Immediate salbutamol responsiveness does not predict long-term benefits of indacaterol in patients with chronic obstructive pulmonary disease.

BACKGROUND: The purpose of this study was to evaluate the correlation between immediate responsiveness with the short-acting ß2-agonist salbutamol and effects of treatment with the ultra-long-acting ß2-agonist indacaterol in patients with chronic obstructive pulmonary disease (COPD). METHODS: The REVERBREZ study was a phase IV, multicentre, open-label study in which patients with moderate-to-severe COPD received indacaterol 150 µg once-daily for 5 months. The primary endpoint was the correlation between immediate response of forced expiratory volume in 1 s (FEV1) post-inhalation of salbutamol (400 µg) at study entry and the change from baseline in trough FEV1 after 1 month of indacaterol. Secondary endpoints included dyspnoea measured by the modified Medical Research Council (mMRC) grade and health-related quality of life measured by the clinical COPD questionnaire (CCQ). RESULTS: Of the 602 patients enrolled from 177 centres in France, 543 patients received at least one indacaterol dose, 512 patients completed 1 month of indacaterol treatment (primary endpoint), and 400 patients completed 5 months of treatment. At study entry, mean FEV1 values before and after salbutamol inhalation were 1.54 ± 0.50 L and 1.65 ± 0.53 L, respectively. Based on the magnitude of an immediate response of FEV1 after salbutamol inhalation at study entry, patients were classified into reversible (Rv, ≥12% and ≥200 mL from pre-salbutamol value; n = 106) and non-reversible (NRv, <12% or <200 mL from pre-salbutamol value; n = 431) groups. After 1 month of indacaterol treatment, mean absolute and relative difference in trough FEV1 were 100 mL and 9%, respectively. No significant correlation was found between the immediate FEV1 response to salbutamol at study entry and change from baseline in trough FEV1 after 1 month of indacaterol treatment (correlation coefficient = 0.056 [95% CI;-0.032, 0.144] for absolute response and 0.028 [95% CI;-0.06, 0.116] for relative response). At all subsequent visits, mMRC and CCQ scores, and FEV1 improved from baseline with no significant difference between the Rv and NRv groups. CONCLUSIONS: Immediate FEV1 response to salbutamol did not predict the long-term benefits observed with indacaterol treatment in patients with COPD. Patients considered reversible or non-reversible to salbutamol showed comparable improvements in lung function, dyspnoea and health-related quality of life. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01272362 . Date: January 5, 2011.

Anxiety and Coping Strategy Changes in Multiple Sclerosis Patients Initiating Fingolimod: The GRACE Prospective Study.

The objective of this prospective study was to assess the changes in anxiety levels, and their relationship with coping strategies over the first four months of fingolimod treatment in patients with relapsing remitting multiple sclerosis (RRMS). Data were collected at the inclusion visit (Visit 1) and 4 months later (Visit 2). We used the Hospital Anxiety and Depression Scale (HADS) to assess the level of anxiety and the Coping Inventory for Stressful Situations scale to assess the coping strategies used when engaged with stressful situations. The HADS anxiety scores were compared between Visits 1 and 2, according to the preferred coping strategy. At Visit 1, half of the 198 patients included were considered to be anxious (doubtful or in a certain way). The same proportion preferentially used an avoidance-oriented strategy and one-third preferentially used an emotion-oriented strategy. The mean HADS anxiety score decreased significantly (p = 0.001) at Visit 2 (8.1 ± 4.0) compared to Visit 1 (8.8 ± 4.3), particularly in the group of patients who used an emotion-oriented strategy (p = 0.002). In conclusion, the initiation of fingolimod in patients with RRMS is followed by a decrease of anxiety levels which vary according to the coping strategy used.

Impact of ELN recommendations in the management of first-line treated chronic myeloid leukaemia patients: a French cross-sectional study.

