Primary Adverse Events Research Articles

Photodynamic Therapy of Non-Small Cell Lung Cancer. Narrative Review and Future Directions.

Photodynamic therapy (PDT) is an established treatment modality for non-small cell lung cancer. Phototoxicity, the primary adverse event, is expected to be minimized with the introduction of new photosensitizers that have shown promising results in phase I and II clinical studies. Early-stage and superficial endobronchial lesions less than 1 cm in thickness can be effectively treated with external light sources. Thicker lesions and peripheral lesions may be amenable to interstitial PDT, where the light is delivered intratumorally. The addition of PDT to standard-of-care surgery and chemotherapy can improve survival and outcomes in patients with pleural disease. Intraoperative PDT has shown promise in the treatment of non-small cell lung cancer with pleural spread. Recent preclinical and clinical data suggest that PDT can increase antitumor immunity. Crosslinking of signal transducer and activator of transcription-3 molecules is a reliable biomarker to quantify the photoreaction induced by PDT. Randomized studies are required to test the prognosis value of this biomarker, obtain approval for the new photosensitizers, and test the potential efficacy of interstitial and intraoperative PDT in the treatment of patients with non-small cell lung cancer.

Phase 1 Study of CB-839, a First-in-Class, Orally Administered Small Molecule Inhibitor of Glutaminase in Patients with Relapsed/Refractory Leukemia

Background: Malignant cells alter metabolism in order to enable their highly anabolic state. In addition to a massive increase in glycolysis, neoplastic cells frequently depend on glutamine to feed the TCA cycle and provide key building blocks for cell growth and proliferation. CB-839 is a first-in-class potent and selective inhibitor of the glutaminase (GLS), the first step in glutamine metabolism, and has broad in vitro and in vivo anti-tumor activity in solid and heme malignancies. Acute myeloid leukemia (AML) cells are particularly dependent on glutamine, and treatment of AML cell lines and primary AML cells with CB-839 results in growth arrest and/or cell death (Padre et al., ASH, 2014 and Jacque et al., Blood, 2015). CB-839 causes a decrease in glutamate and glutamate-derived metabolites, such as TCA cycle intermediates and glutathione, crippling the proliferative capacity of these cells and in some cases inducing apoptosis.Methods: CX-839-003 is an ongoing Phase 1 (Ph1) trial of CB-839 in patients with relapsed/refractory hematologic malignancies. This study includes a dose escalation cohort to identify a recommended Phase 2 dose (RP2D), followed by expansion cohorts of patients (pts) with relapsed/refractory AML (IDH wt and mutant), acute lymphocytic leukemia, and IDH-mutant myelodysplastic syndrome (MDS). Pharmacokinetics (PK) is being monitored on Days 1 and 15.Results: Safety data are available for a total of 20 patients (18 AML, 1 ALL, and 1 mixed-lineage leukemia) that have enrolled across the dose escalation and expansion cohorts. These patients have received a median of 3 prior lines of systemic induction therapy, with 5 pts (25%) having received prior allogeneic bone marrow transplantation. Patients' median age was 75 (range 35 to 84). Dose levels from 100-1000 mg TID were explored during the dose escalation. CB-839 has been well tolerated to date, with no DLTs occurring on study. One patient discontinued due to an adverse event (AE) of elevated transaminases, and 5 pts (25%) had G3/4 AEs considered possibly related to study drug. Across three Ph1 studies for CB-839 in solid tumors and heme malignancies, reversible asymptomatic elevations in transaminases have been the primary G3 AE. Although initially CB-839 was given three times daily (TID) without food, the drug is now being given twice daily (BID) with meals based on PK and safety data generated across these 3 studies. Liver abnormalities occurred primarily on the TID schedule in 6/59 (10.2%) pts, but in only one of 60 pts (1.7%) receiving the BID regimen. Pts are currently being enrolled in expansion cohorts at the RP2D, 600 mg BID. Inhibition of GLS activity was evaluated across all 3 Ph1 studies and established clear exposure-dependent inhibition of the target in peripheral blood 4 hr after the first dose of CB-839, with >90% inhibition being maintained for most patients at the RP2D. Preliminary evidence of clinical activity has been noted, including reductions in blast counts in the bone marrow and/or periphery in 2 pts, one of whom achieved a CRi and remains on study for more than one year. 5 (31%) of 16 evaluable pts have remained on study for at least 4 cycles (range 4-17). Additional data from >8 additional patients have recently started on the "BID with meals" regimen will be presented. Correlative studies on clinical samples will also be presented.Conclusions: CB-839 has been well tolerated at and above doses that produced robust inhibition of GLS in blood platelets and in tumors. Dosing BID with food has mitigated the frequency and severity of LFT elevations, which has been the primary safety signal to date. Reductions in marrow and peripheral blast counts in a heavily pretreated acute leukemia population, with a significant number of patients tolerating therapy and remaining on study for a prolonged period, provide the rationale for continued evaluation of CB-839 as a single agent, and in combination with azacitidine, in AML patients. DisclosuresWang:Immunogen: Research Funding. Orford:Calithera Biosciences: Employment, Equity Ownership. Bennett:Calithera Biosciences: Employment, Equity Ownership. Flinn:Cephalon, Inc; Teva Pharmaceutical Industries Ltd; Genentech, inc; Gilead: Research Funding. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding.

