Interactive Response System Research Articles

Clinical remission in patients with moderate-to-severe Crohn's disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial

Filgotinib (GLPG0634, GS-6034) is a once-daily, orally administered, Janus kinase 1 (JAK1)-selective inhibitor. The FITZROY study examined the efficacy and safety of filgotinib for the treatment of moderate-to-severe Crohn's disease. We did a randomised, double-blind, placebo-controlled phase 2 study, which recruited patients from 52 centres in nine European countries. We enrolled eligible patients aged 18-75 years with a documented history of ileal, colonic, or ileocolonic Crohn's disease for 3 months or more before screening, as assessed by colonoscopy and supported by histology, and a Crohn's Disease Activity Index (CDAI) score during screening between 220 and 450 inclusive. Patients were randomly assigned (3:1) to receive filgotinib 200 mg once a day or placebo for 10 weeks. Patients were stratified according to previous anti-tumour necrosis factor alpha exposure, C-reactive protein concentration at screening (≤10 mg/L or >10 mg/L), and oral corticosteroid use at baseline, using an interactive web-based response system. The primary endpoint was clinical remission, defined as CDAI less than 150 at week 10. After week 10, patients were assigned based on responder status to filgotinib 100 mg once a day, filgotinib 200 mg once a day, or placebo for an observational period lasting a further 10 weeks. The filgotinib and placebo treatment groups were compared using ANCOVA models and logistic regression models containing baseline values and randomisation stratification factors as fixed effects. Analyses were done on the intention-to-treat non-responder imputation set. The trial was registered at ClinicalTrials.gov, number NCT02048618. Between Feb 3, 2014, and July 10, 2015, we enrolled 174 patients with active Crohn's disease confirmed by centrally read endoscopy (130 in the filgotinib 200 mg group and 44 in the placebo group). In the intention-to-treat population, 60 (47%) of 128 patients treated with filgotinib 200 mg achieved clinical remission at week 10 versus ten (23%) of 44 patients treated with placebo (difference 24 percentage points [95% CI 9-39], p=0·0077). In a pooled analysis of all periods of filgotinib and placebo exposure over 20 weeks, serious treatment-emergent adverse effects were reported in 14 (9%) of 152 patients treated with filgotinib and three (4%) of 67 patients treated with placebo. Filgotinib induced clinical remission in significantly more patients with active Crohn's disease compared with placebo, and had an acceptable safety profile. Galapagos.

The influence of the application of personal response systems on the effects of teaching and learning physics at the high school level

We report on the effectiveness of using interactive personal response systems in teaching physics in secondary schools. Our research were conducted over the period of 2013–2016 using the system called clickers. The idea is based on a reciprocal interaction allowing one to ask questions and receive immediate responses from all the students simultaneously.Our investigation has confirmed this method to be highly effective and powerful. In particular, students’ ability to acquire knowledge increased with the time spent using clickers. We have successfully applied the system also to entire physics courses.As a result, a positive feedback from students has been observed: not only did they learn more but also the teachers were able to improve their own methods.

Interactive Response Systems (IRS) Socrative Application Sample

In globally developing education system, technology has made instructional improved in many ways. One of these improvements is the Interactive Response Systems (IRS) that are applied in classroom activities. Therefore, it is “smart” to focus on interactive response systems in learning environment. This study was conducted aiming to focus on using Socrative application as a feedback agent among IRSs. The study mainly focused on how could Socrative program as a smart feedback agent be effective in fostering students’ learning. Additionally, students’ responses were examined to have an overall sense of a digitally supported learning period. The study was designed on action research. The research was conducted with 53 junior year students who were prospective teachers in different fields at the same time. In order to obtain, 11 item-survey was developed by the researchers to realize how Socrative program could contribute to reinforce learning in detail. Besides, unsystematic interviews on program’s strong and weak aspects were maintained. The results indicated Socrative program as a feedback agent could be benefited in learning process thanks to its accessibility, immediateness, and continuous interaction. The results also revealed that participants of the study perceived the program positively and attended the course more motivated. The study also reflected that students as prospective teachers more eagerly participated in digitally supported than traditionally maintained instructional activities.

Reducing Rates of Readmission and Development of an Outpatient Management Plan in Pulmonary Hypertension: Lessons From Congestive Heart Failure Management

