Trial In October Research Articles

Phase III trial of tumor-treating fields (TTFields) together with temozolomide compared with temozolomide (TMZ) alone in patients with newly diagnosed glioblastoma multiforme (NCT00916409).

TPS2106 Background: TTFields therapy is a novel, non-invasive, anti-mitotic treatment, inhibiting tumor growth by interfering with the metaphase to anaphase transition during mitosis (Lee et al., 2011). TTF therapy was recently approved by the FDA for recurrent GBM following a prospective, randomized trial. Preclinical studies have shown TTFields and TMZ to have an additive inhibitory effect on glioma cell proliferation. The design for the current study was supported by results from a pilot study with TTFields therapy and TMZ in patients with newly diagnosed GBM demonstrating favorable safety, tolerability and promising efficacy (Kirson et al., 2009). Methods: The hypothesis of the current study is that the addition of TTFields therapy to maintenance TMZ will increase progression free survival (PFS) of newly diagnosed GBM patients. Secondary endpoints include overall survival (OS), radiological response, quality of life and safety. Eligible patients will be randomized (2:1) to continuous TTFields therapy (200 kHz) in combination with maintenance TMZ versus maintenance TMZ alone. Maintenance TMZ will be administered as per the Stupp Protocol for 6 courses (Stupp et al., 2005). TTFields therapy may be administered for up to 24 months. Patients will be stratified based on: extent of resection and MGMT methylation status. Eligibility criteria include: pathological diagnosis of GBM; Karnofsky ≥ 70; previous chemoradiotherapy per Stupp Protocol; no progressive disease at baseline. Patients with infratentorial tumor or implanted electronic devices are excluded. The sample size of 700 patients will have 80% power to detect a 2 month (9 vs 7 months) improvement in PFS using log-rank test with an overall 5% 2-sided type I error. The trial is also powered to detect a 4.5 month increase in median OS in NovoTTF-100A/TMZ patients. Patients will be followed clinically monthly and with bimonthly MRI to assess tumor progression and additional endpoints. 221 patients have been enrolled at the time of abstract submission. The DMC last reviewed the trial in October 2010 and recommended that the trial continue as designed.

Antibiotic prophylaxis for hernia repair.

The use of antibiotic prophylaxis for hernia repair is currently a controversial issue given the disparity among study results in this area. The objective of this systematic review was to clarify the effectiveness of antibiotic prophylaxis in reducing postoperative wound infection rates in elective open inguinal hernia repair. We searched the Cochrane Colorectal Cancer Group specialized register, by crossing the terms herni* and inguinal or groin and the terms antimicr* or antibiot* , as free text and MeSH terms. A similar search were performed in Medline using the following terms: #1 antibiotic* OR antimicrob* OR anti infecti* OR antiinfecti*; #2 prophyla* OR prevent*; #3 #1 AND #2; #4 clean AND (surgery OR tech* OR proced*); #5 herni*; #6 (wound infection) AND #4; #7 #3 AND (#4 or #5 or #6). National Research Register, ISI-Web, DARE, Scirus, TRIPDATABASE, NHS EED, reference list of the included studies and web of clinical trials register (www.controlled-trials.com and clinicaltrials.gov) were checked to identify further studies. Only randomised clinical trials were included. In the present review, we searched for eligible trials in October 2011. This revealed four new included trials, so seventeen trials are included in the meta-analysis. Eleven of them used prosthetic material for hernia repair (hernioplasty) whereas the remaining studies did not (herniorrhaphy). Pooled and subgroup analysis were conducted depending on whether prosthetic material was or not used. A fixed effects model was used in the analysis. The total number of patients included was 7843 (prophylaxis group: 4703, control group: 3140). Overall infection rates were 3.1% and 4.5% in the prophylaxis and control groups, respectively (OR 0.64, 95% CI 0.50 - 0.82). The subgroup of patients with herniorrhaphy had infection rates of 3.5% and 4.9% in the prophylaxis and control groups, respectively (OR 0.71, 95% CI 0.51 - 1.00). The subgroup of patients with hernioplasty had infection rates of 2.4% and 4.2% in the prophylaxis and control groups, respectively (OR 0.56, 95% CI 0.38 - 0.81). Based on the results of this systematic review the administration of antibiotic prophylaxis for elective inguinal hernia repair cannot be universally recommended. Neither can the administration be recommended against when high rates of wound infection are observed.