Leukotriene receptor antagonists as maintenance and intermittent therapy for episodic viral wheeze in children.

Episodic viral wheeze (EVW) associated with viral respiratory tract infections is a common reason for pre-school children to utilise health care resources and for carers to take time away from employment. About a third of children experience a wheezing episode before the age of five years. EVW therefore represents a significant public health problem. Many pre-school children only wheeze in association with viral infections and in such cases EVW appears to be a separate entity from atopic asthma. Some trials have explored the effectiveness of leukotriene receptor antagonists (LTRAs) as regular (maintenance) or episodic (intermittent) treatment in this context. To evaluate the evidence for the efficacy and safety of maintenance and intermittent LTRAs in the management of EVW in children aged one to six years. We searched the Cochrane Airways Group register of trials with pre-specified terms. We performed additional searches by consulting the authors of identified trials, online trial registries of manufacturers' web sites, and reference lists of identified primary papers and reviews. Search results are current to June 2015. We included randomised controlled trials with a parallel-group or cross-over (for intermittent LTRA only) design. Maintenance was considered as treatment for more than two months and intermittent as less than 14 days. EVW was defined as a history of at least one previous episode of wheezing in association with a viral respiratory tract infection in the absence of symptoms between episodes. As far as possible, relevant specific data were obtained from authors of studies that included children of a wider age group or phenotype. Two authors independently assessed studies for inclusion in the review and assessed risk of bias. The primary outcome was number of children with one or more viral-induced episodes requiring one or more treatments with rescue oral corticosteroids. We analysed combined continuous data outcomes with the mean difference and dichotomous data outcomes with an odds ratio (OR). We identified five studies eligible for inclusion in the review (one investigated maintenance treatment, three intermittent therapy and one had both maintenance and intermittent treatment arms) these included 3741 participants. Each study involved oral montelukast and was of good methodological quality, but differed in choice of outcome measures thus limiting our ability to aggregate data across studies. Only primary outcome and adverse event data are reported in this abstract.For maintenance treatment, specific data obtained from a single study, pertaining to children with only an EVW phenotype, showed no statistically significant group reduction in the number of episodes requiring rescue oral corticosteroids associated with daily montelukast versus placebo (OR 1.20, 95% CI 0.70 to 2.06, moderate quality evidence).For intermittent LTRA, pooled data showed no statistically significant reduction in the number of episodes requiring rescue oral steroids in children treated with LTRA versus placebo (OR 0.77, 95% CI 0.48 to 1.25, moderate quality evidence). Specific data for children with an EVW phenotype obtained from a single study of intermittent montelukast treatment showed a small, but statistically significant reduction in unscheduled medical attendances due to wheeze (RR 0.83, 95% CI 0.71 to 0.98).For maintenance compared to intermittent LTRA treatment no data relating to the primary outcome of the review were identified.There were no other significant group differences identified in other secondary efficacy outcomes for maintenance or intermittent LTRA treatment versus placebo, or maintenance versus intermittent LTRA treatment. We collected descriptive data on adverse events as reported by four of the five included studies, and rates were similar between treatment and placebo groups.Potential heterogeneity in the phenotype of participants within and across trials is a limitation of the evidence. In pre-school children with EVW, there is no evidence of benefit associated with maintenance or intermittent LTRA treatment, compared to placebo, for reducing the number of children with one or more viral-induced episodes requiring rescue oral corticosteroids, and little evidence of significant clinical benefit for other secondary outcomes. Therefore until further data are available, LTRA should be used with caution in individual children. When used, we suggest a therapeutic trial is undertaken, during which efficacy should be carefully monitored. It is likely that children with an apparent EVW phenotype are not a homogeneous group and that subgroups may respond to LTRA treatment depending on the exact patho-physiological mechanisms involved.

Pulmonary Vein Isolation Using the Visually Guided Laser Balloon: A Prospective, Multicenter, and Randomized Comparison to Standard Radiofrequency Ablation

