentre, phase 4 trial. After 16 weeks of open-label secukinumab 150 mg (Treatment Period 1), patients who did not achieve inactive disease (Ankylosing Spondylitis Disease Activity Score [ASDAS] <1.3) at both Weeks 12 and 16 were considered to have an inadequate response and were randomized 1:1 to receive secukinumab 300 or 150 mg every 4 weeks until week 52 (Treatment Period 2). The primary efficacy variable was achievement of ASDAS <1.3 at week 52 using week 16 as baseline. Safety was evaluated by the incidence of treatment-emergent adverse events through week 52. RESULTS: Of 322 patients treated with secukinumab in Treatment Period 1, 207 (64.3%) had inadequate response. Similar proportions of patients with inadequate response randomized to secukinumab 300 mg (n = 101) and 150 mg (n = 105) in Treatment Period 2 completed the study (83.8% and 84.3%, respectively). At week 52, 8.8% and 6.7% of patients receiving secukinumab 300 and 150 mg, respectively, achieved ASDAS <1.3. The incidence of treatment-emergent adverse events was similar in both groups through week 52. No new safety signals were observed. CONCLUSION: Patients with AS who did not achieve ASDAS <1.3 after receiving secukinumab 150 mg for 16 weeks experienced similar clinical response and safety through week 52 regardless of dose escalation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03350815.

Psoriasis improvements and inflammatory biomarker normalization with secukinumab: the randomized ObePso-S study.

BACKGROUND: The IL-17A inhibitor secukinumab has demonstrated consistent efficacy and safety in patients with moderate-to-severe plaque psoriasis, with normalization of molecular and histopathologic psoriasis markers. OBJECTIVE: To investigate treatment effects of secukinumab on clinical signs and psoriatic inflammation markers over 52 weeks in patients with psoriasis. METHODS: In the ObePso-S study (NCT03055494), patients with psoriasis were randomized 2:1 to receive secukinumab 300 mg (n = 54) or placebo (n = 28), stratified by body weight (<90 or ≥90 kg), for 52 weeks. At Week 12, patients receiving placebo were switched to secukinumab. Psoriasis Area and Severity Index improvement of 90% (PASI90) and Investigator's Global Assessment modified 2011 0/1 responses were assessed at Weeks 12 and 52. Immunohistochemistry for keratin 16 (K16) and gene expression profiles were evaluated in lesional and non-lesional skin biopsies collected at baseline, Week 12, and Week 52. RESULTS: Of patients receiving secukinumab, 55.8% and 59.6% achieved PASI90 at Weeks 12 and 52, respectively. K16 was absent in 93.1% of Week 12 PASI90 responders and 93.6% of Week 52 PASI90 responders, which mirrored the down-regulated expression of psoriatic inflammation. Week 52 PASI90 non-responders experienced regression of clinical and inflammatory marker responses toward baseline levels. Lower control of inflammatory gene expression at Week 12 was associated with suboptimal clinical responses at Week 52. CONCLUSION: Sustained clinical responses with secukinumab were associated with rapid and sustained normalization of K16 and inflammatory gene expression in most patients. Molecular anti-inflammatory effects of secukinumab at Week 12 were associated with clinical responses at Week 52.

Secukinumab in United States Biologic-Naïve Patients With Psoriatic Arthritis: Results From the Randomized, Placebo-Controlled CHOICE Study.