Challenges in the design and analysis of non-inferiority trials: a case study

The literature on the design, conduct, and analysis of non-inferiority trials is continuously evolving. Several design issues continue to be researched including the choice of active control, choice of non-inferiority margin, and optimal analytic approaches. To date, there has been relatively little in the literature documenting actual experiences with implementing available methodology for non-inferiority trials. This article serves as a case study and highlights some of the challenges encountered in the design of a Phase III non-inferiority trial in status epilepticus that is being conducted under a Food and Drug Administration Investigational New Drug Application (IND). The IND application was put on clinical hold by the Food Drug and Administration due to concerns with the design. Specifically, support for the active control, non-inferiority margin, and overall interpretability of trial results were questioned, and a recommendation was made to consider a superiority design. The authors describe their interactions with the Food Drug and Administration and their application of available methods and approaches to address these concerns. The investigators' response to the clinical hold provided detailed information to support the conduct of a non-inferiority trial. The study team received Food Drug and Administration approval to initiate the trial in October 2008. The trial enrollment began in June 2009 and is being conducted by roughly 800 paramedic units in over 40 Emergency Medicine Service systems across the United States. There is still a great deal of methodological research needed to fully understand the application and impact of the non-inferiority trial design. It is evident that non-inferiority trials have an important place in clinical trial design and analysis. These trials may be the only way and only opportunity to answer certain questions; so, they must be designed and conducted with rigor. This case study is an attempt to share our experiences in implementation.

Cochrane Review: Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants

AbstractBackgroundPatent ductus arteriosus (PDA) and intraventricular haemorrhage (IVH) are both associated with increased mortality and morbidity in preterm infants. Indomethacin has been used successfully to treat symptomatic PDA and may also prevent or limit IVH in the neonatal period. There are however potential unwanted side effects of indomethacin, in particular a potential for reduced organ perfusion that might outweigh any clinical benefits. The prophylactic use of indomethacin, where infants who may not have gone on to develop a symptomatic PDA or IVH would be exposed to indomethacin, warrants particular scrutiny.ObjectivesThis review examines the effectiveness of prophylactic intravenous indomethacin in reducing the mortality and morbidity associated with PDA and IVH in preterm infants.Search strategyAn initial literature search was conducted in three computerised databases: MEDLINE; EMBASE; and the Oxford Database of Perinatal Trials in October 1994. The search was updated in February 1997 and October 2001.Selection criteriaStrict selection criteria were applied to clinical trials: the population had to be newborn preterm infants (less than 37 completed weeks gestation); the intervention had to be prophylactic intravenous indomethacin; the trial had to be randomised and controlled; and at least one of several prespecified outcomes had to be reported in the results.Data collection and analysisThe methodological quality of each study was assessed using explicit criteria. Data on relevant outcome measures were extracted and, where appropriate, the results of individual trials were combined using meta‐analysis techniques to provide a pooled estimate of effect.Main resultsNineteen eligible trials randomising 2872 infants were identified.There is no evidence of difference in mortality at latest follow‐up between infants receiving prophylactic indomethacin and controls, pooled relative risk (RR) = 0.96 [95% CI 0.81 to 1.12].There is no evidence to suggest prophylactic indomethacin is associated with any reduction in long‐term neurosensory impairment, ie no significant difference in rates of cognitive delay, cerebral palsy, blindness or deafness.The incidence of symptomatic patent ductus arteriosus is significantly reduced in treated infants, pooled RR = 0.44 [0.38 to 0.50] but there is no evidence that treatment affects respiratory outcomes. Prophylactic indomethacin reduces the need for surgical PDA ligation [RR = 0.51 (0.37,0.71)].Prophylactic indomethacin significantly reduces the incidence of Grade 3 and 4 intraventricular haemorrhage, pooled RR = 0.66 [0.53 to 0.82].There is no evidence of difference in rates of necrotising enterocolitis, excessive clinical bleeding or sepsis. Increased incidence of oliguria is seen with prophylactic indomethacin [RR = 1.90 (1.45,2.47] but this is not associated with major renal impairment.Authors' conclusionsProphylactic treatment with indomethacin has a number of immediate benefits, in particular a reduction in symptomatic patent ductus arteriosus, the need for duct ligation and severe intraventricular haemorrhage. There is no evidence to suggest either benefit or harm in longer term outcomes including neurodevelopment. Depending on clinical circumstances and personal preferences, there may be a role for prophylactic indomethacin in some infants on some neonatal units.Plain Language SummaryProphylactic intravenous indomethacin for preventing mortality and morbidity in preterm infantsPatent ductus arteriosus (PDA) occurs when an artery near the heart and lungs, which should close off soon after birth, stays open. Babies born too early (preterm) with PDA are at increased risk of severe illness and death. Indomethacin has been given to very small babies within 24 hours of birth to help close a PDA, at the same time reducing the risk of bleeding into the head ‐ intraventricular hemorrhage (IVH). The review found that giving indomethacin to preterm babies reduced their risk of both PDA and IVH. Indomethacin may also reduce blood flow in some organs including the brain but this does not seem to cause any serious lasting adverse effects. However, giving prophylactic indomethacin has no effect on the development of the babies in the longer term ‐ development is neither better nor worse than the development of babies who have not received the treatment ‐ suggesting its use may be limited to achieving short‐term benefits only.