BackgroundBalloon catheters have been designed to facilitate pulmonary vein (PV) isolation in patients with paroxysmal atrial fibrillation (AF). The visually guided laser balloon (VGLB) employs laser energy to ablate tissue under direct visual guidance. ObjectivesThis study compared the efficacy and safety of VGLB ablation with standard irrigated radiofrequency ablation (RFA) during catheter ablation of AF. MethodsPatients with drug-refractory paroxysmal AF were enrolled in a multicenter, randomized controlled study of PV isolation using either the VGLB or RFA (control). The primary efficacy endpoint was freedom from protocol-defined treatment failure at 12 months, including symptomatic AF occurring after the 90-day blanking period. The primary efficacy and safety endpoints were powered for noninferiority. ResultsA total of 353 patients (178 VGLB, 175 control) were randomized at 19 clinical sites. The mean procedure, ablation, and fluoroscopy times were longer with VGLB compared with controls. The primary efficacy endpoint was met in 61.1% in the VGLB group versus 61.7% in controls (absolute difference −0.6%; lower limit of 95% confidence interval [CI]: −9.3%; p = 0.003 for noninferiority). The primary adverse event rate was 11.8% in the VGLB group versus 14.5% in controls (absolute difference −2.8%; upper limit of 95% CI: 3.5; p = 0.002 for noninferiority), and was mainly driven by cardioversions. Diaphragmatic paralysis was higher (3.5% vs. 0.6%; p = 0.05), but PV stenosis was lower (0.0% vs. 2.9%; p = 0.03) with VGLB. ConclusionsDespite minimal prior experience, the safety and efficacy of VGLB ablation proved noninferior to RFA for the treatment of paroxysmal AF. (Pivotal Clinical Study of the CardioFocus Endoscopic Ablation System–Adaptive Contact [EAS-AC] [HeartLight] in Patients With Paroxysmal Atrial Fibrillation [PAF] [HeartLight]; NCT01456000)

Pulmonary Vein Isolation Using the Visually Guided Laser Balloon: Results of the U.S. Feasibility Study.

Visually guided laser balloon (VGLB) ablation is unique in that the operator delivers ablative energy under direct visual guidance. In this multicenter study, we sought to determine the feasibility, efficacy, and safety of performing pulmonary vein isolation (PVI) using this VGLB. Patients with symptomatic, drug-refractory paroxysmal atrial fibrillation (AF) underwent PVI using the VGLB with the majority of operators conducting their first-ever clinical VGLB cases. The primary effectiveness endpoint was defined as freedom from treatment failure that included: Occurrence of symptomatic AF episodes ≥1 minutes beyond the 90-day blanking, the inability to isolate 1 superior and 2 total PVs, occurrence of left atrial flutter or atrial tachycardia, or left atrial ablation/surgery during follow-up. A total of 86 patients (mean age 56±10 years, 67% male) were treated with the VGLB at 10 US centers. Mean fluoroscopy, ablation, and procedure times were 39.8±24.3 minutes, 205.2 ± 61.7 minutes, and 253.5±71.3 minutes, respectively. Acute PVI was achieved in 314/323 (97.2%) of targeted PVs. Of 84 patients completing follow-up, the primary effectiveness endpoint was achieved in 50 (60%) patients. Freedom from symptomatic or asymptomatic AF was 61%. The primary adverse event rate was 16.3% (8.1% pericarditis, phrenic nerve injury 5.8%, and cardiac tamponade 3.5%). There were no cerebrovascular events, atrioesophageal fistulas, or significant PV stenosis. This multicenter study of operators in the early stage of the learning curve demonstrates that PVI can be achieved with the VGLB with a reasonable safety profile and an efficacy similar to radiofrequency ablation.

Prospective multicenter study with a 1-year analysis of a new vascular graft used for early cannulation in patients undergoing hemodialysis

More than 85% of patients with end-stage renal disease start dialysis through a tunneled dialysis catheter (TDC) for long periods while their arteriovenous fistula or vascular access graft (arteriovenous graft [AVG]) matures. Because TDCs are associated with a high risk of complications, including death and infection, use of an AVG that can be cannulated safely immediately after implantation may reduce morbidity in these patients by allowing earlier TDC removal. We report a prospective multicenter study of a new early-cannulation AVG (Gore ACUSEAL Vascular Graft; W. L. Gore & Associates, Flagstaff, Ariz). Patients requiring creation of a prosthetic vascular access for hemodialysis were enrolled between July 2010 and February 2012 and observed for 12 months. Data were collected on the patients' baseline characteristics; location, position, loss of patency, and revisions of prior AVGs; dialysis sessions using the AVG; and major adverse events related to graft implantation or cannulation. Cumulative and primary unassisted graft patency rates were calculated. A subgroup analysis compared outcomes in patients in whom the AVG was first cannulated within 72 hours after implantation with outcomes in patients in whom the initial cannulation was performed >21 days postoperatively. The population of this study was formed by 138 patients who received an ACUSEAL graft. During follow-up, 17 patients died and the AVG was abandoned in 27. The median value for follow-up was 360 days for all patients (variance 15,387). The overall mean time to initial cannulation was 15 days, with 54 grafts (40%) first cannulated within 72 hours after graft implantation and 33 grafts first cannulated >21 days afterward. The reason for late cannulation in some patients was dependent on the implanting surgeon's decision and the surgeon's personal experience with early cannulating grafts. The 1-year overall cumulative patency rate was 79% (95% confidence interval, 71%-85%); the primary unassisted patency rate was 35% (95% confidence interval, 27%-44%). Adverse events included 6 hematomas (two of which were related to cannulation and occurred 107 and 169 days, respectively, after AVG implantation), 15 graft infections, and 15 cases of steal syndrome requiring intervention. Patients in the early- and later-cannulation groups had similar characteristics and no significant differences in rates of cumulative or primary unassisted patency or adverse events. This study demonstrated that the new, early-cannulation AVG graft can be cannulated soon after implantation without a significant difference in patency and complication rates compared with rates associated with standard cannulation of expanded polytetrafluoroethylene grafts in the literature. This new AVG may allow early removal or avoidance of TDC use in patients undergoing hemodialysis, potentially reducing or eliminating the number of days of catheter-dependent dialysis, but further studies will be needed to demonstrate this potential.