OBJECTIVE: To evaluate secukinumab (SEC) 300 mg and 150 mg vs placebo in a United States-only population of biologic-naïve patients with psoriatic arthritis (PsA). METHODS: CHOICE was a double-blind, randomized controlled trial conducted in the US. Biologic-naïve patients with PsA and psoriasis (PsO) were randomized 2:2:1 to SEC 300 mg (n = 103), SEC 150 mg (n = 103), or placebo (n = 52). The primary objective was to show superiority of SEC 300 mg vs placebo in American College of Rheumatology 20% (ACR20) response at week 16. Additional objectives included the effect of SEC on dactylitis, enthesitis, PsO, and safety. RESULTS: ACR20 response rates at week 16 were higher with SEC 300 mg than with placebo (51.5% vs 23.1%; odds ratio 3.51 [95% CI 1.65-7.45]; P = 0.001). SEC 300 mg also led to greater ACR50/70 responses and improvements in other variables vs placebo. Responses were generally sustained over time. Patients with inadequate response to SEC 150 mg at weeks 16, 28, or 40 who received dose escalation to 300 mg experienced improved clinical response after uptitration. The most common adverse events were upper respiratory tract infections and diarrhea. No inflammatory bowel disease was reported or new safety signals observed. CONCLUSION: SEC 300 mg led to rapid and significant improvements over placebo in symptoms of PsA in this heavier population of US-only, biologic-naïve patients. Findings were consistent with previous studies and suggest that SEC 300 mg is a safe and efficacious first-line biologic treatment for patients with PsA. [ClinicalTrials.gov: NCT02798211].

Disease Burden and Long-Term Risk of Persistent Very Poorly Controlled Asthma: TENOR II.

BACKGROUND: Severe/difficult-to-treat disease occurs in 5% to 10% of patients with asthma, but accounts for more than 50% of related economic costs. Understanding factors associated with persistent very poorly controlled (VPC) asthma may improve outcomes. OBJECTIVE: To characterize persistent VPC asthma after more than 10 years of standard of care. METHODS: The Epidemiology and Natural history of asthma: Outcomes and treatment Regimens (TENOR) II (N = 341) was a multicenter, observational study of patients with severe/difficult-to-treat asthma with a single, cross-sectional visit more than 10 years after TENOR I. Persistent VPC asthma was defined as VPC asthma at TENOR I and TENOR II enrollment; without VPC asthma was defined as well- or not well-controlled asthma at either or both visits. Multivariable logistic regression assessed long-term predictors of persistent VPC asthma using TENOR I baseline variables. RESULTS: Of 327 patients, nearly half (48.0%, n = 157) had persistent VPC asthma. Comorbidities and asthma triggers were more frequent in patients with persistent VPC asthma than in patients without VPC asthma. Total geometric mean IgE was higher in patients with persistent VPC asthma (89.3 IU/mL vs 55.7 IU/mL); there was no difference in eosinophil levels. Lung function was lower in patients with persistent VPC asthma (mean % predicted pre- and postbronchodilator FEV1, 63.0% vs 82.8% and 69.6% vs 87.2%, respectively). Exacerbations in the previous year were more likely in patients with persistent VPC asthma (29.7% vs 9.0%, respectively). Predictors of persistent VPC asthma were black versus white race/ethnicity, allergic trigger count (4 vs 0), systemic corticosteroid use, and postbronchodilator FEV1 (per 10% decrease). CONCLUSIONS: The burden of persistent VPC asthma is high in severe/difficult-to-treat disease; management of modifiable risk factors, maximization of lung function, and trigger avoidance may improve outcomes.

A Randomized Placebo-Controlled Trial of Secukinumab on Aortic Vascular Inflammation in Moderate-to-Severe Plaque Psoriasis (VIP-S).

Psoriasis, a chronic immune-mediated disease, is associated with an increased risk of cardiovascular events and mortality. Secukinumab selectively neutralizes IL-17A and has reported high efficacy with a favorable safety profile in various psoriatic disease manifestations. Subsequent to the 12-week randomized, placebo-controlled, double-blind treatment period, patients with moderate-to-severe psoriasis received secukinumab for 40 weeks. Vascular inflammation using 18F-2-fluorodeoxyglucose-positron emission tomography/computed tomography imaging and blood-based cardiometabolic was assessed at week 0, 12, and 52. The difference in change in aortic inflammation from baseline to week 12 for secukinumab (n = 46) versus placebo (n = 45) was -0.053 (95% confidence interval = -0.169 to 0.064; P= 0.37). Small increases in total cholesterol, low-density lipoprotein, and low-density lipoprotein particles, but no changes in markers of inflammation, adiposity, insulin resistance, or predictors of diabetes, were observed with secukinumab treatment compared with placebo. At week 52, reductions in TNF-α (P= 0.0063) and ferritin (P= 0.0354), and an increase in fetuin-A (P= 0.0024), were observed with secukinumab treatment compared with baseline. No significant changes in aortic inflammation or markers of advanced lipoprotein characterization, adiposity, or insulin resistance were observed with secukinumab treatment compared with baseline. Secukinumab exhibited a neutral impact on aortic vascular inflammation and biomarkers of cardiometabolic disease after 52 weeks of treatment.

