Tocilizumab,a Proposed Therapy for the Cachexia of Interleukin6-Expressing Lung Cancer

Background

We previously reported the role of IL-6 in a murine model of cancer cachexia and currently documented a patient in whom tocilizumab, anti-IL-6 receptor antibody, dramatically improved cachexia induced by IL-6 over-expressing lung cancer. Despite this potential to alleviate cancer cachexia, tocilizumab has not been approved for this clinical use. Therefore, preceding our planned clinical trial of tocilizumab, we designed the two studies described here to evaluate the levels of IL-6 in patients with lung cancer and the effect of tocilizumab in a murine model of human cancer cachexia.

Methods

First, we measured serum IL-6 levels in patients with lung cancer and analyzed its association with cachexia and survival. Next, we examined the effect of a rodent analog of tocilizumab (MR16-1) in the experimental cachexia model.

Results

Serum IL-6 levels were higher in patients with cachexia than those without cachexia. In patients with chemotherapy-resistant lung cancer, a high IL-6 serum level correlated strongly with survival, and the cut-off level for affecting their prognosis was 21 pg/mL. Meanwhile, transplantation of IL-6-expressing Lewis Lung Carcinoma cells caused cachexia in mice, which then received either MR16-1 or 0.9% saline. Tumor growth was similar in both groups; however, the MR16-1 group lost less weight, maintained better food and water intake and had milder cachectic features in blood. MR16-1 also prolonged the survival of LLC-IL6 transplanted mice (36.6 vs. 28.5 days, p = 0.016).

Conclusion

Our clinical and experimental studies revealed that serum IL-6 is a surrogate marker for evaluating cachexia and the prognosis of patients with chemotherapy resistant metastatic lung cancer and that tocilizumab has the potential of improving prognosis and ameliorating the cachexia that so devastates their quality of life. This outcome greatly encourages our clinical trials to evaluate the safety and efficacy of tocilizumab treatment for patients with increased serum IL-6.     

Is IL-6 an appropriate target to treat spondyloarthritis patients refractory to anti-TNF therapy? a multicentre retrospective observational study

Introduction

The aim of this study was to evaluate, under real-life conditions, the safety and efficacy of tocilizumab in patients having failed anti-TNFα therapy for spondyloarthritis.

Methods

French rheumatologists and internal-medicine practitioners registered on the Club Rhumatismes et Inflammations website were asked to report on patients given tocilizumab (4 or 8 mg/kg) to treat active disease meeting Assessment of SpondyloArthritis International Society (ASAS) criteria for axial or peripheral spondyloarthritis, after anti-TNFα treatment failure. Safety and efficacy after 3 and 6 months were assessed retrospectively using standardised questionnaires.

Results

Data were obtained for 21 patients, 13 with axial spondyloarthritis (46% men; median age, 42 years; disease duration, 11 years; HLA-B27-positive, 92.3%) and eight with peripheral spondyloarthritis (25% men; median age, 40 years; disease duration, 10 years; HLA-B27-positive, 62.5%). No patients with axial disease had at least a 20 mm decrease in the BASDAI, nor a BASDAI50 response or major ASAS-endorsed disease activity score improvements after 3 or 6 months; an ASAS-endorsed disease activity score clinically important improvement was noted at month 3 in five of 13 patients and at month 6 in one of four patients. A good DAS28 response was achieved in four patients with peripheral disease, including one in EULAR remission at month 3. Four patients were still taking tocilizumab at month 6, including one in EULAR remission and one with a good DAS28 response. Tocilizumab was well tolerated, with no serious adverse events. Initially elevated acute-phase reactants declined during tocilizumab therapy.

Conclusion

In patients having failed anti-TNFα therapy, tocilizumab decreased acute-phase reactants but failed to substantially improve axial spondyloarthritis and was inconsistently effective in peripheral spondyloarthritis.     

Validation of a model-based virtual trials method for tight glycemic control in intensive care

Background  

In-silico virtual patients and trials offer significant advantages in cost, time and safety for designing effective tight glycemic control (TGC) protocols. However, no such method has fully validated the independence of virtual patients (or resulting clinical trial predictions) from the data used to create them. This study uses matched cohorts from a TGC clinical trial to validate virtual patients and in-silico virtual trial models and methods.     