A randomized clinical trial of the efficacy and safety of terconazole vaginal suppository versus oral fluconazole for treating severe vulvovaginal candidiasis

Terconazole is a new, broad-spectrum, triazole antifungal agent. The aim of this study was to compare the efficacy and safety of a 6-day course of a terconazole vaginal suppository (80 mg) with two doses of oral fluconazole (150 mg) for the treatment of severe vulvovaginal candidiasis (SVVC). In this prospective, randomized case-control study, 140 consecutive patients with SVVC were enrolled at the Department of Obstetrics and Gynecology of Peking University Shenzhen Hospital from July 1, 2013, through June 31, 2014. Patients with SVVC, initially at a 1:1 ratio, were randomly assigned to receive treatment with either the terconazole vaginal suppository or oral fluconazole. The patients had follow-up visits at 7-14 days and 30-35 days following the last dose of therapy. The clinical cure rates in the terconazole group and the fluconazole group were, respectively, 81.0% (47/58) and 75.8% (50/66) at follow-up day 7-14 and 60.3% (35/58) and 56.1% (37/66) at day 30-35. The mycological cure rates in the two groups were, respectively, 79.3% (46/58) and 71.2% (47/66) at follow-up day 7-14 and 62.1% (36/58) and 53.0% (35/66) at day 30-35 (P > .05 for all). Local irritation was the primary adverse event associated with terconazole, whereas systemic side effects were associated with fluconazole; however, these effects were minimal. This study demonstrated that a terconazole vaginal suppository (80 mg daily for 6 days) was as effective as two dose of oral fluconazole (150mg) in the treatment of patients with SVVC; as such, terconazole could be a choice for therapy of this disorder.

Long-term clinical and real-world experience with pirfenidone in the treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, irreversible, progressively destructive lung disease that culminates in respiratory failure and death. Randomised controlled trials have demonstrated that treatment of IPF patients with pirfenidone reduces lung function decline, improves progression-free survival and significantly reduces the risk of all-cause mortality at 1 year. Pirfenidone has been shown to have a favourable safety profile and was generally well tolerated over the long term in clinical trials and real-world experience. However, side-effect management is critical to help some patients remain on treatment over the long term. The primary treatment-related adverse events associated with pirfenidone therapy are gastrointestinal upset, rash and photosensitivity. Gastrointestinal events may be mitigated by ensuring that pirfenidone is taken with food, while skin symptoms may be reduced by avoiding sun exposure and frequent use of sunblock. Educating patients about the potential for these adverse events to occur and providing instructions prior to treatment to avoid adverse drug reactions are an important means of ensuring patients may derive the important benefits provided by long-term treatment with pirfenidone.

Levetiracetam efficacy in children with epilepsy with electrical status epilepticus in sleep

PurposeEpilepsy with electrical status epilepticus in sleep (ESES) is a devastating disease, and we sought to evaluate the efficacy of levetiracetam (LEV) for the treatment of patients with this epileptic encephalopathy in China. MethodsClinical data from all patients with ESES who received LEV therapy at our pediatric neurology outpatient clinic between 2007 and 2014 (n=71) were retrospectively analyzed. The LEV dosage was 30–50mg/kg/day. Electroencephalography recordings and neuropsychological evaluations were performed repeatedly for 3–75months after the start of LEV therapy. ResultsThirty-five (70%) of 50 patients who had seizures at the start of LEV therapy had a >50% reduction in seizure frequency. Positive response on EEG was found during the first 3–4months of LEV therapy in 32 (45%) of 71 patients, with normalization of EEG in 5 patients. Relapse occurred in 8 (25%) of the initial electrical responders. Hence, 47 patients (66%) still suffered from ESES and only 13 patients regained their baseline level of function at the last follow-up. The response to LEV was significantly associated with ESES duration, age at onset of ESES, and etiology of epilepsy. Although fatigue and anorexia were the primary adverse events, LEV was well-tolerated by all patients. ConclusionsLevetiracetam is safe and may be efficient when used to treat ESES syndrome; however, the efficacy EEG neuropsychological outcomes is limited on the whole.