Effect of omalizumab on lung function and eosinophil levels in adolescents with moderate-to-severe allergic asthma.

BACKGROUND: Omalizumab improves clinical outcomes in patients with asthma. Several studies have shown lung function improvements with omalizumab; however, this has not been examined exclusively in adolescents. OBJECTIVE: To assess the effect of omalizumab on lung function and eosinophil counts in adolescents with uncontrolled moderate-to-severe allergic asthma. METHODS: In this post hoc analysis, data from adolescents aged 12 to 17 years from 8 randomized trials of omalizumab were pooled (studies 008, 009, and 011, and SOLAR, INNOVATE, ALTO, ETOPA, and EXTRA). Changes from baseline to end of study in forced expiratory volume in 1 second (FEV1), percent predicted FEV1 (ppFEV1), forced vital capacity (FVC), and blood eosinophil counts were assessed by fitting an analysis of covariance model and calculating least squares mean (LSM) difference for omalizumab vs placebo. RESULTS: A total of 340 adolescents were identified (omalizumab, n = 203 [59.7%]; placebo, n = 137 [40.3%]). Omalizumab increased all baseline lung function variables more than placebo by end of study: LSM treatment differences (95% confidence interval) were 3.0% (0.2%-5.7%; P = .035), 120.9 mL (30.6-211.2 mL; P = .009), and 101.5 mL (8.3-194.6 mL; P = .033) for ppFEV1, absolute FEV1, and FVC, respectively. The LSM difference demonstrated a greater reduction in eosinophil counts for omalizumab vs placebo: -85.9 cells/µL (-137.1 to -34.6 cells/µL; P = .001). CONCLUSION: Omalizumab was associated with lung function improvements and circulating eosinophil counts reductions in adolescents with moderate-to-severe uncontrolled asthma. Findings emphasize the effect of omalizumab in young patients and the need to optimize treatment early in the disease course. https://clinicaltrials.gov/: NCT00314574, NCT00046748, NCT00401596.

More than a decade follow-up in patients with severe or difficult-to-treat asthma: The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) II.

BACKGROUND: The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR I) study demonstrated high morbidity in patients with severe or difficult-to-treat asthma despite standard-of-care treatment. OBJECTIVE: We sought to determine the long-term natural history of disease and outcomes in patients in TENOR I after more than a decade. METHODS: TENOR I was a multicenter observational study (2001-2004) of 4756 patients with severe or difficult-to-treat asthma. TENOR II was a follow-up study of TENOR I patients using a single cross-sectional visit in 2013/2014. Overall, the sites participating in TENOR II originally enrolled 1230 patients in TENOR I. Clinical and patient-reported outcomes were assessed, including very poorly controlled asthma based on National Heart, Lung, and Blood Institute guidelines. RESULTS: A total of 341 (27.7%) patients were enrolled in TENOR II and were representative of the TENOR I cohort. The most frequent comorbidities were rhinitis (84.0%), sinusitis (47.8%), and gastroesophageal reflux disease (46.3%). Mean percent predicted prebronchodilator and postbronchodilator FEV1 were 72.7% (SD, 21.4%) and 78.2% (SD, 20.7%), respectively. A total of 231 (72.9%) of 317 patients had positive test responses to 1 or more allergen-specific IgEs. The mean blood eosinophil count was 200/µL (SD, 144/µL). Eighty-eight (25.8%) patients experienced an asthma exacerbation in the prior 3 months requiring hospital attention, oral corticosteroids, or both. More than half (197/339 [58.1%]) had very poorly controlled asthma. Medication use suggested undertreatment. CONCLUSION: TENOR II provides longitudinal data to characterize disease progression, heterogeneity, and severity in patients with severe or difficult-to-treat asthma. Findings show continued morbidity, including a high degree of comorbid conditions, allergic sensitization, exacerbations, and very poorly controlled asthma, including reduced lung function.