Current trend of breast cancer therapeutics from the U.S. clinical trial database

e17546 Background: The standard of breast cancer care has been based on clinical trial results. With the International Committee of Medical Journal Editors (ICMJE) requiring all clinical trials registered in a public trial registry as a condition of publication, the US trials registry “ClinicalTrials.gov” has become a global registry of currently available clinical trials. We aim to explore the current clinical trials to study the trend of breast cancer therapeutics development based on analysis of a comprehensive breast cancer trial database. Methods: We performed a systematic review of all breast cancer therapeutic clinical trials. All data were captured from ClinicalTrials.gov for all “industry-sponsored” phase I-IV trials in October, 2007 including trials that were first registered between October 2005 and September 2007. Essential data was extracted by a tailor-made Statistical Analysis System Program developed by Professor JP Karlberg at the University of Hong Kong. The data included register identity, study phase, study compounds and recruitment status etc. Results: Altogether 443 clinical therapeutic interventional trials were identified and classified into 10 modes of action. The latest five mostly studied compounds accounted for 32.73% of all the therapeutic trials (n = 145). Lapatinib, a dual kinase inhibitor is studied most in 31 trials (9 monotherapy). Docetaxel, a mitotic inhibitor is studied in 27 trials (10 monotherapy) while letrozole, an aromatase inhibitor, currently used in adjuvant setting is tested in 18 out of a total 22 trials as monotherapy. Antimetabolites such as gemcitabine being involved in 24 trials (2 monotherapy) with capecitabine studied in 21 trials (11 monotherapy), were followed by bevacizumab, a VEGF monoclonal antibody which is currently studied in 20 trials, and tested as combinations in 75% of the related trials. Conclusions: According to the US trial registry, current most commonly tested compounds for breast cancer include lapatinib, followed by docetaxel, gemcitabine, letrozole, and capecitabine. There is increasing new therapeutics with combination strategy. This supports the trend of personalized medicine in the management of breast cancer which is a heterogeneous disease. No significant financial relationships to disclose.

Initial Mortality and Retention Associated with Using Passive Integrated Transponders in Black Crappies

AbstractWe assessed initial retention and mortality associated with using passive integrated transponders (PITs) for marking black crappies Pomoxis nigromaculatus by conducting 48‐h net‐pen trials (N = 4 trials) in April–May 2007 and one 14‐d trial in October 2007. Black crappies (N = 175; total length (TL) range = 175–328 mm; mean TL = 265 mm; SE = 2.1 mm) were captured from a Minnesota lake by boat electrofishing or angling. Before being placed in the net‐pen, each fish received one of four treatments: (1) a 12‐mm PIT, (2) a left pectoral fin clip, (3) a PIT and a fin clip, and (4) no fin clip or PIT (i.e., reference fish). We injected PITs posterior to the pelvic girdle using a 12‐gauge hypodermic needle. Average water temperature during trials ranged from 10.5°C to 16°C. No fish died and no PITs were shed during the 48‐h trials. All PITs were retained during the 14‐d trial in October, but 5 of the 42 black crappies died between days 12 and 14. None of the dead fish belonged to the PIT‐only treatment. Mortality was probably the result of net‐pen confinement, but four of the five mortalities had received a fin clip. Black crappies that retained PITs were filleted, and all PITs were observed to remain outside the typical range of meat removed by anglers for consumption. We conclude that PITs applied in this manner were initially safe (i.e., were not consumed in fillets), were effective (i.e., 100% retention), and did not increase initial mortality of black crappies at these water temperatures. Depending on fin regeneration rates, fin clips might serve as an effective secondary mark for assessing PIT retention in black crappies over certain periods of time, but mortality associated with fin‐clipping should be assessed to ensure that mortality rates are low.

