Early Symptomatic Improvement After Ustekinumab Therapy in Patients With Ulcerative Colitis: 16-Week Data From the UNIFI Trial.

BACKGROUND & AIMS: Rapid symptomatic relief is an important treatment goal for patients with ulcerative colitis (UC). We aimed to characterize early response with ustekinumab in patients with moderate-to-severe UC during the initial 16 weeks of treatment. METHODS: We performed a post hoc analysis of data from A Study to Evaluate the Safety and Efficacy of Ustekinumab Induction and Maintenance Therapy in Participants With Moderately to Severely Active Ulcerative Colitis trial. Patients (N = 961) were randomized (1:1:1) to receive intravenous 130 mg ustekinumab, approximately 6 mg/kg ustekinumab, or placebo at week 0. Symptomatic remission, absolute stool number, Mayo stool frequency and rectal bleeding subscores, partial Mayo score, C-reactive protein, and fecal calprotectin were assessed in the overall population and for patients in the biologic-naïve or prior biologic failure subgroups. RESULTS: A significantly greater percentage of patients in the 130-mg ustekinumab (20.0%; P = .015) or approximately 6-mg/kg ustekinumab (20.2%; P = .012) groups achieved symptomatic remission at week 2 vs placebo (12.9%). Mean [SD] changes from baseline in daily stool number on day 7 were greater in the ustekinumab groups (-1.1 [2.6] in 130 mg [P = .065] and -1.2 [2.5] in ∼6 mg/kg [P = .017]) vs placebo (-0.7 [2.7]). The percentage of patients with Mayo stool frequency subscore of 1 or less and rectal bleeding subscore of 0 increased from baseline through week 16 for both ustekinumab groups. Significant improvements in partial Mayo scores were observed by week 2 in both ustekinumab groups vs placebo (P ≤ .001). Significantly more patients in the ustekinumab groups had normalized C-reactive protein levels from week 2 to week 8 vs placebo (P ≤ .05). Similar results were observed with normalized fecal calprotectin levels between week 2 and week 4 (P ≤ .05). CONCLUSIONS: Ustekinumab improved symptoms in patients with UC compared with placebo in as early as 7 days, indicating rapid onset of effect after induction. CLINICAL TRIAL REGISTRY NUMBER: ClinicalTrials.gov: NCT02407236.

Safety of Ustekinumab in Inflammatory Bowel Disease: Pooled Safety Analysis of Results from Phase 2/3 Studies.

BACKGROUND: Ustekinumab is currently approved globally in Crohn's disease (CD) and psoriatic diseases. Recent phase 3 data demonstrate safety/efficacy in ulcerative colitis (UC). Crohn's disease and UC phase 3 programs had similar study designs, facilitating integrated safety analyses. METHODS: Data from 6 ustekinumab phase 2/3 CD and UC studies were pooled, and safety was evaluated through 1 year. Patients received 1 placebo or ustekinumab (generally 130 mg or ~6 mg/kg) intravenous induction, then subcutaneous (90 mg) maintenance every 8/12 weeks. Analyses incorporated all patients who received ≥1 ustekinumab dose. Safety outcomes are presented as percentages of patients (induction) and as number of patients with events per 100 patient-years of follow-up (through 1 year). For key safety events, 95% confidence intervals (CIs) are provided, as appropriate. Hazard ratios with 95% CIs from time-to-event analyses for serious adverse events and serious infections were also performed. RESULTS: Through 1 year, 2574 patients received ustekinumab (1733 patient-years of follow-up). The number of patients with adverse events per 100 patient-years (placebo 165.99 [95% CI, 155.81-176.67] vs ustekinumab 118.32 [95% CI, 113.25-123.55]), serious AEs (27.50 [95% CI, 23.45-32.04] vs 21.23 [95% CI, 19.12-23.51]), infections (80.31 [95% CI, 73.28-87.84] vs 64.32 [95% CI, 60.60-68.21]), serious infections (5.53 [95% CI, 3.81-7.77] vs 5.02 [95% CI, 4.02-6.19]), and malignancies excluding nonmelanoma skin cancer (0.17 [95% CI, 0.00-0.93] vs 0.40 [95% CI, 0.16-0.83]) were similar between placebo and ustekinumab. CONCLUSIONS: The safety profile of ustekinumab across the pooled inflammatory bowel disease population through 1 year was favorable and generally comparable to placebo. These data are consistent with the established safety profile of ustekinumab across indications. CLINICALTRIALS.GOV NUMBERS: NCT00265122; NCT00771667; NCT01369329; NCT01369342; NCT01369355; NCT02407236.

Ustekinumab is effective and safe for ulcerative colitis through 2 years of maintenance therapy.