The effect of secukinumab on moderate-to-severe scalp psoriasis: Results of a 24-week, randomized, double-blind, placebo-controlled phase 3b study.

BACKGROUND: Moderate-to-severe scalp psoriasis has not been evaluated in prospective trials of patients without moderate-to-severe body psoriasis. OBJECTIVE: Evaluate the efficacy and safety of secukinumab in moderate-to-severe scalp psoriasis. METHODS: In this 24-week, double-blind, phase 3b study, 102 patients were randomized 1:1 to subcutaneous secukinumab 300 mg or placebo at baseline, weeks 1, 2, and 3, and then every 4 weeks from week 4 to 20. The primary efficacy variable was 90% improvement of Psoriasis Scalp Severity Index (PSSI 90) score from baseline to week 12. RESULTS: At week 12, PSSI 90 (secukinumab 300 mg vs placebo, 52.9% vs 2.0%) and Investigator's Global Assessment modified 2011 scalp responses of 0 or 1 (secukinumab 300 mg vs placebo, 56.9% vs 5.9%) were significantly greater with secukinumab 300 mg than placebo (P < .001 for both). In addition, significantly more patients achieved complete clearance of scalp psoriasis at week 12 with secukinumab 300 mg than placebo (35.3% vs 0%; P < .001). The median time to 50% reduction in PSSI score was 3.29 weeks with secukinumab 300 mg. The safety profile of secukinumab was consistent with previous phase 3 studies. LIMITATIONS: There was no active comparator arm. CONCLUSION: Secukinumab is efficacious and well-tolerated for patients with extensive moderate-to-severe scalp psoriasis.

Omalizumab in children with uncontrolled allergic asthma: Review of clinical trial and real-world experience.

Asthma is one of the most common chronic diseases of childhood. Allergen sensitization and high frequencies of comorbid allergic diseases are characteristic of severe asthma in children. Omalizumab, an anti-IgE mAb, is the first targeted biologic therapeutic approved for the treatment of moderate-to-severe persistent allergic asthma (AA) that remains uncontrolled despite high-dose inhaled corticosteroids plus other controller medications. Since its initial licensing for use in adults and adolescents 12 years of age and older, the clinical efficacy, safety, and tolerability of omalizumab have been demonstrated in several published clinical trials in children aged 6 to less than 12 years with moderate-to-severe AA. These studies supported the approval of the pediatric indication (use in children aged ≥6 years) by the European Medicines Agency in 2009 and the US Food and Drug Administration in 2016. After this most recent change in licensing, we review the outcomes from clinical trials in children with persistent AA receiving omalizumab therapy and observational studies from the past 7 years of clinical experience in Europe. Data sources were identified by using PubMed in 2016. Guidelines and management recommendations and materials from the recent US Food and Drug Administration's Pediatric Advisory Committee meeting are also reviewed.

Clinical features of adolescents with chronic idiopathic or spontaneous urticaria: Review of omalizumab clinical trials.

BACKGROUND: Adults and adolescents were included in 3 phase 3 omalizumab trials in chronic idiopathic urticaria (CIU): ASTERIA I, ASTERIA II, and GLACIAL. OBJECTIVE: To describe the baseline clinical profile of adolescent patients with CIU enrolled in the omalizumab trials to add to the limited literature available on CIU in this population. METHODS: Data for patient demographics, baseline clinical disease characteristics, medical history, and previous CIU medication information (not efficacy assessments) from phase 3 omalizumab trials were pooled and descriptive statistical analyses performed for adolescent (12 to <18 years old) and adult (≥18 years old) subgroups. Inferential analysis was inappropriate, partly because of small sample size in the adolescent subgroup. RESULTS: The pooled population of 975 patients with CIU included 39 adolescents (4.0%). Demographics of adolescents and adults with CIU were similar, but compared with adults, fewer adolescents had positive Chronic Urticaria Index test results. Baseline clinical disease characteristics were also similar between the subgroups, with the number of previous CIU medications slightly lower in adolescents compared with adults. Medical history and existing conditions in adolescents tended to be more allergy than cardiovascular related, and fewer experienced angioedema compared with adults. CONCLUSION: Pooled data indicate differences in baseline demographic and clinical characteristics between adult and adolescent patient subgroups. This finding helps augment our understanding of the clinical profile of CIU in adolescents, but larger-scale studies in this population are warranted. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT01287117 (ASTERIA I), NCT01292473 (ASTERIA II), and NCT01264939 (GLACIAL).