The effect of mussel seed density on tunicate settlement and growth for the cultured mussel, Mytilus edulis

Anecdotal reports from mussel growers suggest that increased stocking density decreases the settlement and growth of the fouling organisms Styela clava (clubbed tunicate) and Ciona intestinalis (vase tunicate). To evaluate this hypothesis, 15 mussel socks of low (90 mussels per 30 cm), medium (250 mussels per 30 cm) and high (500 mussels per 30 cm) densities were placed on three longlines in the Brudenell estuary in the fall 2005 and in the spring 2006. Sampling was conducted in June, August and October of 2006 to determine the effect of different stocking densities and socking time on mussel productivity and C. intestinalis recruitment and growth. Mussel Condition Index and shell length were not significantly different between the three stocking densities by the end of the field trial in October. In August, the mean length of C. intestinalis was significantly lower on the medium and high density socks and C. intestinalis weight was less on medium and high density socks from the fall socking period (no difference within spring socked densities), however, by the October sampling there was no biologically significant difference in the weight of C. intestinalis between stocking density treatments. Time of socking did not appear to have any significant effect on the results, although the abundance of C. intestinalis was marginally higher in August on the socks deployed in December, 2005. Mussel loss was between 50 and 60% for all treatments, with no clear pattern being evident.

Metal Toxicity: Tattoos: Safe Symbols?

A 2003 Harris Poll reported that 16% of U.S. adults are tattooed, including over a third of those aged 25–29. Despite the art’s growing popularity, the toxicology of tattoos is poorly understood. Now some ink components—particularly heavy metals—have raised concerns. A lawsuit set to go to trial in October 2005 has been filed against nine tattoo ink companies for violations of California’s Proposition 65, which requires that Californians be warned before exposure to chemicals causing cancer, birth defects, or other reproductive harm. “One reason we started looking at tattoos is that the research we’ve done suggests teenage girls in particular are a huge market now for tattoos,” says Deborah Sivas, president of the nonprofit American Environmental Safety Institute (AESI), which filed the suit. The concern is not that the inks are acutely harmful, but rather that chronic exposure to some metals—especially lead—is a known problem. Titanium and aluminum are often used as colorants in tattoos; more worrisome, inks using nonmetal colorants may include traces of antimony, arsenic, beryllium, chromium, cobalt, lead, nickel, and selenium (AESI filed over the latter eight metals). Sivas says the ink used for a 3 by 5 inch tattoo contains 1–23 micrograms of lead, versus the 0.5 micrograms per day permitted under Proposition 65. Understanding exposure to lead and other metals once incorporated into a tattoo is not simple. A healed tattoo is a complicated array of ink particles trapped within dermal fibroblasts, macrophages, and mast cells. “One of the biggest problems is, over the period of time, how is exposure evaluated?” says Westley Wood, president of Unimax Supply, a tattoo equipment supplier and ink producer, which settled out of court in the AESI lawsuit. “Should it be counted every single day for the rest of your life, or is it dissipated in the body within a month?” “Metal toxicity has not been an observed problem,” asserts physician Linda Dixon, president of the American Academy of Micropigmentation, a cosmetic tattooing trade group and manufacturer of Kolorsource brand of cosmetic ink. However, she adds, “Information about pigments in traditional tattoo products is usually a trade secret and not shared. We need information which is scientifically based.” Dixon suggests publishing a list of pigments that are known to be safe and those known to be toxic. “Know your colors, know your pigments,” she says. “The scientists know what to avoid, and this should be common knowledge in the tattoo industries.” Though tattoo inks are subject to regulation by the Food and Drug Administration as cosmetics and color additives, that agency does not currently attempt to actually regulate tattooing or the pigments involved. Despite the upcoming court battle, among the 17% of tattooed Americans the Harris Poll say regret their indelible marks, the greatest reason for dissatisfaction is not the safety of the tattoo but having been inscribed with the wrong person’s name.