The availability of tyrosine kinase inhibitors has extended therapeutic options for chronic myeloid leukaemia (CML) patients. Monitoring recommendations and clinical response goals have recently been updated. The objective of this study was to describe the profile of CML patients in chronic phase currently receiving first-line therapy, including treatment, monitoring and response kinetics. A multicentre, cross-sectional, epidemiological survey in unselected chronic phase CML patients in France attending consultations during a one-month period was performed. 438 of 697 (62·8%) reported patients were currently receiving first-line treatment and were analysed. Imatinib was the most frequently received treatment (72·4% of patients). Retrospective cytogenetic and molecular assessments at 3, 6, 12 or 18 months were available in 88·4% of patients. At the 12-month assessment, 32·2% were not in major molecular response (MMR). At last assessment, among 355 patients with duration of treatment ≥ 12 months, 91·5% had achieved MMR and 66·5% were in deep molecular response. This study, performed in everyday practice population of CML patients, suggests that monitoring of molecular responses in real-life practice is aligned with European LeukaemiaNet recommendations. The majority of patients still receiving first-line treatment are in optimal response, with a few being classified as in the warning area or responding to failure.

A proof-of-concept, randomized, controlled trial of omalizumab in patients with severe, difficult-to-control, nonatopic asthma.

BACKGROUND: While up to 50% of patients with severe asthma have no evidence of allergy, IgE has been linked to asthma, irrespective of atopic status. Omalizumab, an anti-IgE monoclonal antibody, is reported to significantly benefit a subset of patients with severe, persistent, allergic asthma. Therefore, we investigated whether omalizumab has biologic and clinical effects in patients with refractory nonatopic asthma. METHODS: Forty-one adult patients who, despite daily treatment with or without maintenance oral corticosteroids, had severe, nonatopic, refractory asthma according to GINA (Global Initiative for Asthma) step 4, were randomized to receive omalizumab or placebo in a 1:1 ratio. The primary end point was the change in expression of high-affinity IgE receptor (FcεRI) on blood basophils and plasmacytoid dendritic cells (pDC2) after 16 weeks. The impact of omalizumab on lung function and clinical variables was also examined. RESULTS: Compared with placebo, omalizumab resulted in a statistically significant reduction in FcεRI expression on basophils and pDC2 (P < .001). The omalizumab group also showed an overall increase in FEV1 compared with baseline (+250 mL, P = .032; +9.9%, P = .029). A trend toward improvement in global evaluation of treatment effectiveness and asthma exacerbation rate was also observed. CONCLUSIONS: Omalizumab negatively regulates FcεRI expression in patients with severe nonatopic asthma, as it does in severe atopic asthma. Omalizumab may have a therapeutic role in severe nonatopic asthma. Nonetheless, our preliminary findings support further investigation to better assess the clinical efficacy of omalizumab. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01007149; URL: www.clinicaltrials.gov and European Clinical Trials Database, EudraCT; No.: 2009-010937-38; URL: https://www.clinicaltrialsregister.eu.

SALTO: a randomized, multicenter study assessing octreotide LAR in inoperable bowel obstruction.

This phase II, multicenter, randomized, double-blind, non-comparative study assessed the efficacy and safety of immediate-release octreotide and octreotide LAR, in combination with corticosteroids and standard medical care, on the symptoms of inoperable malignant bowel obstruction (MBO) due to peritoneal carcinomatosis. The primary efficacy endpoint was "success" at day 14 defined as a composite endpoint including the absence of a nasogastric tube, and vomiting less than twice per day and no use of anticholinergic agents. Patients in the octreotide arm received octreotide LAR 30 mg intramuscular (im) on days 1, 29 and 57, as well as daily immediate-release octreotide 600 µg per day plus methylprednisolone on days 1 to 6. Placebo-treated patients received methylprednisolone and matched placebo instead of octreotide. Difficulties associated with enrolling patients at palliative-care stage meant only 64 patients (instead of the planned 102 patients) were randomized, 32 to octreotide and 32 to placebo. Despite randomization, more patients in the octreotide arm (46.4%) than in the placebo arm (21.9%) had a baseline Karnofsky score less than 50. An intention-to-treat analysis showed that in the octreotide and placebo arms, 12 (38%) and nine (28%), respectively, patients were successfully treated at day 14, which increased to 9/15 (60%) and 7/25 (28%), respectively, among patients with a baseline Karnofsky score greater or equal to 50. Octreotide-treated patients reported three drug-related adverse events (AEs), and no drug-related serious AEs or deaths. Octreotide LAR may have a key role in treating patients with a MBO due to peritoneal carcinomatosis, particularly in those with moderately severe disease.