Cluster analysis and its application to healthcare claims data: a study of end-stage renal disease patients who initiated hemodialysis.

BACKGROUND: Cluster analysis (CA) is a frequently used applied statistical technique that helps to reveal hidden structures and "clusters" found in large data sets. However, this method has not been widely used in large healthcare claims databases where the distribution of expenditure data is commonly severely skewed. The purpose of this study was to identify cost change patterns of patients with end-stage renal disease (ESRD) who initiated hemodialysis (HD) by applying different clustering methods. METHODS: A retrospective, cross-sectional, observational study was conducted using the Truven Health MarketScan® Research Databases. Patients aged ≥18 years with ≥2 ESRD diagnoses who initiated HD between 2008 and 2010 were included. The K-means CA method and hierarchical CA with various linkage methods were applied to all-cause costs within baseline (12-months pre-HD) and follow-up periods (12-months post-HD) to identify clusters. Demographic, clinical, and cost information was extracted from both periods, and then examined by cluster. RESULTS: A total of 18,380 patients were identified. Meaningful all-cause cost clusters were generated using K-means CA and hierarchical CA with either flexible beta or Ward's methods. Based on cluster sample sizes and change of cost patterns, the K-means CA method and 4 clusters were selected: Cluster 1: Average to High (n = 113); Cluster 2: Very High to High (n = 89); Cluster 3: Average to Average (n = 16,624); or Cluster 4: Increasing Costs, High at Both Points (n = 1554). Median cost changes in the 12-month pre-HD and post-HD periods increased from $185,070 to $884,605 for Cluster 1 (Average to High), decreased from $910,930 to $157,997 for Cluster 2 (Very High to High), were relatively stable and remained low from $15,168 to $13,026 for Cluster 3 (Average to Average), and increased from $57,909 to $193,140 for Cluster 4 (Increasing Costs, High at Both Points). Relatively stable costs after starting HD were associated with more stable scores on comorbidity index scores from the pre-and post-HD periods, while increasing costs were associated with more sharply increasing comorbidity scores. CONCLUSIONS: The K-means CA method appeared to be the most appropriate in healthcare claims data with highly skewed cost information when taking into account both change of cost patterns and sample size in the smallest cluster.

Switching to iloperidone: An omnibus of clinically relevant observations from a 12-week, open-label, randomized clinical trial in 500 persons with schizophrenia.

OBJECTIVE: To describe secondary analyses from a 12-week, randomized, open-label trial where adult schizophrenia outpatients receiving risperidone, olanzapine, or aripiprazole were switched to iloperidone. METHODS: Patients were randomized into two groups: one where the antecedent antipsychotic dose was titrated downwards to zero over 2 weeks (n=240), and the other group where the antecedent antipsychotic was abruptly stopped (n=260). Adaptations of the Clinical Global Impression scale were used to evaluate clinical changes. Other assessments included the reporting of adverse events (AEs), study discontinuation, body weight, and metabolic variables. RESULTS: Improvement was steady throughout the study for both gradual- and immediate-switch groups starting at Week 1 and continuing through Week 12. Discontinuations due to AEs in the first 2 weeks of treatment were higher for the immediate-switch group compared with the gradual-switch group (10.8% vs. 5.4%, NNT 19, 95% CI 10-151). Fewer patients in the gradual-switch group experienced dizziness as an AE, whereas a higher percentage of patients in the immediate-switch group exhibited earlier onset of a therapeutic response within the first 2 weeks; both groups were comparable thereafter with low rates of dizziness and similar efficacy outcomes. CONCLUSIONS: Switching to iloperidone can be accomplished either with a gradual crossover or immediate discontinuation of the prior antipsychotic; however, the immediate-switch method is associated with greater proportion of initial dizziness. The observed outcomes are consistent with what has been previously reported regarding iloperidone's favorable akathisia/EPS profile and modest impact on somnolence/sedation, body weight, and metabolic variables.