The Impact of Newer Biological Disease Modifying Anti-Rheumatic Drugs on Cardiovascular Risk Factors: A 12-Month Longitudinal Study in Rheumatoid Arthritis Patients Treated with Rituximab,Abatacept and Tociliziumab

Objectives

To assess whether treatment with one of three novel biological DMARDs; rituximab, abatacept or tocilizumab reduce cardiovascular disease (CVD) risk factors in patients with rheumatoid arthritis (RA).

Methods

This is an open, observational and prospective study with visits at baseline, 3, 6, and 12 months. Patients were assigned to receive rituximab, abatacept or tocilizumab according to clinical indications assessed by an independent rheumatologist. Disease activity was quantified by the disease activity score (DAS28) and extensive ultrasonography. CVD risk was assessed by total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), blood pressure and arterial stiffness measurements [pulse wave velocity (PWV) and augmentation index (AIx)]. Within group change in disease activity and CVD risk over 3 months was explored using paired samples bivariate tests. Predictors of change in CVD risk at 3 months were identified in linear regression models. Changes in CVD risk markers over the 12- month follow-up in patients receiving rituximab were assessed by mixed models repeated analyses.

Results

24 patients on rituximab, 5 on abatacept and 7 on tocilizumab were included. At 3 months PWV was significantly reduced in the tocilizumab group only, but at 12 months rituximab patients showed a significant reduction in PWV. Reduced inflammation at 3 months was associated with increased TC and HDL-c in the entire cohort.

Conclusion

Treatment with tocilizumab and rituximab reduces PWV, a marker of CVD risk, in patients with RA.     

Effect of tocilizumab on haematological markers implicates interleukin-6 signalling in the anaemia of rheumatoid arthritis

Introduction

Our objective was to determine the interrelationships of interleukin (IL)-6 receptor inhibition with haemoglobin, acute-phase reactants and iron metabolism markers (including hepcidin) in patients with rheumatoid arthritis (RA).

Methods

Data of patients receiving tocilizumab or placebo in the MEASURE study were analysed. We investigated associations at baseline and during tocilizumab treatment among haemoglobin, parameters of haemoglobin and iron homeostasis [ferritin, total iron-binding capacity (TIBC), hepcidin, haptoglobin], IL-6 and acute-phase reactants [C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)] to identify statistical correlates of rise in haemoglobin level.

Results

At baseline, CRP and haptoglobin were inversely correlated (modestly) with haemoglobin levels. After treatment with tocilizumab, CRP, hepcidin, ferritin and haptoglobin levels fell alongside increases in TIBC and haemoglobin. The falls in CRP, hepcidin and haptoglobin levels in the first 2 weeks correlated with a week 12 rise in TIBC and haemoglobin.

Conclusions

Inflammatory anaemia improves in patients with RA treated with tocilizumab. This improvement correlates with the degree of suppression of systemic inflammation, reduction in hepcidin and haptoglobin and increase in iron-binding capacity. These clinical data provide evidence of a role for IL-6 signalling in the inflammatory anaemia of RA.     

Pooling, meta-analysis, and the evaluation of drug safety

Background  

The "integrated safety report" of the drug registration files submitted to health authorities usually summarizes the rates of adverse events observed for a new drug, placebo or active control drugs by pooling the safety data across the trials. Pooling consists of adding the numbers of events observed in a given treatment group across the trials and dividing the results by the total number of patients included in this group. Because it considers treatment groups rather than studies, pooling ignores validity of the comparisons and is subject to a particular kind of bias, termed "Simpson's paradox." In contrast, meta-analysis and other stratified analyses are less susceptible to bias.     

A Phase 1 Trial of pharmacologic interactions between transdermal selegiline and a 4-hour cocaine infusion

Background  

The selective MAO-B inhibitor selegiline has been evaluated in clinical trials as a potential medication for the treatment of cocaine dependence. This study evaluated the safety of and pharmacologic interactions between 7 days of transdermal selegiline dosed with patches (Selegiline Transdermal System, STS) that deliver 6 mg/24 hours and 2.5 mg/kg of cocaine administered over 4 hours.     