BACKGROUND: The ongoing UNIFI long-term extension evaluates subcutaneous ustekinumab for moderate-to-severe ulcerative colitis (UC) from weeks 44 through 220. AIMS: To assess efficacy (through week 92) and safety (through week 96) during the long-term extension METHODS: Overall, 399 responders to intravenous ustekinumab induction and who were randomised to maintenance therapy were treated in the long-term extension (115 received subcutaneous placebo, 141 received ustekinumab 90 mg every 12 weeks [q12w], and 143 received ustekinumab 90 mg q8w). Placebo treatment was discontinued at unblinding after week 44. Partial Mayo scores were collected every 12 weeks and at each dosing visit after unblinding. Safety was evaluated throughout. RESULTS: Among all patients randomised in maintenance, symptomatic remission rates (stool frequency = 0/1; rectal bleeding = 0) at week 92 were, 64.5% and 67.6% in the ustekinumab q12w and q8w groups, respectively. Among randomised patients treated in the long-term extension, 78.7% and 83.2% of patients receiving q12w and q8w, respectively, attained symptomatic remission at week 92; >95% of patients in symptomatic remission at week 92 were corticosteroid-free. Both ustekinumab groups maintained efficacy through week 92. From weeks 44 to 96, adverse events (AEs) per hundred patient-years (PY) of follow-up for combined ustekinumab vs placebo were: 255.68 vs 267.93; serious AEs, 9.34 vs 12.69; malignancies (including non-melanoma skin cancers), 0.93 vs 1.49; and serious infections, 2.33 vs 2.99. One patient with multiple comorbidities who received one ustekinumab dose after dose adjusting from placebo experienced a fatal cardiac arrest. CONCLUSIONS: The efficacy of ustekinumab in patients with UC was sustained through 92 weeks. No new safety signals were observed (ClinicalTrials.gov number, NCT02407236).

Maintenance Golimumab Treatment in Pediatric UC Patients With Moderately to Severely Active UC: PURSUIT PEDS PK Long-Term Study Results.

Background: Long-term safety, pharmacokinetics, and efficacy of open-label golimumab therapy in children with moderate-severe ulcerative colitis were evaluated. Methods: Week-6 golimumab responders (Mayo score decrease of ≥30% and ≥3 points from baseline, rectal bleeding subscore of 0/1 or ≥1 decrease from baseline) entered the long-term extension at week 14 and received maintenance therapy (subcutaneous, q4w). Patients ≥45 kg could receive at-home treatments at week 18. Pharmacokinetic, safety, and efficacy results were summarized through week 126 (2 years). Results: Among 35 enrolled children, 21 (60%) responded at week 6 and 20 entered the long-term extension (median age of 14.5 years and median weight of 46.1 kg). Eleven of 20 patients (55%) completed 2 years of treatment. No anaphylactic or serum sickness-like reactions, opportunistic infections, malignancies, tuberculosis, or deaths occurred. The safety profile of golimumab from weeks 14 through 126 and that observed through week 14 was generally consistent. Median trough golimumab concentrations in evaluable patients were consistent from weeks 14 (1.39, interquartile range 0.67-3.60) through 102 (1.18, 0.78-2.16), but higher at week 110 (4.10, 1.30-4.81). The incidence of antigolimumab antibodies increased from 10% (2/20) at week 30 to 25.0% (5/20) at week 126; 1 patient had neutralizing antibodies. At week 110, 50% (10/20) of patients were in remission (ie, Pediatric Ulcerative Colitis Activity Index <10). Among all enrolled patients, 28.6% (10/35) achieved remission at week 110. Conclusions: Among children with ulcerative colitis who initially responded to golimumab induction and received q4w maintenance treatment in the long-term extension, 50% showed continued clinical benefit through 2 years. No new safety signals were observed.

Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis.

BACKGROUND: The efficacy of ustekinumab, an antagonist of the p40 subunit of interleukin-12 and interleukin-23, as induction and maintenance therapy in patients with ulcerative colitis is unknown. METHODS: We evaluated ustekinumab as 8-week induction therapy and 44-week maintenance therapy in patients with moderate-to-severe ulcerative colitis. A total of 961 patients were randomly assigned to receive an intravenous induction dose of ustekinumab (either 130 mg [320 patients] or a weight-range-based dose that approximated 6 mg per kilogram of body weight [322]) or placebo (319). Patients who had a response to induction therapy 8 weeks after administration of intravenous ustekinumab were randomly assigned again to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 12 weeks [172 patients] or every 8 weeks [176]) or placebo (175). The primary end point in the induction trial (week 8) and the maintenance trial (week 44) was clinical remission (defined as a total score of ≤2 on the Mayo scale [range, 0 to 12, with higher scores indicating more severe disease] and no subscore >1 [range, 0 to 3] on any of the four Mayo scale components). RESULTS: The percentage of patients who had clinical remission at week 8 among patients who received intravenous ustekinumab at a dose of 130 mg (15.6%) or 6 mg per kilogram (15.5%) was significantly higher than that among patients who received placebo (5.3%) (P<0.001 for both comparisons). Among patients who had a response to induction therapy with ustekinumab and underwent a second randomization, the percentage of patients who had clinical remission at week 44 was significantly higher among patients assigned to 90 mg of subcutaneous ustekinumab every 12 weeks (38.4%) or every 8 weeks (43.8%) than among those assigned to placebo (24.0%) (P = 0.002 and P<0.001, respectively). The incidence of serious adverse events with ustekinumab was similar to that with placebo. Through 52 weeks of exposure, there were two deaths (one each from acute respiratory distress syndrome and hemorrhage from esophageal varices) and seven cases of cancer (one each of prostate, colon, renal papillary, and rectal cancer and three nonmelanoma skin cancers) among 825 patients who received ustekinumab and no deaths and one case of cancer (testicular cancer) among 319 patients who received placebo. CONCLUSIONS: Ustekinumab was more effective than placebo for inducing and maintaining remission in patients with moderate-to-severe ulcerative colitis. (Funded by Janssen Research and Development; UNIFI ClinicalTrials.gov number, NCT02407236.).