Once-daily indacaterol 75 µg in moderate- to-severe COPD: results of a Phase IV study assessing time until patients' perceived onset of effect.

BACKGROUND: Indacaterol 75 µg once daily is a long-acting ß2 agonist approved for maintenance bronchodilator treatment in patients with chronic obstructive pulmonary disease (COPD). The purpose of this study was to evaluate patients' perception of onset of effect with a single dose. METHODS: In this double-blind, crossover, Phase IV study, 40 patients were randomized to receive a single dose of indacaterol 75 µg or placebo via a dry powder inhaler device. The primary variable was time until patient's perception of onset of effect, using a simple self-administered (nonvalidated) questionnaire that patients answered at nine protocol-specified time points. Exploratory variables included change in forced expiratory volume in 1 second (FEV1) and change in percent predicted FEV1 from predose to postdose (determined 60-75 minutes postdose). RESULTS: The least-squares mean time to patient's perception of onset of effect was 25.4 minutes and 23.9 minutes for indacaterol and placebo, respectively. There was no significant effect for treatment, period, or sequence on the time to patient's perception. In addition, no statistically significant differences between treatments were observed for patient's global satisfaction with onset of effect and global expectation of treatment adherence. For the exploratory variable change in FEV1 from predose to postdose, indacaterol showed superiority over placebo with a clinically relevant least-squares mean treatment difference of 0.12 L (P<0.0001). There was little or no association between patient's perception of time to onset of effect and change in FEV1, or change in percent predicted FEV1. Both treatments were well tolerated. CONCLUSION: A single dose of indacaterol 75 µg did not separate from placebo in terms of patient perception of onset, although there was an improvement in FEV1 for indacaterol compared with placebo. Development and use of a validated questionnaire may be needed to address the inconsistency in evaluating this patient-related outcome.

A trial evaluating gradual- or immediate-switch strategies from risperidone, olanzapine, or aripiprazole to iloperidone in patients with schizophrenia.

In a 12-week randomized open-label trial, adults diagnosed with schizophrenia experiencing inadequate efficacy and/or poor tolerability on risperidone, olanzapine, or aripiprazole were randomized to switch to iloperidone either gradually (ie, down-titration of current therapy over the first 2weeks [to 50% on Day 1, 25% by Week 1, 0% by Week 2]) or immediately. All patients were titrated on iloperidone to 6mg BID by Day 4, then flexibly dosing between 6 and 12mg BID, as needed. The primary variable was the Integrated Clinical Global Impression of Change (I-CGI-C) and the primary analysis time point was Week 12. A total of 500 patients were randomized and received iloperidone (gradual switch, 240; immediate switch, 260), with 175, 155, and 170 patients switched from risperidone, olanzapine, and aripiprazole, respectively. I-CGI-C Results confirmed improved outcomes at Week 12, with scores that were similar between the gradual- and immediate-switch groups, respectively, for risperidone, 2.82 and 2.67 (95% CI: -0.229, 0.511); olanzapine, 2.87 and 3.03 (95% CI: -0.548, 0.235); and aripiprazole, 2.79 and 2.81 (95% CI: -0.405, 0.368). Incidence of adverse events (AEs) was similar in both switch groups, with the most frequently reported (≥10%) being dizziness, dry mouth, somnolence, and weight increase. In conclusion, switching to iloperidone by either a gradual or an immediate method did not reveal any clinically significant differences in ratings of overall efficacy and safety/tolerability outcomes, based on the I-CGI-C at 12weeks. Similar overall safety/AE profiles were observed regardless of the specific agent from which patients were switched.