Comparative evaluation of the effects of treatment with tocilizumab and TNF-α inhibitors on serum hepcidin,anemia response and disease activity in rheumatoid arthritis patients

Introduction

Anemia of inflammation (AI) is a common complication of rheumatoid arthritis (RA) and has a negative impact on RA symptoms and quality of life. Upregulation of hepcidin by inflammatory cytokines has been implicated in AI. In this study, we evaluated and compared the effects of IL-6 and TNF-α blocking therapies on anemia, disease activity, and iron-related parameters including serum hepcidin in RA patients.

Methods

Patients (n = 93) were treated with an anti-IL-6 receptor antibody (tocilizumab) or TNF-α inhibitors for 16 weeks. Major disease activity indicators and iron-related parameters including serum hepcidin-25 were monitored before and 2, 4, 8, and 16 weeks after the initiation of treatment. Effects of tocilizumab and infliximab (anti-TNF-α antibody) on cytokine-induced hepcidin expression in hepatoma cells were analyzed by quantitative real-time PCR.

Results

Anemia at base line was present in 66% of patients. Baseline serum hepcidin-25 levels were correlated positively with serum ferritin, C-reactive protein (CRP), vascular endothelial growth factor (VEGF) levels and Disease Activity Score 28 (DAS28). Significant improvements in anemia and disease activity, and reductions in serum hepcidin-25 levels were observed within 2 weeks in both groups, and these effects were more pronounced in the tocilizumab group than in the TNF-α inhibitors group. Serum hepcidin-25 reduction by the TNF-α inhibitor therapy was accompanied by a decrease in serum IL-6, suggesting that the effect of TNF-α on the induction of hepcidin-25 was indirect. In in vitro experiments, stimulation with the cytokine combination of IL-6+TNF-α induced weaker hepcidin expression than did with IL-6 alone, and this induction was completely suppressed by tocilizumab but not by infliximab.

Conclusions

Hepcidin-mediated iron metabolism may contribute to the pathogenesis of RA-related anemia. In our cohort, tocilizumab was more effective than TNF-α inhibitors for improving anemia and normalizing iron metabolism in RA patients by inhibiting hepcidin production.     

Reversible inactivation of the transcriptional function of P53 protein by farnesylation

Background  

The use of integrating viral vectors in Gene therapy clinical trials has pointed out the problem of the deleterous effect of the integration of the ectopic gene to the cellular genome and the safety of this strategy. We proposed here a way to induce the death of gene modified cells upon request by acting on a pro-apoptotic protein cellular localization and on the activation of its apoptotic function.     

Validating English- and Spanish-language patient-reported outcome measures in underserved patients with rheumatic disease

Introduction  

Rheumatic diseases are among the most common and debilitating health problems in the United States. These diseases are chronic, can result in severe decrements of physical and psychosocial functioning and affect patients' overall quality of life. A consensus regarding the best patient outcomes to be measured in randomized, controlled trials and prospective natural history studies is essential to provide best estimates of efficacy and safety of interventions across diverse patient populations.     

Rituximab and abatacept but not tocilizumab impair antibody response to pneumococcal conjugate vaccine in patients with rheumatoid arthritis

Introduction

The objective of the study was to investigate the impact of newer biologic treatments including rituximab, abatacept and tocilizumab on antibody response following pneumococcal vaccination using a 7-valent conjugate vaccine in patients with established rheumatoid arthritis (RA).

Methods

Patients with RA receiving rituximab, abatacept or tocilizumab as monotherapy or combined with methotrexate (MTX) participated in the study. Specific IgG antibodies against 23F and 6B serotypes were measured at vaccination and 4 to 6 weeks after vaccination using standardised ELISA. Geometric mean antibody levels (GML) were calculated. Antibody response (AR) was defined as the ratio between post- and pre-vaccination antibody levels and a positive antibody response (posAR) was AR ≥2.

Results

In total, 88 patients were enrolled in the study. Of 55 patients treated with rituximab, 26 (46%) were on concomitant MTX. Of patients receiving abatacept (n = 17) and tocilizumab (n = 16) biologic treatment was given in combination with MTX in 13 (76%) and 9 (56%) patients, respectively. Patients treated with rituximab had significantly lower AR compared to those on tocilizumab, as well as compared to previously reported RA patients on MTX and controls (spondylarthropathy patients treated with NSAIDs and/or analgesics). In total, 10.3% of patients on rituximab monotherapy and no patient on rituximab + MTX had posAR for both serotypes. For abatacept and tocilizumab the corresponding figures were 17.6% and 50%.