Peficitinib, an Oral Janus Kinase Inhibitor, in Moderate-to-severe Ulcerative Colitis: Results From a Randomised, Phase 2 Study.

BACKGROUND AND AIMS: Janus kinase [JAK] inhibitors have shown efficacy in ulcerative colitis [UC]. We studied the dose-response, efficacy, and safety of peficitinib, an oral JAK inhibitor, in patients with moderate-to-severe UC. METHODS: In this Phase 2b, dose-ranging trial, we evaluated peficitinib at 25 mg once daily [o.d.], 75 mg o.d., 150 mg o.d., and 75 mg twice daily versus placebo for efficacy and safety in 219 patients with moderate-to-severe UC. The primary outcome was peficitinib dose-response at Week 8, with response assessed using Mayo score change from baseline. Secondary endpoints were clinical response, clinical remission, mucosal healing, change from baseline in Inflammatory Bowel Disease Questionnaire [IBDQ], and normalisation of inflammatory biomarkers at Week 8; other secondary endpoints were treatment response through Week 16 and through Week 32 for patients in clinical response at Week 8. Safety was assessed through Week 36 or 4 weeks after the last dose. RESULTS: A statistically significant peficitinib dose-response was not demonstrated at Week 8, although a numerically greater proportion of patients receiving peficitinib ≥75 mg o.d. achieved clinical response, remission, and mucosal healing at Week 8, supported by IBDQ improvement and inflammatory biomarker normalisation. Treatment-emergent adverse event [TEAE] rates reported through Week 8 and the final safety visit were higher in the combined peficitinib group than in the placebo group; patients receiving doses of ≥75 mg o.d. peficitinib reported TEAEs more frequently. CONCLUSIONS: No dose-response in patients with moderate-to-severe UC was demonstrated with peficitinib, but evidence of efficacy was suggested at doses ≥75 mg o.d. The safety profile of peficitinib was consistent with current information. ClinicalTrials.gov NCT01959282.

A Randomized, Placebo-Controlled Phase 2 Trial of CNTO 6785 in Chronic Obstructive Pulmonary Disease.

Interleukin (IL)-17A may be an underlying factor in the pathophysiology of chronic obstructive pulmonary disease (COPD). Anti-IL-17 monoclonal antibodies have been used successfully in treating several immune-mediated inflammatory diseases. This phase 2, randomized, placebo-controlled, double-blind, parallel-group, proof-of-concept study is the first clinical study evaluating the efficacy and safety of the anti-IL-17A monoclonal antibody CNTO 6785 in patients with symptomatic moderate-to-severe COPD. Patients were treated with CNTO 6785 (n = 93) or placebo (n = 94) intravenously at Weeks 0, 2, and 4 (induction), then Weeks 8 and 12, and followed till Week 24. The primary efficacy endpoint was the change from baseline in pre-bronchodilator percent-predicted forced expiratory volume in 1 second at Week 16. Samples were collected at all visits for pharmacokinetic (PK) evaluation, and standard safety assessments were performed. The mean difference in the primary efficacy endpoint between CNTO 6785 and placebo was not statistically significant (-0.49%; p = 0.599). No other efficacy endpoints demonstrated clinically or statistically significant differences with CNTO 6785 compared with placebo. CNTO 6785 was generally well tolerated; no major safety signals were detected. The most frequently reported treatment-emergent adverse events were infections and infestations; however, no notable differences were observed between CNTO 6785 and placebo in terms of rates of infections. PK results suggested that the steady state of serum CNTO 6785 concentration was reached within 16 weeks. These results suggest that IL-17A is unlikely to be a dominant driver in the pathology of, or a viable therapeutic target for, COPD. ClinicalTrials.gov Identifier: NCT01966549; EudraCT Identifier: 2012-003607-36.

Long-term safety and asthma control measures with a budesonide/formoterol pressurized metered-dose inhaler in African American asthmatic patients: a randomized controlled trial.