Virological response after 6 week triple-drug regimens for hepatitis C: a proof-of-concept phase 2A cohort study

Direct-acting antiviral drugs have a high cure rate and favourable tolerability for patients with hepatitis C virus (HCV). Shorter courses could improve affordability and adherence. Sofosbuvir and ledipasvir with ribavirin have high efficacy when taken for 8 weeks but not for 6 weeks. We assessed whether the addition of a third direct-acting antiviral drug to sofosbuvir and ledipasvir would allow a shorter treatment duration. In this single-centre, open-label, phase 2A trial, we sequentially enrolled treatment-naive patients with HCV genotype 1 infection into three treatment groups: 12 weeks of sofosbuvir and ledipasvir; 6 weeks of sofosbuvir, ledipasvir, and GS-9669; or 6 weeks of sofosbuvir, ledipasvir, and GS-9451. Patients and investigators were not masked to treatment assignment. The primary endpoint was the propotion of patients with sustained viral response at 12 weeks after treatment completion (SVR12), assessed by serum HCV RNA concentrations lower than 43 IU/mL (the lower limit of quantification). We did an intention-to-treat analysis for the primary endpoint and adverse events. This study is registered with ClinicalTrials.gov, number NCT01805882. Between Jan 11, 2013, and Dec 17, 2013, we enrolled 60 patients, and sequentially assigned them into three groups of 20. We noted an SVR12 in all 20 patients (100%, 95% CI 83-100) allocated to sofosbuvir and ledipasvir for 12 weeks; in 19 (95%, 75-100) of the 20 patients allocated to sofosbuvir, ledipasvir, and GS-9669 for 6 weeks (one patient relapsed 2 weeks after completion of treatment); and in 19 (95%, 75-100%) of the 20 patients allocated to sofosbuvir, ledipasvir, and GS-9451 for 6 weeks (one patient was lost to follow-up after reaching sustained viral response at 4 weeks). Most adverse events were mild and no patients discontinued treatment. Two serious adverse events occurred (pain after a post-treatment liver biopsy and vertigo), both unrelated to study drugs. In this small proof-of-concept study, two different three-drug regimens that were given for 6 weeks resulted in high cure rates for HCV infection with excellent tolerability. Addition of a third potent direct-acting antiviral drug can reduce the duration of treatment required to achieve sustained viral response in patients with chronic HCV genotype 1 infection without cirrhosis. National Institute of Allergy and Infectious Diseases (NIAID), National Cancer Institute and Clinical Center Intramural Program, German Research Foundation, National Institutes of Health, Gilead Sciences.

Lapatinib combined with neoadjuvant paclitaxel-trastuzumab-based chemotherapy in patients with human epidermal growth factor receptor 2-positive breast cancer: A meta-analysis of randomized controlled trials.

The purpose of the present study was to quantify the cumulative randomized evidence for the efficacy and safety of lapatinib combined with neoadjuvant therapy in human epidermal growth factor receptor (HER) 2-positive breast cancer. Three electronic databases, MEDLINE, Embase and Cochrane Central Register of Controlled Trials, and the abstracts of major international conferences between inception and 15 December 2013 were searched. Two evaluators independently extracted data. The end-points assessed consisted of the pathological complete response (pCR) rate, breast-conserving surgery (BCS) rate and the occurrence of adverse events. Four randomized controlled trials were assessed in the present study, involving a total of 779 participants. Compared with the patients who did not receive lapatinib, the pCR rate was higher in the hormone receptor (HR)-positive [risk ratio (RR), 1.39; 95% confidence interval (CI), 1.12–1.72; P=0.002) and HR-negative (RR, 1.38; 95% CI, 1.14–1.68; P=0.0009) patients that received lapatinib. No significant difference between the BCS rate of the two treatment arms was observed in two trials (n=382; RR, 1.14; 95% CI, 0.89–1.47; P=0.31). The primary adverse events, including diarrhea, dermatological toxicity, hepatic toxicity and neutropenia, were statistically more frequent in patients that received lapatinib (RR, 2.46; 95% CI, 1.97–3.07; P<0.00001). The present analysis revealed that the addition of lapatinib to neoadjuvant chemotherapy for HER2-positive breast cancer improves the probability of achieving a higher pCR rate, but the use of lapatinib is associated with a higher risk of adverse events.

Colchicine for the prevention of pericarditis: what we know and what we do not know in 2014 - systematic review and meta-analysis.

The purpose of this study was to investigate and summarize available evidence on the efficacy and safety of colchicine for pericarditis prevention. Disease recurrence is the major and most common complication of pericarditis and its prevention may reduce morbidity and management costs. Colchicine has been intensively studied in the last decade for pericarditis prevention. Controlled clinical studies were searched in several databases and were included provided they focused on the pharmacologic primary or secondary prevention of pericarditis. We performed a meta-analysis including studies of primary outcome, adverse events and drug withdrawal. From the initial sample of 175 citations, seven controlled clinical trials were finally included (1275 patients): five studies were double-blind randomized controlled trials (RCT), and two studies were open-label RCTs. Trials followed patients for a mean of 19 months. Meta-analytic pooling showed that colchicine use was associated with a reduced risk of pericarditis during follow-up [odds ratio (OR) 0.33 (0.25-0.44), P for effect <0.001, P for heterogeneity 0.98, I = 0%] either for primary or secondary prevention without a significant higher risk of adverse events [OR 1.28 (0.84-1.93), P for effect = 0.25, P for heterogeneity = 0.72, I = 0%], and drug withdrawals compared with placebo [OR 1.54 (0.98-2.41), P for effect = 0.06, P for heterogeneity = 0.54, I = 0%]. Gastrointestinal intolerance is the most frequent side-effect (mean incidence 8%), but no severe adverse events were recorded. Colchicine is well tolerated and efficacious for the primary and secondary prevention of pericarditis without a significant increase of the risk of side-effects and drug withdrawals.