Conclusion

In this cohort of patients with established RA, treatment with rituximab and abatacept was associated with diminished antibody response but this was most pronounced for rituximab. Pneumococcal conjugate vaccine administrated during ongoing tocilizumab treatment seems to be associated with sufficient antibody response. Pneumococcal vaccination should preferably be encouraged before initiation of rituximab or abatacept treatment.

Trial registration

NCT00828997 and EudraCT EU 2007-006539-29.     

Publication delay of randomized trials on 2009 influenza A (H1N1) vaccination

Background

Randomized evidence for vaccine immunogenicity and safety is urgently needed in the setting of pandemics with new emerging infectious agents. We carried out an observational survey to evaluate how many randomized controlled trials testing 2009 H1N1 vaccines were published among those registered, and what was the time lag from their start to publication and from their completion to publication.

Methods

PubMed, EMBASE and 9 clinical trial registries were searched for eligible randomized controlled trials. The units of the analysis were single randomized trials on any individual receiving influenza vaccines in any setting.

Results

73 eligible trials were identified that had been registered in 2009–2010. By June 30, 2011 only 21 (29%) of these trials had been published, representing 38% of the randomized sample size (19905 of 52765). Trials starting later were published less rapidly (hazard ratio 0.42 per month; 95% Confidence Interval: 0.27 to 0.64; p<0.001). Similarly, trials completed later were published less rapidly (hazard ratio 0.43 per month; 95% CI: 0.27 to 0.67; p<0.001). Randomized controlled trials were completed promptly (median, 5 months from start to completion), but only a minority were subsequently published.

Conclusions

Most registered randomized trials on vaccines for the H1N1 pandemic are not published in the peer-reviewed literature.     

Reporting randomised clinical trials of analgesics after traumatic or orthopaedic surgery is inadequate: a systematic review

Background  

Several randomised clinical trials (RCTs) of analgesics in postoperative pain after traumatic or orthopaedic surgery (TOS) have been published, but no studies have assessed the quality of these reports. We aimed to examine the quality of reporting RCTs on analgesics for postoperative pain after TOS.     

Long-term vitamin E supplementation fails to reduce lipid peroxidation in people at cardiovascular risk: analysis of underlying factors

Background  

Antioxidant supplementation with vitamin E had no effect in the prevention of cardiovascular diseases (CVD) in three recent large, randomized clinical trials. In order to reassess critically the role of vitamin E in CVD prevention, it is important to establish whether these results are related to a lack of antioxidant action.     

Safety of Cell Therapy with Mesenchymal Stromal Cells (SafeCell): A Systematic Review and Meta-Analysis of Clinical Trials

Background

Mesenchymal stromal cells (MSCs, “adult stem cells”) have been widely used experimentally in a variety of clinical contexts. There is interest in using these cells in critical illness, however, the safety profile of these cells is not well known. We thus conducted a systematic review of clinical trials that examined the use MSCs to evaluate their safety.

Methods and Findings

MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (to June 2011), were searched. Prospective clinical trials that used intravascular delivery of MSCs (intravenously or intra-arterially) in adult populations or mixed adult and pediatric populations were identified. Studies using differentiated MSCs or additional cell types were excluded. The primary outcome adverse events were grouped according to immediate events (acute infusional toxicity, fever), organ system complications, infection, and longer term adverse events (death, malignancy). 2347 citations were reviewed and 36 studies met inclusion criteria. A total of 1012 participants with clinical conditions of ischemic stroke, Crohn''s disease, cardiomyopathy, myocardial infarction, graft versus host disease, and healthy volunteers were included. Eight studies were randomized control trials (RCTs) and enrolled 321 participants. Meta-analysis of the RCTs did not detect an association between acute infusional toxicity, organ system complications, infection, death or malignancy. There was a significant association between MSCs and transient fever.