BACKGROUND: Information surrounding the long-term safety of combination inhaled corticosteroid/long-acting ß(2)-adrenergic agonist medications in African American asthmatic patients is limited. OBJECTIVE: We sought to assess safety and asthma control with a budesonide/formoterol pressurized metered-dose inhaler (pMDI) versus budesonide over 1 year in African American patients. METHODS: This 52-week, randomized, double-blind, parallel-group, multicenter, phase 3B safety study (NCT00419952) was conducted in 742 self-reported African American patients 12 years or older with moderate-to-severe asthma previously receiving medium- to high-dose inhaled corticosteroids. After 2 weeks using a 320 µg twice-daily budesonide pMDI, patients were randomized 1:1 to 320/9 µg twice-daily budesonide/formoterol pMDI or 320 µg twice-daily budesonide pMDI. RESULTS: Both treatments were well tolerated. Asthma exacerbation incidence and rate (per patient-treatment year) were lower with budesonide/formoterol versus budesonide (incidence, 7.7% vs 14.0% [P= .006]; rate ratio, 0.615 [P= .002]). Time to first asthma exacerbation was longer (P= .018) with budesonide/formoterol versus budesonide. The most common adverse events, regardless of study drug relationship, were headache (9.5% and 7.7%), nasopharyngitis (6.9% and 8.0%), sinusitis (4.0% and 6.3%), and viral upper respiratory tract infection (5.8% and 4.4%) for budesonide/formoterol and budesonide, respectively. Serious adverse events occurred in 12 and 15 patients, respectively; none were considered drug related. No substantial or unexpected patterns of abnormalities were observed in laboratory, electrocardiographic, or Holter monitoring assessments. Hospitalization caused by asthma exacerbation occurred in 0 and 4 patients in the budesonide/formoterol and budesonide groups, respectively. Pulmonary function and asthma control measures generally favored budesonide/formoterol. CONCLUSIONS: In this population budesonide/formoterol pMDI was well tolerated over 12 months, with a safety profile similar to that of budesonide; the asthma exacerbation rate was reduced by 38.5% versus budesonide.

A randomised, placebo-controlled, dose-finding study of AZD9668, an oral inhibitor of neutrophil elastase, in patients with chronic obstructive pulmonary disease treated with tiotropium.

AZD9668 is a fully reversible, selective, oral inhibitor of neutrophil elastase, a protease implicated in chronic obstructive pulmonary disease (COPD). Efficacy, safety and tolerability of AZD9668 (5, 20 and 60 mg bid) were compared with placebo in a randomised, double-blind, placebo-controlled, 12-week, Phase IIb trial (NCT00949975: approved by an Investigational Review Board), in patients with symptomatic COPD receiving maintenance tiotropium. The primary endpoint was pre-bronchodilator forced expiratory volume in 1 second (FEV1). Secondary endpoints included forced vital capacity and inspiratory capacity, peak expiratory flow, Breathlessness, Cough and Sputum Scale score, exercise capacity, quality of life (QoL), exacerbation assessments, safety and pharmacokinetics. Exploratory endpoints included inflammatory and tissue degradation biomarkers. A total of 838 patients were randomised to AZD9668 5 mg bid (212 patients), 20 mg bid (206 patients), 60 mg bid (202 patients) or placebo (218 patients). AZD9668 showed no effect on lung function, respiratory signs and symptoms, QoL or biomarkers. At end of treatment, the change in mean pre-bronchodilator FEV1 for AZD9668 60 mg bid compared with placebo was 0.00L (95% confidence interval: -0.05, 0.04; p = 0.873). Overall, AZD9668 was well tolerated; the numbers of patients with adverse events (AEs), serious AEs and AEs leading to discontinuation were similar in each of the four study groups. AZD9668 60 mg bid showed no clinical benefit and no effect on biomarkers of inflammation or tissue degradation when added to tiotropium in patients with COPD. These results raise important questions for future investigation of anti-inflammatory and disease-modifying agents in patients with COPD.

AZD9668, a neutrophil elastase inhibitor, plus ongoing budesonide/formoterol in patients with COPD.

