Summary Background Cervical dystonia is managed mainly by repeated botulinum toxin injections. We aimed to establish whether pallidal neurostimulation could improve symptoms in patients not ...adequately responding to chemodenervation or oral drug treatment. Methods In this randomised, sham-controlled trial, we recruited patients with cervical dystonia from centres in Germany, Norway, and Austria. Eligible patients (ie, those aged 18–75 years, disease duration ≥3 years, Toronto Western Spasmodic Torticollis Rating Scale TWSTRS severity score ≥15 points) were randomly assigned (1:1) to receive active neurostimulation (frequency 180 Hz; pulse width 120 μs; amplitude 0·5 V below adverse event threshold) or sham stimulation (amplitude 0 V) by computer-generated randomisation lists with randomly permuted block lengths stratified by centre. All patients, masked to treatment assignment, were implanted with a deep brain stimulation device and received their assigned treatment for 3 months. Neurostimulation was activated in the sham group at 3 months and outcomes were reassessed in all patients after 6 months of active treatment. Treating physicians were not masked. The primary endpoint was the change in the TWSTRS severity score from baseline to 3 months, assessed by two masked dystonia experts using standardised videos, analysed by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00148889. Findings Between Jan 19, 2006, and May 29, 2008, we recruited 62 patients, of whom 32 were randomly assigned to neurostimulation and 30 to sham stimulation. Outcome data were recorded in 60 (97%) patients at 3 months and 56 (90%) patients at 6 months. At 3 months, the reduction in dystonia severity was significantly greater with neurostimulation (–5·1 points SD 5·1, 95% CI −7·0 to −3·5) than with sham stimulation (−1·3 2·4, −2·2 to −0·4, p=0·0024; mean between-group difference 3·8 points, 1·8 to 5·8) in the intention-to-treat population. Over the course of the study, 21 adverse events (five serious) were reported in 11 (34%) of 32 patients in the neurostimulation group compared with 20 (11 serious) in nine (30%) of 30 patients in the sham-stimulation group. Serious adverse events were typically related to the implant procedure or the implanted device, and 11 of 16 resolved without sequelae. Dysarthria (in four patients assigned to neurostimulation vs three patients assigned to sham stimulation), involuntary movements (ie, dyskinesia or worsening of dystonia; five vs one), and depression (one vs two) were the most common non-serious adverse events reported during the course of the study. Interpretation Pallidal neurostimulation for 3 months is more effective than sham stimulation at reducing symptoms of cervical dystonia. Extended follow-up is needed to ascertain the magnitude and stability of chronic neurostimulation effects before this treatment can be recommended as routine for patients who are not responding to conventional medical therapy. Funding Medtronic.
Abstract Background EXCELS was a postmarketing commitment to the US Food and Drug Administration to assess long-term safety of omalizumab in an observational setting, focusing predominantly on ...malignancies. Objective To examine a potential association between omalizumab and cardiovascular (CV)/cerebrovascular (CBV) events in EXCELS. Methods Cohort study of patients (≥12 years of age) with moderate-to-severe allergic asthma followed ≤5 years, treated with omalizumab (n = 5007) or not treated with omalizumab (n = 2829) at baseline. Analyses included overall CV/CBV events, but focused on the subset of arterial thromboembolic events (ATE), comprising CV death, myocardial infarction, ischemic stroke, transient ischemic attack, or unstable angina. A prespecified analysis for the endpoint of ATE was conducted to control for available potential confounders. A blinded independent expert panel adjudicated all events. Results At baseline, cohorts had similar demographic characteristics, but severe asthma was more common in the omalizumab versus non-omalizumab cohorts (50% vs 23%). Omalizumab-treated patients had a higher rate of CV/CBV serious adverse events (13.4 per 1000 person-years PY) than non-omalizumab–treated patients (8.1 per 1000 PY). ATE rate per 1000 PY was 6.66 (101 patients/15,160 PY) for the omalizumab cohort and 4.64 (46 patients/9904 PY) for the non-omalizumab cohort. After controlling for available confounding factors, the hazard ratio was 1.32 (95% CI, 0.91-1.91). Conclusion Results from this observational study demonstrated a higher incidence rate of CV/CBV events in the omalizumab versus non-omalizumab cohorts. Differences in asthma severity between cohorts likely contributed to this imbalance, but some increase in risk cannot be excluded (NCT00252135). Clinical implications Current asthma management guidelines should not be affected. However, health professionals should be aware of a possible association of omalizumab and serious cardiovascular/cerebrovascular events.