Parkinson's disease dementia can be easily detected in routine clinical practice.

Parkinson's disease (PD) is mainly characterized by its motor manifestations, but it is also frequently associated with dementia. Early diagnosis of PD dementia (PDD) is particularly important because effective cholinesterase inhibitor treatments are available. This study aimed at validating a short procedure for screening for PDD in routine clinical practice and which adopts recently published diagnostic criteria. One hundred eighty-eight patients with PD participated in the study. The examination procedure comprised three steps: standard clinical examination, a short cognitive function assessment fulfilling the requirements of the Movement Disorders Society (Mini Mental State Examination, five-word test, word generation task, and impact on daily life, including a questionnaire on compliance with medication) and an extensive evaluation of cognitive functions and behavior. After each step, the suspected presence or absence of dementia was recorded. After the short cognitive function assessment, PDD was suspected in 18.62% of the patients [95% confidence interval (CI): 13.32-24.93%]. After the extensive assessment, 21.81% (95% CI: 16.13-28.40%) met the criteria for probable PDD. The short battery's sensitivity and specificity were 65.85% (95% CI = 49.41-79.92%) and 94.56% (95% CI = 89.56-97.62%), respectively. A stepwise logistic regression analysis showed that use of a specific cut-off considerably enhanced the short battery's sensitivity (85.37%, 95% CI = 70.83-94.43%) without decreasing its specificity (83.67%, 95% CI = 76.69-89.25%). With an easy-to-use, short battery of tests that are commonly used in routine clinical practice, it is possible to diagnose PDD in accordance with reference criteria and with the same sensitivity and specificity as in a more extensive evaluation.

Insights into severe asthma control as assessed by guidelines, pulmonologist, patient, and partner.

INTRODUCTION: The most recent guidelines on asthma management advocate a treatment strategy based on control of the disease rather than severity, a switch based on reported evidence. AIMS: This observational, questionnaire-based study set out to investigate how control of the disease is assessed by the physician as well as the patient and his/her live-in partner and to compare these assessments with an assessment made according to the guidelines. METHODS: In 169 patients with severe, persistent asthma on at least a high-dose inhaled corticosteroid plus an inhaled long-acting ß2-agonist, control of the disease was assessed by the pulmonologist, the patient, and the patient's live-in partner. These assessments were compared with an assessment based on the guidelines. Results. Both patients and partners tended to judge disease control as better than their pulmonologists who, in turn, estimated control as acceptable in 58% of their patients in whom the guidelines would advocate more aggressive treatment. The most common guidelines criteria defining inadequate control in the "uncontrolled" 87.4% of this population were "limitation of physical activity" (72.3%) and "FEV1" ≤ 85% of personal best" (63.3%). CONCLUSIONS: To assess control in severe asthma, the patient's opinion is of limited value, as is that of their partners. Although a guidelines-based strategy has been shown to be effective in clinical trials conducted on large-scale populations in which mild or moderate disease is predominant, more aggressive treatment to achieve definitive control may not be appropriate in the 10% of asthma sufferers with severe disease; in everyday practice, lung specialists appear to implement such a strategy.

Omalizumab-induced decrease of FcξRI expression in patients with severe allergic asthma.

BACKGROUND: It is documented that omalizumab treatment reduces the cell surface expression of immunoglobulin E high-affinity receptor (FcɛRI) on several cell types. This has not been investigated in patients with uncontrolled severe persistent allergic asthma. METHODS: In a double-blind, randomized, placebo-controlled study, patients with severe allergic asthma uncontrolled by high dose inhaled corticosteroids and long-acting ß(2)-agonist received either omalizumab (n = 20) or placebo (n = 11) over 16 weeks at appropriate doses and frequencies. Baseline and end of study (week 16) FcɛRI expression on basophils and plasmacytoid dendritic cells was determined by flow cytometry for the primary endpoint. Secondary efficacy endpoints included asthma control and lung function as part of an initial investigation into the use of FcɛRI expression as a marker of response. RESULTS: In the omalizumab group, and with respect to placebo, FcɛRI expression was significantly reduced at end of study on basophils (-82.6%, p < 0.01) and plasmacytoid dendritic cells (-44.2%, p = 0.029). FcɛRI expression reduction was not found to be correlated with clinical response. CONCLUSIONS: Long-term omalizumab treatment induced reduction of FcɛRI expression on circulating basophils and plasmacytoid dendritic cells. These changes were not associated with those of clinical features related to severe asthma, which does not support further investigation into its use as a predictive marker of response. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov (identifier: NCT00454051) and the European Clinical Trials Database, EudraCT (identifier: 2006-003591-35).