BACKGROUND: Neutrophil elastase (NE) is implicated in chronic obstructive pulmonary disease (COPD). AZD9668 is a reversible and selective inhibitor of NE, well tolerated at doses of 60 mg bid during Phase I/IIa development. METHODS: This 12-week, randomised, double-blind, placebo-controlled, Phase IIb, trial (NCT01023516), investigated the efficacy and safety of AZD9668 (60 mg bid) versus placebo in patients with symptomatic COPD and a history of exacerbation receiving maintenance budesonide/formoterol. Primary outcome variable: forced expiratory volume in one second (FEV1). Secondary endpoints included: post-bronchodilator FEV1, pre- and post-bronchodilator forced vital capacity, FEV6, forced expiratory flow between 25% and 75% of vital capacity and inspiratory capacity; peak expiratory flow and FEV1 measured at home; EXAcerbations of Chronic pulmonary disease Tool and Breathlessness, Cough and Sputum Scores; St George's respiratory questionnaire for COPD (SGRQ-C) scores; exacerbations; and safety assessments. RESULTS: Six hundred and fifteen patients were randomised: placebo (302), AZD9668 60 mg bid (313). AZD9668 showed no effect on lung function: change in mean pre-bronchodilator FEV1 versus placebo was 0.01L (95% confidence interval: -0.03, 0.05; p=0.533). AZD9668 did not significantly improve respiratory signs and symptoms, SGRQ-C score or time to first exacerbation. Adverse events were similar for AZD9668 and placebo. CONCLUSIONS: Three months' treatment with AZD9668 did not improve lung function, respiratory signs and symptoms or SGRQ-C score when added to budesonide/formoterol maintenance therapy in patients with COPD. In the absence of definitive biomarkers of short-term disease progression, further research is needed to determine the optimal duration of studies to evaluate NE inhibitors as disease-modifying agents.

Budesonide/formoterol pressurized metered-dose inhaler versus budesonide: a randomized controlled trial in black patients with asthma.

OBJECTIVE: Concerns exist that responses to long-acting ß(2)-adrenergic agonists in black patients may differ from the general population. The efficacy and safety of budesonide/formoterol (BUD/FM) pressurized metered-dose inhaler (pMDI) versus budesonide dry powder inhaler (BUD DPI) were evaluated in adolescent and adult black asthma patients. METHODS: This 12-week, randomized, double-blind, multicenter, phase IV US study was conducted in 311 self-reported black patients aged ≥12 years with moderate to severe persistent asthma, previously receiving medium- to high-dose inhaled corticosteroid. After 2 weeks on BUD 90 µg × 2 inhalations twice daily (bid), symptomatic patients were randomized to BUD/FM 160/4.5 µg × 2 inhalations bid or BUD 180 µg × 2 inhalations bid. RESULTS: Improvement in predose forced expiratory volume in 1 second from baseline to the treatment mean (primary variable) was greater with BUD/FM versus BUD (0.16 vs. 0.07 L; p = .008); this effect was also observed at weeks 2, 6, and end of treatment (p ≤ .032). Greater improvements (p < .001) in peak expiratory flow with BUD/FM versus BUD were seen at first measurement and maintained during 12 weeks (morning: 25.34 vs. 7.53 L/minute, respectively; evening: 21.61 vs. 7.67 L/minute, respectively); greater improvements in daily asthma symptom score and rescue medication use were also observed (p ≤ .039). Both treatments were well tolerated, with similar safety profiles. CONCLUSIONS: In this population of black asthma patients, BUD/FM pMDI resulted in greater improvements in pulmonary function and asthma control versus BUD DPI, with similar safety profiles.

Efficacy of budesonide/formoterol pressurized metered-dose inhaler versus budesonide pressurized metered-dose inhaler alone in Hispanic adults and adolescents with asthma: a randomized, controlled trial.

BACKGROUND: Few clinical trials in asthma have focused on Hispanic populations. OBJECTIVE: To compare the efficacy and safety of budesonide/formoterol (BUD/FM) with BUD in an ethnically diverse group of Hispanic participants with asthma previously treated with inhaled corticosteroids (ICS). METHODS: This 12-week, randomized, double-blind, active-controlled study (NCT00419757) was designed to enroll Hispanic participants (self-reported) (≥12 years of age) with moderate to severe asthma requiring medium- to high-dose ICS. After a 2-week run-in period (low-dose BUD pressurized metered-dose inhaler [pMDI] 80 µg × 2 inhalations [160 µg] twice daily), participants with a symptom score greater than 0 (scale: 0-3) on 3 or more of 7 run-in days and forced expiratory volume in 1 second (FEV(1)) 45%-85% predicted were randomized to BUD/FM pMDI 160/4.5 µg × 2 inhalations (320/9 µg) twice daily or BUD pMDI 160 µg × 2 inhalations (320 µg) twice daily. RESULTS: Randomized participants (n = 127 BUD/FM; n = 123 BUD) were predominately Mexican (51%) or Puerto Rican (21%). During low-dose ICS run-in, the mean symptom score was 1.0; however, mean predose FEV(1) improved (2.10-2.21 L). During randomized treatment, small, but not statistically significant, improvements favored BUD/FM vs BUD (am peak expiratory flow [PEF; primary efficacy variable] 25.4 vs 19.9 L/min; pm PEF 20.6 vs 15.8 L/min; predose FEV(1) 0.16 vs 0.11 L; rescue medication use -0.7 vs -0.6 inhalations/d). Most adverse events were mild or moderate in intensity. CONCLUSIONS: Improvement in clinically relevant control end points occurred in both BUD/FM and BUD groups; both treatments were well tolerated in this Hispanic asthma population but were not significantly differentiated.