Development and evaluation of tools and an intervention to improve patient- and carer-centred outcomes in Longer-Term Stroke care and exploration of adjustment post stroke: the LoTS care research programme

BackgroundEvidence-based care pathways are required to support stroke patients and their carers in the longer term.AimsThe twofold aim of this programme of four interlinking projects was to enhance the care of stroke survivors and their carers in the first year after stroke and gain insights into the process of adjustment.Methods and resultsWe updated and further refined a purposely developed system of care (project 1) predicated on a patient-centred structured assessment designed to address areas of importance to patients and carers. The structured assessment is linked to evidence-based treatment algorithms, which we updated using a structured protocol: reviewing available guidelines, Cochrane reviews and randomised trials. A pragmatic cluster randomised controlled trial evaluation of the clinical effectiveness and cost-effectiveness of this system of care was undertaken in 29 community-based UK stroke care co-ordinator services (project 2). In total, 15 services provided the system of care and 14 continued with usual practice. The primary objective was to determine whether the intervention improved patient psychological outcomes (General Health Questionnaire-12) at 6 months; secondary objectives included functional outcomes for patients, outcomes for carers and cost-effectiveness, as measured through self-completed postal questionnaires at 6 and 12 months. A total of 800 patients and 208 carers were recruited; numbers of participants and their baseline characteristics were well balanced between intervention and control services. There was no evidence of statistically significant differences in primary or secondary end points or adverse events between the two groups, nor evidence of cost-effectiveness. Intervention compliance was high, indicating that this is an appropriate approach to implement evidence into clinical practice. A 22-item Longer-term Unmet Needs after Stroke (LUNS) questionnaire was developed and robustly tested (project 3). A pack including the LUNS questionnaire and outcome assessments of mood and social activity was posted to participants 3 or 6 months after stroke to assess acceptability and validity. The LUNS questionnaire was re-sent 1 week after return of the first pack to assess test–retest reliability. In total, 850 patients were recruited and the acceptability, validity and test–retest reliability of the LUNS questionnaire as a screening tool for post-stroke unmet need were confirmed. This tool is now available for clinical use. An in-depth qualitative investigation was undertaken with 22 patients (and carers) at least 1 year after stroke (project 4) to gain further insights into the experience of adjustment. This included initial semistructured interviews, limited observations and solicited diaries with a follow-up interview 3–4 months after the initial interview and highlighted a range of different trajectories for post-stroke recovery.ConclusionsThe programme has been completed as planned, including one of the largest ever stroke rehabilitation trials. This work highlights that successfully addressing the needs of a heterogeneous post-stroke population remains problematic. Future work could explore stratifying patients and targeting services towards patients (and carers) with specific needs, leading to a more specialised bespoke service. The newly developed LUNS questionnaire and the qualitative work will help inform such services.Trial registrationCurrent Controlled Trials ISRCTN67932305.FundingThe National Institute for Health Research (NIHR) Programme Grants for Applied Research programme. The Bradford Teaching Hospitals NHS Foundation Trust received additional funding for project 2 in the submitted work from the Stroke Association, reference number TSA 2006/15. The initial development work for the LUNS tool and the Longer-Term Stroke care (LoTS care) trial carried out before the start of the programme grant was funded by the Stroke Association, reference number TSADRC 2006/01.

The Past versus the Present, 1980-2004: Reduction of Mean Initial Low-Dose, Long-Term Glucocorticoid Therapy in Rheumatoid Arthritis from 10.3 to 3.6 mg/Day, Concomitant with Early Methotrexate, with Long-Term Effectiveness and Safety of Less than 5 mg/Day