Conclusions

Based on the current clinical trials, MSC therapy appears safe. However, further larger scale controlled clinical trials with rigorous reporting of adverse events are required to further define the safety profile of MSCs.     

Reporting of adverse drug reactions in randomised controlled trials – a systematic survey

Background  

Decisions on treatment are guided, not only by the potential for benefit, but also by the nature and severity of adverse drug reactions. However, some researchers have found numerous deficiencies in trial reports of adverse effects. We sought to confirm these findings by evaluating trials of drug therapy published in seven eminent medical journals in 1997.     

Safety education of pedestrians for injury prevention: a systematic review of randomised controlled trials

ObjectivesTo quantify the effectiveness of safety education of pedestrians.DesignSystematic review of randomised controlled trials of safety education programmes for pedestrians of all ages.ResultsWe identified 15 randomised controlled trials of safety education programmes for pedestrians. Fourteen trials targeted children, and one targeted institutionalised adults. None assessed the effect of safety education on the occurrence of pedestrian injury, but six trials assessed its effect on behaviour. The effect of pedestrian education on behaviour varied considerably across studies and outcomes.ConclusionsPedestrian safety education can change observed road crossing behaviour, but whether this reduces the risk of pedestrian injury in road traffic crashes is unknown. There is a lack of good evidence of effectiveness of safety education for adult pedestrians, specially elderly people. None of the trials was conducted in low or middle income countries.

What is already known on this topic

Road traffic crashes are a leading cause of death and disablement, and pedestrians are particularly vulnerable road usersSeveral organisations strongly recommend road safety educationAs resources are limited, a key question concerns the relative effectiveness of different prevention strategies, including road safety education of pedestrians

What this study adds

This systematic review showed safety education for pedestrians could improve children''s knowledge and change their observed road crossing behaviourHowever, effects on pedestrian injury were unknownThere is a lack of good evidence of effectiveness of safety education for adult pedestrians, especially elderly people, and in low and middle income countries     

Pregnancy Incidence and Risk Factors among Women Participating in Vaginal Microbicide Trials for HIV Prevention: Systematic Review and Meta-Analysis

Introduction

Pregnancy is contraindicated in vaginal microbicide trials for the prevention of HIV infection in women due to the unknown maternal and fetal safety of the microbicides. Women who become pregnant are taken off the microbicide during pregnancy period but this result in reduction of the power of the trials. Strategies to reduce the pregnancy rates require an understanding of the incidence and associated risk factors of pregnancy in microbicide trials. This systematic review estimates the overall incidence rate of pregnancy in microbicide trials and describes the associated risk factors.

Methods

A comprehensive literature search was carried out to identify eligible studies from electronic databases and other sources. Two review authors independently selected studies and extracted relevant data from included studies. Meta-analysis of incidence rates of pregnancy was carried out and risk factors of pregnancy were reported narratively.

Results

Fifteen studies reporting data from 10 microbicide trials (N=27,384 participants) were included. A total of 4,107 participants (15.0%) fell pregnant and a meta-analysis of incidence rates of pregnancy from 8 microbicide trials (N=25,551) yielded an overall incidence rate of 23.37 (95%CI: 17.78 to 28.96) pregnancies per 100 woman-years. However, significant heterogeneity was detected. Hormonal injectable, intra-uterine device (IUD) or implants or sterilization, older age, more years of education and condom use were associated with lower pregnancy. On the other hand, living with a man, history of pregnancy, self and partner desire for future baby, oral contraceptive use, increased number of unprotected sexual acts and inconsistent use of condoms were associated with higher pregnancy.

Conclusions

The incidence rate of pregnancy in microbicide trials is high and strategies for its reduction are urgently required in order to improve the sample size and power of these trials.     

Validation of the post sleep questionnaire for assessing subjects with restless legs syndrome: results from two double-blind,multicenter, placebo-controlled clinical trials

Background  

Because of the subjective nature of Restless Legs Syndrome (RLS) symptoms and the impact of these symptoms on sleep, patient-reported outcomes (PROs) play a prominent role as study endpoints in clinical trials investigating RLS treatments. The objective of this study was to validate a new measure, the Post Sleep Questionnaire (PSQ), to assess sleep dysfunction in subjects with moderate-to-severe RLS symptoms.