Once- vs twice-daily budesonide/formoterol in 6- to 15-year-old patients with stable asthma.

OBJECTIVE: To assess efficacy/tolerability of once-daily budesonide/formoterol pressurized metered-dose inhaler (pMDI) versus budesonide pMDI (primary) and twice-daily budesonide/formoterol (secondary) in children/adolescents with asthma stabilized with twice-daily budesonide/formoterol. METHODS: This 12-week multicenter, double-blind randomized controlled study (www.clinicaltrials.gov identifier NCT00646321) included 521 patients aged 6 to 15 years with mild/moderate persistent asthma. Patients stabilized during a 4- to 5-week run-in with twice-daily budesonide/formoterol pMDI 40/4.5 microgx2 inhalations (160/18 microg daily) received twice-daily budesonide/formoterol pMDI 40/4.5 microgx2 inhalations (160/18 microg daily), once-daily budesonide/formoterol pMDI 80/4.5 microgx2 inhalations (160/9 microg daily; evening), or once-daily budesonide pMDI 80 microgx2 inhalations (160 microg daily; evening). RESULTS: Once- or twice-daily budesonide/formoterol was more effective than budesonide for evening peak expiratory flow (primary variable) at the end of the 24-hour once-daily dosing interval (P

The functionality of a budesonide/formoterol pressurized metered-dose inhaler with an integrated actuation counter.

Integration of an actuation counter into pressurized metered-dose inhalers (pMDIs) can allow patients to accurately determine the remaining number of medication doses. This study was designed to assess the functionality of budesonide/formoterol (Symbicort; AstraZeneca, Dunkerque, France) pMDI with an integrated actuation counter in a clinical setting. Children aged > or =6 years, adolescents, and adults with inhaled corticosteroid-dependent asthma participated in this 6-week, randomized, open-label, multicenter study (SD-039-0743; D5896C00743). Patients were treated with budesonide/formoterol pMDI with no actuation counter (80/4.5 micrograms x 2 inhalations [160/9 micrograms] twice daily) during a 7- to 10-day run-in period. Qualifying patients were then randomized into one of three groups treated with budesonide/formoterol pMDI with actuation counter (80/4.5 micrograms x 2 inhalations [160/9 micrograms] twice daily): group 1, 96 actuations (24 days); group 2, 120 actuations (30 days); or group 3, 128 actuations (32 days). Actuation count was assessed using position of the counter arrow, patient/caregiver reports (daily log and actuation counter final reading), and device (canister plus actuation counter assembly) weight change. Patients/caregivers rated ease of device use. There was good agreement across treatment groups (n = 254) between patient/caregiver-reported actuation counts and counts determined by the angular position of the arrow. Analysis of device weight change versus other estimates of actuation counts in groups 1 and 2 indicated that the device did not undercount the number of actuations sprayed. Most patients (93%) indicated the device was "extremely easy" or "very easy" to use. Clinical functionality and reliability of the budesonide/formoterol pMDI device with an actuation counter were established.

The safety and clinical benefit of budesonide/formoterol pressurized metered-dose inhaler versus budesonide alone in children.

Few studies have evaluated inhaled corticosteroid (ICS)/long-acting beta(2)-adrenergic agonist combination therapy in asthmatic children. This study was designed to evaluate the safety (primary) and clinical benefits (secondary) of budesonide/formoterol pressurized metered-dose inhaler (pMDI) versus budesonide dry powder inhaler (DPI) in children with persistent asthma. This was a 26-week, multicenter, randomized, open-label U.S. study of 187 children 6-11 years of age previously receiving ICS. After 1 week of usual ICS therapy, subjects received twice-daily budesonide/formoterol pMDI 160/4.5 micrograms x 2 inhalations (320/9 micrograms; n = 124) or budesonide DPI 200 micrograms x 2 inhalations (400 micrograms [320 micrograms delivered ex-mouthpiece]; n = 63). Budesonide/formoterol and budesonide were well tolerated with a similar incidence of adverse events (AEs) (84.6% and 85.7%, respectively), most of mild or moderate intensity. Treatment-related AE incidence was low (5.4%) and similar across groups (budesonide/formoterol, 4.9%; budesonide, 6.3%). No clinically important treatment differences were observed for 12-lead electrocardiograms, hematology, serum glucose and potassium, and 24-hour urinary cortisol. Compared with budesonide, budesonide/formoterol decreased health care use (urgent care visits and interference with daily activities [child] or work [caregiver]; p < or = 0.012) and improved health-related quality of life (Pediatric Asthma Quality of Life Questionnaire [standardized] and Pediatric Asthma Caregiver Quality of Life Questionnaire overall scores; p < or = 0.006) and pulmonary function (predose forced expiratory volume in 1 second and forced expiratory flow during the middle half of exhalation; p < or = 0.007). In this 26-week study of asthmatic children (6-11 years), safety profiles were similar and clinical benefits were greater with budesonide/formoterol than with budesonide.