Quantitative observations are presented concerning treatment with glucocorticoids of 308 patients with rheumatoid arthritis (RA) at a weekly academic rheumatology setting over 25 years from 1980 to 2004. A database of all visits included medications and multidimensional health assessment questionnaire scores for physical function, pain and routine assessment of patient index data (RAPID3; and a surrogate RAPID3-EST), completed by each patient at each visit in routine care. Over the 5-year periods of 1980-1984, 1985-1989, 1990-1994, 1995-1999 and 2000-2004, the mean initial prednisone daily dose declined from 10.3 to 6.5, 5.1, 4.1 and 3.6 mg/day, as initial doses were >5 mg/day in 49, 16, 7, 7 and 3% of patients, 5 mg/day in 51, 80, 70, 26 and 10%, and <5 mg/day in 0, 4, 23, 67 and 86%. Reduction of prednisone doses in the respective five-year periods was accompanied by increased and earlier use of methotrexate as the first disease-modifying antirheumatic drug (DMARD) in 10, 26, 57, 71 and 78%, and methotrexate treatment in 10, 26, 74, 82 and 92% of patients within the first year of disease. Higher methotrexate doses in the respective five-year periods were used after 1990, along with lower prednisone doses. Most patients were treated indefinitely with both low-dose prednisone and methotrexate; 80% continued both medications for more than 5 years. The primary adverse events were skin-thinning and bruising. New hypertension, diabetes and cataracts were seen in fewer than 10% of patients. While efficacy and safety cannot be analyzed definitively from observational data, the data suggest that many patients with RA might be treated effectively with weekly low-dose methotrexate along with initial and long-term, low-dose prednisone of <5 mg/day.

Impact of Carotid Atherosclerosis on the Risk of Adverse Cardiac Events in Patients With and Without Coronary Disease

Carotid atherosclerosis (CA) is reportedly a strong predictor of imminent cardiac events even in the absence of established coronary artery disease (CAD). We examined the differential impact of CA on the risk of major adverse cardiovascular events in patients with and without CAD diagnosed angiographically. We conducted a follow-up survey of 1391 patients who underwent clinically driven coronary angiography and a same-day carotid ultrasound and Doppler study. Definitions of CAD, CA, and carotid artery stenosis were in accordance with current practice guidelines. Of 1391 patients, angiographic CAD was present in 1105 (79%) patients. Mean and median follow-up was 1574 and 1702 days, respectively. Rates of the primary composite major adverse cardiovascular event end point were higher among patients with CAD compared with those without CAD (48% versus 20%; P<0.001), whereas the rates of all-cause mortality (10% versus 9%; P=0.81) and stroke (7% versus 5%; P=0.3) did not differ significantly between both groups. Carotid artery stenosis and CA were associated with an increased risk of the composite major adverse cardiovascular event end point among patients without CAD (hazard ratio=3.17 [95% confidence interval, 1.52-6.60]; P<0.01; and hazard ratio=1.69 [0.95-3.01]; P=0.07, respectively) though not in patients with CAD. Carotid artery stenosis was associated with an increased risk of all-cause mortality among patients without CAD (hazard ratio=2.93 [1.09-7.87]; P=0.03]) though not among those with CAD. CA and carotid artery stenosis are independent predictors of major adverse cardiovascular event in patients undergoing coronary angiography. The prognostic implications of carotid disease are imparted predominantly in patients without pre-existent CAD.

Efficacy and safety of cholinesterase inhibitors and memantine in cognitive impairment in Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies: systematic review with meta-analysis and trial sequential analysis

ObjectiveRecently, several large randomised controlled trials about the treatments of cognitive impairment or dementia due to Parkinson's disease (CIND-PD or PDD) and dementia with Lewy bodies (DLB) were completed. Here,...

A phase I study of the human monoclonal anti-NRP1 antibody MNRP1685A in patients with advanced solid tumors

The human monoclonal antibody MNRP1685A targets the VEGF binding domain of neuropilin-1 (NRP1), a multi-domain receptor necessary for neural development and blood vessel maturation. In nonclinical studies, MNRP1685A prevents vascular maturation by keeping blood vessels in an immature, highly VEGF-dependent state. We explored the safety and tolerability of MNRP1685A in patients with advanced solid tumors. Patients were treated with MNRP1685A given intravenously every 3 weeks using a 3 + 3 dose-escalation design with 7 dose-escalation cohorts. Twenty-four of 35 patients (69%) experienced drug-related adverse events (AEs) of infusion-related reaction on the day of MNRP1685A administration. With premedication including dexamethasone, infusions were well-tolerated with main symptoms of pruritus and rash. Outside the day of infusion, most common (≥ 2 patients) related AEs were fatigue (17%), pruritus (9%), myalgia and thrombocytopenia (both 6%) (all were Grade 1-2). MNRP1685A-related Grade ≥ 3 AEs consisted of one dose-limiting toxicity of Grade 3 upper gastrointestinal bleeding and one related Grade 3 thrombocytopenia, coinciding with unrelated Grade 3 fungemia and duodenal obstruction. MNRP1685A showed nonlinear PK with more-than-dose proportional increases in exposure, consistent with broad target expression. Transient platelet count reductions (≥ 30% from predose) were observed in 56% of evaluable patients. Nine patients were on study for ≥ 4cycles, one colorectal cancer patient for one year. MNRP1685A was generally well-tolerated. The primary MNRP1685A-related AE was infusion-related reaction, which were attenuated by premedication including dexamethasone. Transient platelet count reductions were frequent but did not impact MNRP1685A dosing.