Background The Epidemiologic Study of Xolair (omalizumab): Evaluating Clinical Effectiveness and Long-term Safety in Patients with Moderate-to-Severe Asthma (EXCELS) assessed the long-term safety of ...omalizumab in a clinical practice setting as part of a phase IV US Food and Drug Administration postmarketing commitment. Objective We sought to evaluate long-term safety in omalizumab-treated and nonomalizumab-treated patients. Primary outcome measures focused on assessment of malignancies. Methods EXCELS was a prospective observational cohort study in patients (≥12 years of age) with moderate-to-severe allergic asthma. There were 2 cohorts: omalizumab (taking omalizumab at baseline) and nonomalizumab (no history of omalizumab treatment). Primary outcomes included all confirmed, incident, study-emergent primary malignancies (malignancies), including and excluding nonmelanoma skin cancer (NMSC); all malignancies were externally adjudicated. Results The omalizumab cohort had a higher proportion of patients with severe asthma compared with the nonomalizumab cohort (50.0% vs 23.0%). Median follow-up was approximately 5 years for both cohorts. Crude malignancy rates were similar in the omalizumab and nonomalizumab cohorts, with a rate ratio of 0.84 (95% CI, 0.62-1.13) for all malignancies and 0.98 (95% CI, 0.71-1.36) for all malignancies excluding NMSC. Kaplan-Meier plots of time to first confirmed study-emergent primary malignancy were similar for the 2 treatment cohorts. Cox proportional hazards modeling, adjusting for confounders and risk factors, resulted in a hazard ratio (omalizumab vs nonomalizumab) of 1.09 (95% CI, 0.87-1.38) for all malignancies and 1.15 (95% CI, 0.83-1.59) for all malignancies excluding NMSC. Conclusion Results from EXCELS suggest that omalizumab therapy is not associated with an increased risk of malignancy.
Background Since initial registration, the omalizumab clinical trial database has expanded considerably, with a doubling of patients exposed in the clinical trial environment. Previous pooled data ...(2003) from phase I to III studies of omalizumab showed a numeric imbalance in malignancies arising in omalizumab recipients (0.5%) compared with control subjects (0.2%). The previous analysis was based on limited available data, warranting further investigation. Objective We sought to examine the incidence of malignancy using comprehensive pooled data from clinical trials of omalizumab-treated patients. Methods This pooled analysis included data from 67 phase I to IV clinical trials. The prespecified primary analysis assessed the incidence of primary malignancy in 32 randomized, double-blind, placebo-controlled (RDBPC) trials. Results There were 11,459 unique patients in all clinical trials (7,789 received omalizumab). The primary analysis identified malignancies in 25 patients (RDBPC trials): 14 in 4,254 omalizumab-treated patients and 11 in 3,178 placebo-treated patients. Incidence rates per 1,000 patient-years of observation time for omalizumab- and placebo-treated patients were 4.14 (95% CI, 2.26-6.94) and 4.45 (95% CI, 2.22-7.94), respectively; the corresponding rate ratio was 0.93 (95% CI, 0.39-2.27). Primary malignancies were of varying histologic type and occurred in a number of different organ systems; no cluster of histologies was identified. Conclusions In this pooled analysis no association was observed between omalizumab treatment and risk of malignancy in RDBPC trials; the rate ratio was below unity. The data suggest that a causal relationship between omalizumab therapy and malignancy is unlikely.
Summary Background Severe forms of primary dystonia are difficult to manage medically. We assessed the safety and efficacy of pallidal neurostimulation in patients with primary generalised or ...segmental dystonia prospectively followed up for 5 years in a controlled multicentre trial. Methods In the parent trial, 40 patients were randomly assigned to either sham neurostimulation or neurostimulation of the internal globus pallidus for a period of 3 months and thereafter all patients completed 6 months of active neurostimulation. 38 patients agreed to be followed up annually after the activation of neurostimulation, including assessments of dystonia severity, pain, disability, and quality of life. The primary endpoint of the 5-year follow-up study extension was the change in dystonia severity at 3 years and 5 years as assessed by open-label ratings of the Burke–Fahn–Marsden dystonia rating scale (BFMDRS) motor score compared with the preoperative baseline and the 6-month visit. The primary endpoint was analysed on an intention-to-treat basis. The original trial is registered with ClinicalTrials.gov ( NCT00142259 ). Findings An intention-to-treat analysis including all patients from the parent trial showed significant improvements in dystonia severity at 3 years and 5 years compared with baseline, which corresponded to −20·8 points (SD 17·1; −47·9%; n=40) at 6 months; −26·5 points (19·7; −61·1%; n=31) at 3 years; and −25·1 points (21·3; −57·8%; n=32). The improvement from 6 months to 3 years (–5·7 points SD 8·4; −34%) was significant and sustained at the 5-year follow-up (–4·3 10·4). 49 new adverse events occurred between 6 months and 5 years. Dysarthria and transient worsening of dystonia were the most common non-serious adverse events. 21 adverse events were rated serious and were almost exclusively device related. One patient attempted suicide shortly after the 6-month visit during a depressive episode. All serious adverse events resolved without permanent sequelae. Interpretation 3 years and 5 years after surgery, pallidal neurostimulation continues to be an effective and relatively safe treatment option for patients with severe idiopathic dystonia. This long-term observation provides further evidence in favour of pallidal neurostimulation as a first-line treatment for patients with medically intractable, segmental, or generalised dystonia. Funding Medtronic.