Can patients with asthma feel inhaler therapy working right away? Two clinical trials testing the effect of timing of assessment on patient perception.

BACKGROUND: Feeling a maintenance therapy work right away may provide positive reinforcement and may offer one way to improve adherence in patients with asthma. Precise measurement is required to accurately compare the presence of this effect across clinical trial treatment groups. METHODS: Two randomized, controlled studies tested whether timing of assessment (daily vs weekly, study 1; and predose vs postdose, study 2) influenced patients' reports of whether they can feel a medication working right away (perception), and their satisfaction with this perception (satisfaction). These 2-week US-based multicenter double-blind, parallel-group studies included patients > or = 18 years of age with mild to moderate persistent asthma. In each, patients were randomized to one of two drugs with different onset profiles: budesonide/formoterol pressurized metered-dose inhaler (pMDI) 80/4.5 microg x 2 inhalations (160/9 microg) twice daily or budesonide pMDI 80 microg x 2 inhalations (160 microg) twice daily. Patients were further randomized to complete previously validated perception and satisfaction questions in a cross-over fashion, either daily and weekly (N = 123) or predose and postdose (N = 134). Patient surveys also assessed perceptions of the onset of effect of medication and their value of these perceptions. RESULTS: No significant differences were observed in patients' reports of perception, either daily versus weekly or predose versus postdose. A statistically significant difference in satisfaction was found in study 1 only, favoring weekly recall (p < 0.05), with sensitivity analysis showing no difference by treatment group (p = 0.162). Across both studies, most patients (87%) who perceived their inhaler working right away (136 of 157 patients) identified positive airway sensations. Most patients reported that feeling their medication work right away is reassuring and would help them manage their asthma. CONCLUSION: Assessment timing has no effect on patient response to the perception of feeling a medication working right away. Differences found in satisfaction levels reported with weekly versus daily recall were consistent across treatment groups, indicating that no bias was introduced in favor of either treatment group. Patients characterized the perception of feeling a maintenance therapy working right away as easier breathing and reported this perception as beneficial to patient self-care.

Interpreting clinical trial results of patient-perceived onset of effect in asthma: methods and results of a Delphi panel.

OBJECTIVE: The purpose of this study was to determine if empirically observed differences in patient perception of, and satisfaction with, onset of effect between an active maintenance treatment and placebo are clinically meaningful to practicing clinicians. A secondary objective was to determine the lowest threshold for a clinically meaningful difference in terms of both between-group differences and maximum acceptable placebo effect. METHODS: Twelve community-based healthcare professionals participated in a Delphi consensus panel. Panelists were provided with blinded results of two clinical trials showing statistically significant treatment effects for treatment A (budesonide/formoterol [Symbicort*]) over placebo in the proportion of patients who could perceive the medication working right away and the proportion of patients satisfied with this perception. Panelists were then asked to respond to a series of questions to identify a threshold for clinically important differences in patient-perceived onset of effect and satisfaction with speed of onset of effect. All expert panelists participated in two rounds of the Delphi process. RESULTS: Panelists were unanimous in their conclusion that the statistically significant results from the two trials were clinically meaningful. According to these practitioners, the empirical results presented to them, showing that patients could feel a maintenance inhaler therapy work right away, were meaningful to clinical decision-making, and the attribute could potentially improve patient adherence with therapy. A group consensus was reached that a minimum active treatment response for these outcomes should range from 50% to 75% and be 2-3 times larger than the placebo response, with a maximum placebo effect of 26-40%. CONCLUSION: A Delphi panel study of practitioners was used to establish a meaningful range of response and a minimal important difference for interpreting results of clinical trials in which patient perception of onset of effect and satisfaction with this perception are tested. While the views of this panel may not be generalized to the entire population of practitioners in the United States, results provide insight into how a typical practitioner is likely to view clinical trial results and how the information might be used in clinical practice.

Long-term safety and asthma control with budesonide/formoterol versus budesonide pressurized metered-dose inhaler in asthma patients.