A 26-week, randomized, double-blind, placebo-controlled, multicenter study to evaluate the effect of omalizumab on asthma control in patients with persistent allergic asthma.

OBJECTIVE: The 2007 National Heart, Lung, and Blood Institute (NHLBI) asthma guidelines shifted the focus of care from asthma severity to ongoing assessment of asthma control using the components of impairment and risk. We evaluated the effect of omalizumab on asthma control in patients with persistent allergic asthma inadequately controlled with NHLBI Step 4 or above asthma therapy. METHODS: In this double-blind, placebo-controlled study, patients ≥12 years (n = 271) received omalizumab (n = 136) or placebo (n = 135) every 2 or 4 weeks for 24 weeks. The primary efficacy variable, change from baseline in Asthma Control Test (ACT) total score, and Investigator's Global Evaluation of Treatment Effectiveness (IGETE, secondary efficacy variable) were evaluated at week 24. RESULTS: ACT score improved more with omalizumab compared with placebo (least squares means [LSMs]: 5.01, 4.36); however, the difference was not significant (p = .1779). Similarly, IGETE was not significantly different (p = .1177), but more patients treated with omalizumab (26/127, 20%) compared with placebo (19/131, 15%) had IGETE rated as "Excellent." Significant benefits were observed for omalizumab compared with placebo for change in ACT score (LSMs: 6.66, 5.27; p = .0334) and IGETE (p = .0321) at week 24 in a subgroup of patients with very poorly controlled asthma (ACT ≤ 15) at baseline. There were no significant differences for the subgroup of patients with forced expiratory volume in 1 second ≤ 80% predicted at baseline. Adverse events (AEs) were similar between groups with no drug-related serious AEs or deaths. CONCLUSIONS: For allergic asthma patients with NHLBI Step 4 or above asthma therapy, omalizumab consistently improved asthma control; however, compared with placebo, differences were not significant. Placebo-treated patients had substantial improvement in their ACT score, which may have limited the ability to detect differences between treatment groups. Subgroup analyses showed significant improvements with omalizumab versus placebo in patients with very poorly controlled asthma.

Effect of zoledronic acid compared with raloxifene on bone turnover markers in postmenopausal women with low bone density.

OBJECTIVE: The aim of this study was to assess the effects of zoledronic acid and raloxifene on bone turnover markers. METHODS: This multicenter, randomized, double-blind study involved 110 postmenopausal women with low bone mineral density who received either a single intravenous infusion of zoledronic acid 5 mg or 6 months of daily oral raloxifene 60 mg. The primary efficacy variable was change from baseline in the bone resorption marker urine N-telopeptide of type I collagen. The secondary efficacy variable was change from baseline in the bone formation marker serum bone-specific alkaline phosphatase. Analysis time points were at 2, 4, and 6 (primary) months. RESULTS: At 6 months, zoledronic acid produced a significantly greater reduction than did raloxifene in urine N-telopeptide of type I collagen (P < 0.001). Zoledronic acid also yielded significantly greater decreases in urine N-telopeptide of type I collagen at 2 and 4 months and in serum bone-specific alkaline phosphatase at all time points (P < 0.001 vs raloxifene for all comparisons). Both treatments were well tolerated. More adverse events occurred in the zoledronic acid group; these were primarily transient postdose symptoms that occurred within the first 3 days after the infusion. CONCLUSIONS: Zoledronic acid demonstrated significantly greater decreases in bone turnover markers than did raloxifene in postmenopausal women with low bone mass.

A guide to the design and analysis of small clinical studies.