Abstract Background Prior research on the risk of depression in chronic obstructive pulmonary disease (COPD) has yielded conflicting results. Furthermore, we have an incomplete understanding of how ...much depression versus respiratory factors contributes to poor health-related quality of life. Methods Among 1202 adults with COPD and 302 demographically matched referents without COPD, depressive symptoms were assessed using the 15-item Geriatric Depression Score. We measured COPD severity using a multifaceted approach, including spirometry, dyspnea, and exercise capacity. We used the Airway Questionnaire 20 and the Physical Component Summary Score to assess respiratory-specific and overall physical quality of life, respectively. Results In multivariate analysis adjusting for potential confounders including sociodemographics and all examined comorbidities, COPD subjects were at higher risk for depressive symptoms (Geriatric Depression Score ≥6) than referents (odds ratio OR 3.6; 95% confidence interval CI, 2.1-6.1; P <.001). Stratifying COPD subjects by degree of obstruction on spirometry, all subgroups were at increased risk of depressive symptoms relative to referents ( P <.001 for all). In multivariate analysis controlling for COPD severity as well as sociodemographics and comorbidities, depressive symptoms were strongly associated with worse respiratory-specific quality of life (OR 3.6; 95% CI, 2.7-4.8; P <.001) and worse overall physical quality of life (OR 2.4; 95% CI, 1.8-3.2; P <.001). Conclusions Patients with COPD are at significantly higher risk of having depressive symptoms than referents. Such symptoms are strongly associated with worse respiratory-specific and overall physical health-related quality of life, even after taking COPD severity into account.
To determine whether baseline plasma levels of the receptor for advanced glycation end products (RAGE), a novel marker of alveolar type I cell injury, are associated with the severity and outcomes of ...acute lung injury, and whether plasma RAGE levels are affected by lower tidal volume ventilation.
Measurement of plasma RAGE levels from 676 subjects enrolled in a large randomised controlled trial of lower tidal volume ventilation in acute lung injury.
Higher baseline plasma RAGE was associated with increased severity of lung injury. In addition, higher baseline RAGE was associated with increased mortality (OR for death 1.38 (95% CI 1.13 to 1.68) per 1 log increment in RAGE; p = 0.002) and fewer ventilator free and organ failure free days in patients randomised to higher tidal volumes. These associations persisted in multivariable models that adjusted for age, gender, severity of illness and the presence of sepsis or trauma. Plasma RAGE was not associated with outcomes in the lower tidal volume group (p = 0.09 for interaction in unadjusted analysis). In both tidal volume groups, plasma RAGE levels declined over the first 3 days; however, the decline was 15% greater in the lower tidal volume group (p = 0.02; 95% CI 2.4% to 25.0%).
Baseline plasma RAGE levels are strongly associated with clinical outcomes in patients with acute lung injury ventilated with higher tidal volumes. Lower tidal volume ventilation may be beneficial in part by decreasing injury to the alveolar epithelium.
ABSTRACT
We present the results from the first two years of the Planet Hunters TESS (PHT) citizen science project, which identifies planet candidates in the TESS (Transiting Exoplanet Survey ...Satellite) data by engaging members of the general public. Over 22 000 citizen scientists from around the world visually inspected the first 26 sectors of TESS data in order to help identify transit-like signals. We use a clustering algorithm to combine these classifications into a ranked list of events for each sector, the top 500 of which are then visually vetted by the science team. We assess the detection efficiency of this methodology by comparing our results to the list of TESS Objects of Interest (TOIs) and show that we recover 85 per cent of the TOIs with radii greater than 4 R⊕ and 51 per cent of those with radii between 3 and 4 R⊕. Additionally, we present our 90 most promising planet candidates that had not previously been identified by other teams, 73 of which exhibit only a single-transit event in the TESS light curve, and outline our efforts to follow these candidates up using ground-based observatories. Finally, we present noteworthy stellar systems that were identified through the Planet Hunters TESS project.