Recent trends in breech delivery in the Netherlands

The effect of publication of the results of the Term Breech Trial in October 2000 on the mode of delivery of babies in breech presentation in the Netherlands was subject of this study. The results showed an immediate amplifying impact on top of the already existing trend of rising caesarean section rates for term singleton breech presentations. The willingness of obstetricians in the Netherlands to adopt the conclusions of the Term Breech Trial so quickly originate from scientific, legal, psychological and emotional sources. The same amplifying impact applied for all non-term breeches and breeches from multiple gestations, but not for babies in other than breech presentation.

Recent trends in breech delivery in the Netherlands

The effect of publication of the results of the Term Breech Trial in October 2000 on the mode of delivery of babies in breech presentation in the Netherlands was subject of this study. The results showed an immediate amplifying impact on top of the already existing trend of rising caesarean section rates for term singleton breech presentations. The willingness of obstetricians in the Netherlands to adopt the conclusions of the Term Breech Trial so quickly originate from scientific, legal, psychological and emotional sources. The same amplifying impact applied for all non-term breeches and breeches from multiple gestations, but not for babies in other than breech presentation.

ExonHit Therapeutics

ExonHit Therapeutics' mission is to be the leader in the application of alternative RNA splicing to the discovery and development of therapeutics and diagnostics for cancer and neurodegenerative diseases. The most advanced drugs in the Company's pipeline are treatments for amyotropic lateral sclerosis. One of these drugs entered Phase II trials in October 2002 and the other is planned for Phase I trials in 2003. Compounds for treating cancer are currently in the preclinical stage. ExonHit is also engaged in the discovery of molecular pharmacogenomic and diagnostic tests derived from RNA splicing events. ExonHit has established alliances with leading pharmaceutical and diagnostics companies, accelerating the R&D programs of its partners. The Company intends to license its pipeline of high-value drugs (after Phase IIb clinical trials) and diagnostics to these and other global partners.

Standard Protocol for Exchange of Health-Checkups Based on SGML: The Health-Checkups Data Markup Language (HDML).

This research aims to provide the protocol to achieve efficient information exchange by means of electronic data communication between health-checkup facilities. Joint Working Group of JMHTS (The Japan Society of Multiphasic Health Testing and Service) and JAHIS (The Japanese Association of HHHealthcaae Information Systems Industry) developed a health/medical data interchange model that stood on the markup information structure. Our data encoding language, HDML (Health-checkups Data Markup Language), was based on SGML that has context-free grammar. HDML had the standard DTD which defined anamnesis, physical examination, laboratory examination, summary findings, and judgment of total health status, etc. The laboratory examination contains following items: item's name, method, unit, device, company name, product name, principle, and standard reference value. We take into account the interchangeability of data with HL7 and other international standard protocols. As a preliminary study, we carried out an experimental trial in October 1999, which transferred laboratory data by translating into HDML, from 2 health-checkup facilities to other 2 health-checkup facilities. We have succeeded in transferring almost all laboratory data appropriately by using the HDML protocol between the health-checkup facilities. Moreover, we could convert and standardize the laboratory data properly from the information written in the DTD. We propose the HDML protocol to standardize health/medical data that will make it available for multihealth facilities on the basis of the standardization of data exchange regarding health-checkups. We found this HDML protocol worked effectively in using the actual health/medical data.

Service Coordinators in the NECC Trial: An RDNS perspective

The Royal District Nursing Service (RDNS) became involved in the North-Eastern Coordinated Care Trial in October 1997. The purpose of this was to assist the trial in exploring the hypothesis, that for people with chronic or complex care needs, care coordination will provide improved outcomes at the same or a reduced cost. There are a number of areas, which help to clarify the process involved in the trial and the benefits for clients: how the coordinators were chosen; the role of the Care and Service Coordinators: benefits experienced by the professionals; benefits experienced by clients: and discussion points.