Prevalence and associated factors of oropharyngeal side effects in users of inhaled corticosteroids in a real-life setting.

BACKGROUND: Inhaled corticosteroids (ICS) are extensively used to treat asthma, and more recently, chronic obstructive pulmonary disease (COPD). Oropharyngeal disorders represent the most frequent side effect of these drugs, which may have a negative impact on adherence. OBJECTIVES: To evaluate the prevalence of oropharyngeal disorders in users of ICS in a real-life setting and investigate the factors associated with their occurrence. METHODS: For this observational cross-sectional study, general practitioners and pulmonologists were contacted and asked to include patients suffering from asthma or COPD treated by ICS. Physicians collected data during a medical examination. A multivariate regression model for the occurrence of oropharyngeal disorders was constructed. RESULTS: A total of 1778 physicians included 6740 patients. The mean (SD) age was 51.3 (18.5) years, 44.0% had no smoking history, and the ICS indication was asthma in 63.9% of subjects. Of the study subjects, 52.3% used beclometasone (43.4% without a long-acting ss(2)-agonist, LABA); 22.1% used budesonide (18.8% with a LABA), and 25.6% used fluticasone (19.3% with a LABA in a single inhaler). One-third (34.7%) of subjects suffered from at least one oropharyngeal disorder; the most frequently reported were hoarseness, tingling, mouth irritation, and reddening. Multivariate regression analysis found that the factors positively associated with oropharyngeal disorders were COPD indication [odds ratio (OR) 1.600; 95% confidence intervals (95% CI) 1.391, 1.839], nominal daily dose (OR = 1.388; 95% CI 1.227, 1.569), decreased adherence (OR = 1.318; 95% CI 1.104, 1.574) and the use of fluticasone (OR = 1.176; 95% CI 1.008, 1.372), whereas those negatively associated were the absence of smoking history (OR = 0.837; 95% CI 0.742, 0.945), increased adherence (OR = 0.663; 95% CI 0.581, 0.755), and beclometasone use (OR = 0.630; 95% CI 0.543, 0.732). CONCLUSIONS: The high prevalence of oropharyngeal disorders and the association of adherence with these must be taken into account by prescribers, especially in patients suffering from COPD, a relatively new group of ICS users.

Is there a difference between levodopa/ dopa-decarboxylase inhibitor and entacapone and levodopa/dopa-decarboxylase inhibitor dose fractionation strategies in Parkinson's disease patients experiencing symptom re-emergence due to wearing-off? The Honeymoon Study.

Two strategies to manage symptom re-emergence due to wearing-off with conventional levodopa/dopa-decarboxylase inhibitor (DDCI) therapy were compared in patients with Parkinson's disease (PD) in this randomized, open-label trial. PD patients receiving 3 daily doses of levodopa/DDCI were randomized to either levodopa/DDCI and entacapone or an increased dose frequency of levodopa/DDCI with or without an increased total daily dose (dose fractionation). After 1 month of treatment, patients were followed up for 1 year. A greater proportion of levodopa/DDCI and entacapone-treated patients had treatment success compared with dose-fractionated patients, according to investigator Clinical Global Impression of Change scores at 1 month (68 vs. 59%, respectively) and 1 year (60 vs. 51%, respectively). Mean 'off' time (time with symptoms) was improved in both groups at 1 month and 1 year, despite a reduction in the mean daily levodopa dose in the levodopa/DDCI and entacapone group at 1 month. The mean daily levodopa dose was increased in the dose fractionation group. At 1 month, there was a 4% reduction in patients experiencing dyskinesia with levodopa/DDCI and entacapone and a 3% increase with dose fractionation. These data suggest that levodopa/DDCI and entacapone reduces time with symptoms, the rate of motor complications and the daily levodopa dose compared with dose fractionation. However, as the observed differences were not statistically significant, further studies are required to confirm these results.