Safety concerns have been raised regarding the regular use of long-acting beta(2)-adrenergic agonists (LABAs) alone or with inhaled corticosteroids (ICSs). The purpose of this study was to examine the long-term safety of budesonide/formoterol pressurized metered-dose inhaler (pMDI). This 52-week, double-blind study (SD-039-0728; n=708) included patients >or=12 years of age with moderate to severe persistent asthma previously receiving ICSs. After 2 weeks on budesonide pMDI 320 microg twice daily (b.i.d.), patients were randomized 3:1:1 overall to budesonide/formoterol pMDI 640/18 microg b.i.d., budesonide/formoterol pMDI 320/9 microg b.i.d., or budesonide pMDI 640 microg b.i.d. The incidence of adverse events (AEs) was similar across the groups. Drug-related AEs (>or=2% overall) were oral candidiasis, tremor, and pharyngolaryngeal pain. No clinically meaningful differences in laboratory, electrocardiogram, or Holter monitor variables were observed. The percentage of patients with >or=1 asthma exacerbation was significantly lower (p=0.006) with budesonide/formoterol 640/18 (12.2%) and numerically lower with budesonide/formoterol 320/9 (14.4%) versus budesonide (21.8%). The number of asthma exacerbations per patient-treatment year was lower with budesonide/formoterol 640/18 (0.174; p=0.004) and budesonide/formoterol 320/9 (0.185; p=0.049) versus budesonide (0.315). Improvements in forced expiratory volume in 1 second and diary variables were significantly greater (p<0.001) with both budesonide/formoterol doses versus budesonide. Budesonide/formoterol 640/18 and 320/9 microg b.i.d. showed an acceptable safety profile relative to budesonide, with no significant or unexpected patterns of abnormalities observed by adding a LABA to budesonide for up to 1 year in this patient population. Improvements in asthma control were shown with both doses of budesonide/formoterol versus budesonide.

Twelve-week, randomized, placebo-controlled, multicenter study of the efficacy and tolerability of budesonide and formoterol in one metered-dose inhaler compared with budesonide alone and formoterol alone in adolescents and adults with asthma.

BACKGROUND: The addition of the long-acting beta(2)-adrenergic agonist formoterol to low- to moderate-dose budesonide has shown clinical efficacy in patients with persistent asthma. Combination therapy with budesonide/formoterol in 1 pressurized metered-dose inhaler (pMDI) has been found to have greater efficacy than its monocomponents in patients with moderate to severe persistent asthma, but it has not been assessed in patients with mild to moderate persistent asthma. OBJECTIVE: The aim of this study was to compare the efficacy and tolerability of budesonide and formoterol delivered via 1 pMDI (budesonide/formoterol pMDI), budesonide pMDI, formoterol dry powder inhaler (DPI), and placebo. METHODS: This 12-week, multicenter, double-blind, randomized, placebo-controlled, double-dummy study was conducted at 56 centers across the United States. Patients aged > or =12 years with mild to moderate persistent asthma treated with inhaled corticosteroids (ICSs) for > or =4 weeks before screening and who had a forced expiratory volume in 1 second (FEV(1)) of > or =60% to < or =90% of predicted normal at screening were eligible. After 2 weeks (current asthma therapy discontinued), patients received twice-daily budesonide/formoterol pMDI 80/4.5 microg x 2 inhalations (160/9 microg), budesonide pMDI 80 microg x 2 inhalations (160 microg), formoterol DPI 4.5 microg x 2 inhalations (9 microg), or placebo. The coprimary efficacy variables were changes from baseline in morning predose FEV(1) and 12-hour mean FEV(1) (from serial spirometry) after administration of the morning dose of study medication. Tolerability was assessed based on adverse events (AEs); routine laboratory assessments; electrocardiography; 24-hour Holter monitor assessments; and physical examinations, including vital signs (eg, systolic and diastolic blood pressure and heart rate). AEs were recorded manually by the patient in paper notebooks and reviewed at each clinic visit by the investigator and during a final follow-up phone call. RESULTS: A total of 480 patients were randomized (299 females, 181 males; mean age, 36 years; mean FEV(1), 2.4 L; budesonide/formoterol pMDI, 123 patients; budesonide pMDI, 121; formoterol DPI, 114; placebo, 122). At end of treatment, the mean increases from baseline in predose FEV(1) were greater with budesonide/formoterol pMDI versus budesonide pMDI, formoterol DPI, and placebo (0.37 vs 0.23, 0.17, and 0.03 L, respectively; all, P<0.005). 0.005). After administration of the first dose and at weeks 2 and 12, mean increases in 12-hour mean FEV(1) were significantly greater with budesonide/formoterol pMDI (0.41, 0.47, and 0.50 L, respectively) versus budesonide pMDI (0.17, 0.30, and 0.32 L) and placebo (0.15, 0.12, and 0.12 L) (all, P < 0.001). Fewer patients receiving budesonide/formoterol pMDI met criteria for (18.7%; P < 0.001) or withdrew because of (7.3%; P < or = 0.010) worsening asthma versus formoterol DPI (42.1% and 18.4%, respectively) and placebo (56.6% and 32.8%); results were similar between budesonide pMDI (21.5% and 6.6%, respectively) and budesonide/formoterol pMDI. Three patients experienced serious AEs; none was considered related to study medication. The proportions of withdrawals due to worsening asthma were not significantly different between the budesonide/formoterol pMDI and budesonide pMDI groups. CONCLUSIONS: In this population of adults and adolescents with mild to moderate persistent asthma previously treated with ICSs, twice-daily budesonide/formoterol pMDI was associated with significantly increased pulmonary function versus its monocomponents. All study drugs were generally well tolerated.