Clinical studies, which have a small number of patients, are conducted by pharmaceutical companies and research institutions. Examples of constraints that lead to a small clinical study include a single investigative site with a highly specialized expertise or equipment, rare diseases, and limited time and budget. We consider the following topics, which we believe will be helpful for the investigator and statistician working together on the design and analysis of small clinical studies: definitions of various types of small studies (exploratory, pilot, proof of concept); bias and ways to mitigate the bias; commonly used study designs for randomized and nonrandomized studies, and some less commonly used designs; potential ethical issues associated with small underpowered clinical studies; sample size for small studies; statistical analysis methods for different types of variables and multiplicity issues. We conclude the paper with recommendations made by an Institute of Medicine committee, which was asked to assess the current methodologies and appropriate situations for conducting small clinical studies.

Effectiveness of omalizumab in reducing corticosteroid burden in patients with moderate to severe persistent allergic asthma.

BACKGROUND: Asthma guidelines advocate maintaining asthma control while minimizing corticosteroid exposure. OBJECTIVE: To assess the reduction in corticosteroid burden during long-term treatment and the corresponding impact of this reduction on asthma control, lung function, and inflammation in patients with moderate to severe allergic asthma. METHODS: We conducted a pooled analysis (N = 1,071) of 2 similarly designed, randomized, double-blind, placebo-controlled omalizumab trials and their extension phases. Each study included a 16-week steroid-stable phase, a 12-week steroid-reduction phase, and a 24-week extension phase. Patients received subcutaneous omalizumab (minimum, 0.016 mg/kg/IU (IgE/mL) every 4 weeks) or placebo every 2 or 4 weeks. Outcomes included change from baseline in inhaled corticosteroid dose, number of oral corticosteroid bursts, and other clinical measures, including asthma exacerbations and change in asthma quality-of-life score (questionnaire), lung function, and eosinophil count. RESULTS: The median reduction from baseline in inhaled corticosteroid dose (beclomethasone dipropionate equivalent dose) by the completion of the extension phase was greater for the omalizumab group than for the placebo group (-420.0 vs -252.0 µg/d; P < .001). During that time, omalizumab-treated patients required fewer oral corticosteroid bursts overall for treatment of acute exacerbations (mean, 0.2 vs 0.3; relative risk, 0.56; 95% confidence interval, 0.41 to 0.76; P < .001) and demonstrated greater improvements in measures of asthma control. CONCLUSION: The addition of omalizumab to baseline therapy in patients 12 years or older with moderate to severe persistent allergic asthma resulted in a durable reduction in the overall steroid burden and improvement in other clinical measures of asthma control.

Effect of pretreatment with omalizumab on the tolerability of specific immunotherapy in allergic asthma.

BACKGROUND: Although specific immunotherapy is a valuable treatment option for patients with allergic asthma, the potential for systemic allergic reactions has limited its use, especially for patients with symptomatic disease. OBJECTIVE: To evaluate omalizumab's effect on the tolerability of specific immunotherapy in patients with symptomatic persistent asthma not adequately controlled with inhaled corticosteroids. METHODS: This multicenter, double-blind, parallel-group study randomized patients to treatment with omalizumab or placebo, after which they received specific immunotherapy to at least 1 of 3 perennial aeroallergens (cat, dog, and house dust mite) according to a 4-week, 18-injection cluster regimen, followed by 7 weeks of maintenance therapy. The primary efficacy variable, a systemic allergic reaction after immunotherapy, was analyzed by using the Cochrane-Mantel-Haenszel test. RESULTS: A total of 248 randomized patients (126 omalizumab, 122 placebo) received at least 1 dose of immunotherapy and were evaluated for efficacy. Patients receiving omalizumab experienced significantly fewer systemic allergic reactions to immunotherapy than those receiving placebo (17/126 [13.5%] vs 32/122 [26.2%]; P = .017; 95% CI, 2.91% to 22.56%) and had fewer respiratory-related (grade 3) systemic allergic reactions (6 vs 24, respectively). Grade 4 reactions were reported in 2 patients in each group. More omalizumab patients were able to reach the target maintenance immunotherapy dose (110 [87.3%] vs 88 [72.1%], respectively; P = .004). CONCLUSION: Use of omalizumab in patients whose asthma was symptomatic despite use of inhaled corticosteroids was associated with fewer systemic allergic reactions to specific immunotherapy and enabled more patients to achieve the target immunotherapy maintenance dose.