Mantle irradiation alone for selected patients with laparotomy-staged IA to IIA Hodgkin's disease: preliminary results of a prospective trial.

To determine the feasibility of omitting prophylactic paraaortic irradiation in selected patients with laparotomy-staged (pathologically staged [PS]) IA to IIA Hodgkin's disease. We initiated a prospective single-arm trial in October 1988 to study the role of mantle irradiation alone in selected PS IA to IIA patients with Hodgkin's disease. A total of 37 patients have been entered onto this trial. Entrance criteria included nodular sclerosis (NS) or lymphocyte predominance (LP) histology, absence of B symptoms, disease limited above the carina, and a negative laparotomy. Results of treatment of 23 patients in the prospective trial, monitored off treatment for > or = 1 year, are presented. Twenty-three additional PS IA to IIA patients, treated with mantle irradiation alone from 1970 to 1987, were analyzed as a comparison group. The median follow-up durations were 32 and 113 months, respectively, for the two groups. The 4-year actuarial rates of freedom from relapse and overall survival are 83% and 100%, respectively, for the prospective trial. The 10-year actuarial rates of freedom from relapse and overall survival are 83% and 89%, respectively, for retrospectively studied patients. There have been five recurrences among 46 patients who received mantle irradiation alone, all with a component of relapse below the diaphragm. These early results support the use of mantle irradiation alone in selected PS IA to IIA patients with NS or LP histology. Relapses, although rare, have occurred predominantly below the diaphragm. This suggests the need for continued long-term surveillance of abdominal and pelvic nodes in this group of treated patients.

Growth of Crawfish Procambarus clarkii as a Function of Density and Food Resources

AbstractThis study utilized enclosures (cylindrical, 5‐mm wire mesh, O.5 m2 bottom surface area) placed over rice‐forage substrates in experimental crawfish ponds to contain crawfish under typical pond culture conditions. Juvenile Procambarus clarkii were stocked at six densities (2, 4, 6, 10, 14, and 18 crawfish/m2) for 12‐wk growth trials in October and again in February. Crawfish relied solely on the detrital food system for their nutritional needs. Supplemental feed was supplied to crawfish in additional enclosures at two of the test densities (2 and 10 crawfish/m2). The commercially formulated feed (25% crude protein) was fed (2.02 g dry feed/m2) 3 d/wk (Monday, Wednesday, Friday). All treatments were replicated with six enclosures. Crawfish growth was inversely correlated to culture density. Mean final weights for crawfish feeding from the detrital‐system only were 15.3, 13.8, 11.2, 7.9, 7.2, and 5.8 g for crawfish densities of 2, 4, 6, 8, 10, 14, and 18/m2, respectively. Mean final weights for crawfish receiving supplemental feed were 20.7 and 12.4 g for densities of 2 and 10 crawfish/m2. When compared with density as a factor influencing growth, feed influenced growth less than density abatement. Supplemental feeding improved crawfish growth in detrital systems an average of 46%, while decreasing initial density improved growth an average of 80.5%.

Model of the Rocket

A FULL-SIZE replica of the locomotive Rocket, as originally designed and constructed by Robert and George Stephenson, has now been acquired for the National Collections in the Science Museum, and will be unveiled by Mr. L. Hore-Belisha, Minister of Transport, at noon on April 11. The model has been made by Messrs. Robert Stephenson and Co., the firm which built the original engine, and represents it, as nearly as possible, in form, materials and workmanship, as it originally appeared. The original engine was built to compete at the Rainhill Trials in October 1829, which was perhaps the most important event in early locomotive history. The success of Stephenson and Booth's Rocket, which won the premium of £500 offered by the directors of the Liverpool and Manchester Railway for the most improved locomotive engine constructed in accordance with certain conditions, definitely proved the suitability of the locomotive as a means of general railway haulage, and showed that speeds hitherto unapproached could be attained. The engine was entered by George and Robert Stephenson and Henry Booth. Its success was mainly due to the adoption of the tubular boiler, which was suggested to George Stephenson by Booth. While George Stephenson is popularly credited with the design of the Rocket, its actual construction, at Newcastle, was carried out by his son Robert, the father's time being fully occupied with the making of the railway itself.