Total reversibility testing as indicator of the clinical efficacy of formoterol in COPD.

RATIONALE: The Global Initiative for Chronic Obstructive Lung Disease guidelines recommend bronchodilator reversibility testing to guide treatment decisions. This study evaluated the relationship between the change in forced expiratory volume in 1 s (FEV1) with salbutamol or formoterol and the clinical effects of a 4-week formoterol (Foradil) treatment. METHODS: At Visit 1, patients (n = 448) with stable chronic obstructive pulmonary disease took an FEV1 reversibility test using 200 microg salbutamol via a metered dose inhaler. At Visit 2 (Day 0), an FEV1 reversibility test was performed using formoterol via a dry-powder inhaler (Aerolizer). Patients then received formoterol 12 microg twice daily until Visit 3 (Day 21-30), when a further formoterol FEV1 reversibility test was performed. Clinical parameters included FEV1, symptom questionnaires and rescue medication use. RESULTS: There was no significant relationship between the immediate change in FEV1 with salbutamol and the absolute change from baseline in FEV1, symptom scores or rescue medication use after a 4-week formoterol treatment. Relative immediate change in FEV1 with formoterol was correlated with change in rescue medication use (P = 0.02) and FEV1 at Visit 3 (P < 0.001). Total reversibility in FEV1 with formoterol (post-dose Visit 3-pre-dose Visit 2) was correlated with all treatment efficacy variables (P<0.01). CONCLUSIONS: Immediate salbutamol reversibility testing, as performed under these study conditions, failed to predict the clinical efficacy of formoterol. Total reversibility after 4 weeks of formoterol treatment may be a better predictor of clinical benefits of long-term bronchodilator therapy.

Formoterol 12 microg BID administered via single-dose dry powder inhaler in adults with asthma suboptimally controlled with salmeterol or on-demand salbutamol: a multicenter, randomized, open-label, parallel-group study.

BACKGROUND: Although salmeterol and formoterol are both long-acting beta(2) adrenergic receptor agonist bronchodilators, there are distinct differences between them that could translate into differences in clinical response in some patients. OBJECTIVE: The goal of this study was to examine the efficacy of formoterol in patients with moderate to severe persistent asthma that was suboptimally controlled with an inhaled corticosteroid (ICS) combined with on-demand salbutamol (albuterol in the United States) with or without salmeterol. METHODS: This multicenter, 4-week, randomized, open-label, parallel-group study included adult patients (age >/=18 years) with suboptimally controlled asthma (mean salbutamol use, >/=2 puffs/d via pressurized metered-dose inhaler [100 microg/puff]). Patients were randomized in a 2:1 ratio to receive formoterol 12 microg BID via single-dose dry powder inhaler plus on-demand salbutamol or to continue their existing treatment with either on-demand salbutamol alone or salmeterol 50 microg BID via multidose dry powder inhaler plus on-demand salbutamol. ICS regimens were unchanged during the trial. The primary efficacy variable was evening predose peak expiratory flow (PEF). Secondary variables included further measures of asthma symptom control. RESULTS: A total of 6239 adult patients entered the study; data from 6155 patients were available for analysis. Patients who were switched from salmeterol to formoterol reported a significant increase in mean (SD) evening predose PEF compared with patients who continued their existing treatment (402.9 [112.1] vs 385.5 [107.5] Umin, respectively; P < 0.001). Similarly, patients who were switched from on-demand salbutamol alone to formoterol plus on-demand salbutamol reported a significant increase in mean evening predose PEF compared with those who continued treatment with on-demand salbutamol alone (409.3 [105.6] vs 385.0 [105.3] L/min, respectively; P < 0.001). The results for the secondary efficacy measures mirrored the significant improvements seen in patients switched to formoterol compared with those who continued to receive on-demand salbutamol alone or salmeterol plus on-demand salbutamol. CONCLUSION: In this study, formoterol significantly improved lung function and control of asthma symptoms and decreased use of rescue medication in patients whose asthma had been suboptimally controlled with an ICS in combination with on-demand salbutamol with or without salmeterol.