In phase 2 trials, lebrikizumab, an anti-interleukin-13 monoclonal antibody, reduced exacerbation rates and improved FEV
in patients with uncontrolled asthma, particularly in those with high ...concentrations of type 2 biomarkers (eg, periostin or blood eosinophils). We undertook replicate phase 3 studies to assess the efficacy and safety of lebrikizumab in patients with uncontrolled asthma despite inhaled corticosteroids and at least one second controller medication.
Adult patients with uncontrolled asthma, pre-bronchodilator FEV
40-80% predicted, and stable background therapy were randomly assigned (1:1:1) with an interactive voice-web-based response system to receive lebrikizumab 37·5 mg or 125 mg, or placebo subcutaneously, once every 4 weeks. Randomisation was stratified by screening serum periostin concentration, history of asthma exacerbations within the last 12 months, baseline asthma medications, and country. The primary efficacy endpoint was the rate of asthma exacerbations over 52 weeks in biomarker-high patients (periostin ≥50 ng/mL or blood eosinophils ≥300 cells per μL), analysed with a Poisson regression model corrected for overdispersion with Pearson χ
that included terms for treatment group, number of asthma exacerbations within the 12 months before study entry, baseline asthma medications, geographic region, screening periostin concentration, and blood eosinophil counts as covariates. Both trials are registered at ClinicalTrials.gov, LAVOLTA I, number NCT01867125, and LAVOLTA II, number NCT01868061.
1081 patients were treated in LAVOLTA I and 1067 patients in LAVOLTA II. Over 52 weeks, lebrikizumab reduced exacerbation rates in biomarker-high patients in the 37·5 mg dose group (rate ratio RR 0·49 95% CI 0·34-0·69, p<0·0001) and in the 125 mg dose group (RR 0·70 0·51-0·95, p=0·0232) versus placebo in LAVOLTA I. Exacerbation rates were also reduced in biomarker-high patients in both dose groups versus placebo in LAVOLTA II (37·5 mg: RR 0·74 95% CI 0·54-1·01, p=0·0609; 125 mg: RR 0·74 0·54-1·02, p=0·0626). Pooling both studies, the proportion of patients who experienced treatment-emergent adverse events (79% 1125 of 1432 patients for both lebrikizumab doses vs 80% 576 of 716 patients for placebo), serious adverse events (8% 115 patients for both lebrikizumab doses vs 9% 65 patients for placebo), and adverse events leading to study drug discontinuation (3% 49 patients for both lebrikizumab doses vs 4% 31 patients for placebo) were similar between lebrikizumab and placebo. The following serious adverse events were reported in the placebo-controlled period: one event of aplastic anaemia and five serious adverse events related to raised concentrations of eosinophils in patients treated with lebrikizumab and one event of eosinophilic pneumonia in the placebo group.
Lebrikizumab did not consistently show significant reduction in asthma exacerbations in biomarker-high patients. However, it blocked interleukin-13 as evidenced by the effect on interleukin-13-related pharmacodynamic biomarkers, and clinically relevant changes could not be ruled out.
F Hoffmann-La Roche.
Summary Background Human retinal pigment epithelial (RPE) cells produce levodopa and their transplantation into the striatum might improve continuity of administration compared with that achieved ...with oral levodopa. We aimed to assess the safety, tolerability, and efficacy of transplantation of microcarrier-bound human RPE cells versus a sham surgery control in patients with advanced Parkinson's disease. Methods In this randomised, double-blind study eligible patients were aged 36–70 years, had been symptomatic for at least 5 years, were in Hoehn and Yahr stage 3–4 and had unified Parkinson's disease rating scale (UPDRS) motor scores of 38–70 when off medication (off state), and had symptoms that responded to oral levodopa but were insufficiently controlled by optimised pharmacotherapy. Randomisation was done in a 1:1 ratio. Only the neurosurgical team was aware of treatment assignments. During stereotactic transplantation around 325 000 cells per side were injected into the postcommissural putamen; sham surgery patients received partial burr holes. The primary efficacy endpoint was change in UPDRS off-state motor score at 12 months. This study is registered with ClinicalTrials.gov , number NCT00206687. Findings Of 71 enrolled patients, 35 underwent cell transplantation and 36 sham surgery. Change in mean motor scores did not differ significantly between groups (−10·5 SD 10·26 for transplantation vs −10·1 SD 12·26 for sham surgery, p=0·9). The overall rate of adverse events was similar in the two study groups, although the number attributable to surgery or RPE cells (mostly neurological or psychiatric) was higher in transplant recipients. Two and seven patients died in the sham surgery and transplantation group, respectively; one death in the latter group was possibly related to surgery or RPE cells. Interpretation Transplantation of human RPE cells provided no antiparkinsonian benefits compared with sham surgery. Funding Bayer HealthCare AG.
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