Abstract T MP19: Intreped Registry: Association of Procedure Time With Complications

Purpose: To assess the association of procedure time with neurologic adverse events post Pipeline Embolization Device (PED) placement for intracranial aneurysm treatment. Methods: In the IntrePED Registry, a retrospective review was performed at 17 centers to identify consecutive intracranial aneurysms treated with the PED following regulatory approval in the given country. All patients in whom at least one PED was placed and follow-up was available prior to IRB approval were enrolled. “Primary adverse events” included major stroke, major hemorrhage, and neurological mortality. Results: 793 patients with 906 aneurysms, including 311 large ICA, 536 other anterior and 59 posterior circulation aneurysms were enrolled and followed for a mean duration of 19.3 months. 689 (77%) of 906 aneurysms were saccular and 116(13%) were fusiform. 824 (91%) were unruptured. 308 (34%) treated with multiple PEDs. Incidence of major hemorrhage, stroke and neurological mortality was 2.4%, 4.7% and 3.8% respectively. Heparin was administered in 89% of the patients during the procedure. An average of 1.5 PEDs were utilized per case. The mean procedure time was 101.5 ± 50.5 mins. Patients with a major complication (major stroke, major hemorrhage, neurological mortality) had procedure time of 138.2 + 81.5 min, and those without a major complication had procedure time of 98.3 + 45.5 min (p&lt; 0.001). A logistic regression incorporating aneurysm size and number of PEDs used still showed a highly significant relationship between major complications and procedure time (p&lt;0.001) and also found aneurysm size to be an independent predictor of longer procedures (p=0.007). Conclusions: The present analysis of IntrePED Registry subjects demonstrates a strong association of procedure time with complication rates. Further analyses of factors leading to longer procedure times is needed.

Are Concerns About Reliability in the Trial to Assess Chelation Therapy Fair Grounds for a Hasty Dismissal?

> Preconceived notions are the locks on the door to wisdom. > > — Merry Browne Trial to Assess Chelation Therapy (TACT) was a prospective, randomized, double-blind, placebo-controlled trial designed to evaluate the effect of ethylenediaminetetraacetic acid-based intravenous chelation therapy on cardiovascular outcomes.1,2 A total of 1708 stable patients >50 years of age with a previous myocardial infarction were enrolled at 134 North American sites and followed for a median of 55 months. The overall results showed that chelation therapy reduced the risk of primary major adverse cardiac events plus end point—a composite of death, myocardial infarction, stroke, coronary revascularization, or hospitalization for angina.2 Article see p 15 In this report, the TACT investigators present the results of a prespecified subgroup analysis in the diabetic cohort.3 The investigators used an expanded definition of diabetes mellitus compared with what was prespecified in trial design1 or reported previously.2 As a result, the size of the cohort increased from 538 to 633, and the number of primary end point events accrued increased from 169 to 197. The principal finding is that chelation therapy was associated with a reduction in the primary MACE plus and secondary stringent MACE end point—a composite of death, nonfatal myocardial infarction, or stroke. In contrast, chelation failed to yield benefit in patients without diabetes mellitus (nominal P for interaction=0.0037). There was no significant heterogeneity in treatment effect across individual end points. The treatment benefit was observed independent of changes in lipid or glycemic control. Although randomization was not stratified by diabetes mellitus status, there was sufficient overlap and balance between treatment arms to ensure valid causal estimates. The investigators appropriately conclude that although treatment benefit with chelation is suggested, additional studies are warranted to replicate the findings and determine the mechanism of action. Several findings …

Lamivudine Treatment Failure Risks in Chronic Hepatitis B Patients with Low Viral Load

Aim: To analyze the risk factors of lamivudine treatment failure (LTF) for the long-term use in patients with low viral load (LVL). Material and Methods: In this multicenter study, 548 antiviral naïve noncirrhotic adult patients with LVL (for HBeAg+ patients HBV DNA <10⁹ copies/ml and for HBeAg- patients HBV DNA <10⁷ copies/ml) were enrolled. As a control group, 46 lamivudine-initiated patients with high viral load (HVL) were included. Primary outcome was switching to or adding on another antiviral drug as a consequence of primary nonresponse, partial response, viral breakthrough or adverse events. Secondary outcomes included LTF rates at 1, 2, 3, 4 and 5 years and LTF-related viral and host factors. Results: Among 594 patients, 294 had to change lamivudine at the follow-up. Primary nonresponse, partial response, viral breakthrough or adverse events frequencies were 6.8, 1.6, 64.5 and 0.1%, respectively. Five-year LTF rates were 61.3 and 84.2% in patients with LVL and HVL, respectively. Among patients with LVL, patients with <100,000 copies/ml and ≥100,000 copies/ml had 54.8 and 67.3% LTF rates at the end of the 5th year, respectively. Logistic regression analysis of risk factors showed HBeAg+, hepatic activity index, HBV DNA, virological response at 6 months and duration of follow-up were independent predictors for LTF (p values were 0.001, 0.008, 0.003, 0.020 and 0.003, respectively). Conclusion: Similar to patients with HVL, first-line lamivudine therapy is not efficient for long-term use in patients with LVL. LTF risk is so high even in the absence of worse predictive factors.