SESSION TITLE: Pulmonary Vascular Disease I SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, October 26, 2016 at 01:30 PM - 02:30 PM PURPOSE: Pulmonary Hypertension (PH) is a progressive group of diseases that remains difficult to treat and carries significant morbidity and mortality despite available medical therapy. There are currently minimal guidelines on chronic outpatient management and prevention of hospitalization owing to the low number of patients and orphan status of the disease. In contrast, congestive heart failure (CHF) outpatient management interventions have been investigated in multiple trials. A common reason for admission in PH and CHF is heart failure exacerbation. The disease states share similar dietary and fluid management challenges, disease management and compliance issues. CHF has well established intervention models that have successfully decreased hospital readmission rates and mortality. We aimed to analyze outpatient CHF disease management interventions that have shown reductions in hospital readmissions and mortality as a starting point for developing an outpatient pulmonary hypertension intervention and management plan. METHODS: A comprehensive review of literature was performed, including original trials and meta-analysis and reviews. We reviewed the topics of outpatient CHF interventions to decrease CHF mortality and readmission and patient management strategies in CHF. RESULTS: The most studied interventions included case management (CM-specialist nurse driven, education pre/post discharge, specialist nurse home visits, scheduled telephone calls for symptom management, when to seek help), multidisciplinary Intervention ( MI-coordinated interventions and communications; specialist nurse driven, patient-caregiver education regarding disease, medication and diet, nurse clinic visits, regular telephone calls, individualized follow-up plan, access to physician, nurse, dietician, pharmacist, social worker), remote monitoring programs consisting of structured telephone strategy (STS-monitoring collected data via human-human or human-machine interactive response system) or tele-monitoring (TM-physiologic data transmission of EKG, blood pressure, weight, respiratory rate digitally). Clinic visits did not have a significant effect on CHF readmission or mortality. CM showed decreased all-cause mortality (ACM) at 12 months, all-cause readmission (ACR) at 12 months and CHF readmission at 6 and 12 months. MI resulted in decreased ACR and CHF readmission. There was some discrepancy on effectiveness of TM programs alone in individual studies, however large meta-analysis suggests TM provided a reduction in ACM and risk of CHF hospitalization. STS had similar results to TM including decreased risk of CHF hospitalization, without an effect on mortality. CONCLUSIONS: Extrapolating from CHF data, it seems that strategies to improve the health of PH patients should include structured telephone strategy and/ or tele-monitoring, case management strategies and multi-disciplinary interventions. CLINICAL IMPLICATIONS: There is no consensus on the most effective outpatient management of PH or strategies to reduce hospital readmission. Successful CHF interventions can provide us with a starting point as we aim to develop and validate PH specific interventions. DISCLOSURE: The following authors have nothing to disclose: Justin Dolan, Viviana Navas, James Tarver, Jinesh Mehta, Franck Rahaghi No Product/Research Disclosure Information

Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials

Elevated lipoprotein(a) (Lp[a]) is a highly prevalent (around 20% of people) genetic risk factor for cardiovascular disease and calcific aortic valve stenosis, but no approved specific therapy exists to substantially lower Lp(a) concentrations. We aimed to assess the efficacy, safety, and tolerability of two unique antisense oligonucleotides designed to lower Lp(a) concentrations. We did two randomised, double-blind, placebo-controlled trials. In a phase 2 trial (done in 13 study centres in Canada, the Netherlands, Germany, Denmark, and the UK), we assessed the effect of IONIS-APO(a)Rx, an oligonucleotide targeting apolipoprotein(a). Participants with elevated Lp(a) concentrations (125-437 nmol/L in cohort A; ≥438 nmol/L in cohort B) were randomly assigned (in a 1:1 ratio in cohort A and in a 4:1 ratio in cohort B) with an interactive response system to escalating-dose subcutaneous IONIS-APO(a)Rx (100 mg, 200 mg, and then 300 mg, once a week for 4 weeks each) or injections of saline placebo, once a week, for 12 weeks. Primary endpoints were mean percentage change in fasting plasma Lp(a) concentration at day 85 or 99 in the per-protocol population (participants who received more than six doses of study drug) and safety and tolerability in the safety population. In a phase 1/2a first-in-man trial, we assessed the effect of IONIS-APO(a)-LRx, a ligand-conjugated antisense oligonucleotide designed to be highly and selectively taken up by hepatocytes, at the BioPharma Services phase 1 unit (Toronto, ON, Canada). Healthy volunteers (Lp[a] ≥75 nmol/L) were randomly assigned to receive a single dose of 10-120 mg IONIS-APO(a)LRx subcutaneously in an ascending-dose design or placebo (in a 3:1 ratio; single-ascending-dose phase), or multiple doses of 10 mg, 20 mg, or 40 mg IONIS-APO(a)LRx subcutaneously in an ascending-dose design or placebo (in an 8:2 ratio) at day 1, 3, 5, 8, 15, and 22 (multiple-ascending-dose phase). Primary endpoints were mean percentage change in fasting plasma Lp(a) concentration, safety, and tolerability at day 30 in the single-ascending-dose phase and day 36 in the multiple-ascending-dose phase in participants who were randomised and received at least one dose of study drug. In both trials, the randomised allocation sequence was generated by Ionis Biometrics or external vendor with a permuted-block randomisation method. Participants, investigators, sponsor personnel, and clinical research organisation staff who analysed the data were all masked to the treatment assignments. Both trials are registered with ClinicalTrials.gov, numbers NCT02160899 and NCT02414594. From June 25, 2014, to Nov 18, 2015, we enrolled 64 participants to the phase 2 trial (51 in cohort A and 13 in cohort B). 35 were randomly assigned to IONIS-APO(a)Rx and 29 to placebo. At day 85/99, participants assigned to IONIS-APO(a)Rx had mean Lp(a) reductions of 66·8% (SD 20·6) in cohort A and 71·6% (13·0) in cohort B (both p<0·0001 vs pooled placebo). From April 15, 2015, to Jan 11, 2016, we enrolled 58 healthy volunteers to the phase 1/2a trial of IONIS-APO(a)-LRx. Of 28 participants in the single-ascending-dose phase, three were randomly assigned to 10 mg, three to 20 mg, three to 40 mg, six to 80 mg, six to 120 mg, and seven to placebo. Of 30 participants in the multiple-ascending-dose phase, eight were randomly assigned to 10 mg, eight to 20 mg, eight to 40 mg, and six to placebo. Significant dose-dependent reductions in mean Lp(a) concentrations were noted in all single-dose IONIS-APO(a)-LRx groups at day 30. In the multidose groups, IONIS-APO(a)-LRx resulted in mean reductions in Lp(a) of 66% (SD 21·8) in the 10 mg group, 80% (SD 13·7%) in the 20 mg group, and 92% (6·5) in the 40 mg group (p=0·0007 for all vs placebo) at day 36. Both antisense oligonucleotides were safe. There were two serious adverse events (myocardial infarctions) in the IONIS-APO(a)Rx phase 2 trial, one in the IONIS-APO(a)Rx and one in the placebo group, but neither were thought to be treatment related. 12% of injections with IONIS-APO(a)Rx were associated with injection-site reactions. IONIS-APO(a)-LRx was associated with no injection-site reactions. IONIS-APO(a)-LRx is a novel, tolerable, potent therapy to reduce Lp(a) concentrations. IONIS-APO(a)-LRx might mitigate Lp(a)-mediated cardiovascular risk and is being developed for patients with elevated Lp(a) concentrations with existing cardiovascular disease or calcific aortic valve stenosis. Ionis Pharmaceuticals.

Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial

Outcomes are poor for patients with recurrent or metastatic nasopharyngeal carcinoma and no well established first-line chemotherapy is available for the disease. We compared the efficacy and safety of gemcitabine plus cisplatin versus fluorouracil plus cisplatin in patients with recurrent or metastatic nasopharyngeal carcinoma. In this multicentre, randomised, open-label, phase 3 trial, patients with recurrent or metastatic nasopharyngeal carcinoma were recruited from 22 hospitals in China. Key inclusion criteria were Eastern Cooperative Oncology Group performance status of 0 or 1, adequate organ function, and measurable lesions according to Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned in a 1:1 ratio to receive either gemcitabine (1 g/m2 intravenously on days 1 and 8) and cisplatin (80 mg/m2 intravenously on day 1), or fluorouracil (4 g/m2 in continuous intravenous infusion over 96 h) and cisplatin (80 mg/m2 on day 1 given intravenously) once every 3 weeks for a maximum of six cycles. The randomisation was done centrally via an interactive phone response system using block randomisation with a size of six. The primary endpoint was progression-free survival assessed by the independent image committee in the intention-to-treat population. Safety analyses were done in patients who received at least one cycle of study drug. This study is ongoing and is registered with ClinicalTrials.gov, number NCT01528618. Between Feb 20, 2012, and Oct 30, 2015, 362 patients were randomly assigned to a group (181 to the gemcitabine [plus cisplatin] group and 181 to the fluorouracil [plus cisplatin] group). Median follow-up time for progression-free survival was 19·4 months (IQR 12·1-35·6). The median progression-free survival was 7·0 months (4·4-10·9) in the gemcitabine group and 5·6 months (3·0-7·0) in the fluorouracil group (hazard ratio [HR] 0·55 [95% CI 0·44-0·68]; p<0·0001). A total of 180 patients in the gemcitabine group and 173 patients in the fluorouracil group were included in the safety analysis. Significantly different treatment-related grade 3 or 4 adverse events between the gemcitabine and fluorouracil groups were leucopenia (52 [29%] vs 15 [9%]; <0·0001), neutropenia (41 [23%] vs 23 [13%]; p=0·0251), thrombocytopenia (24 [13%] vs three [2%]; p=0·0007), and mucosal inflammation (0 vs 25 [14%]; <0·0001). Serious treatment-related adverse events occurred in seven (4%) patients in the gemcitabine group and ten (6%) in the fluorouracil group. Six (3%) patients in the gemcitabine group and 14 (8%) patients in the fluorouracil group discontinued treatment because of drug-related adverse events. No treatment-related deaths occurred in either group. Gemcitabine plus cisplatin prolongs progression-free survival in patients with recurrent or metastatic nasopharyngeal carcinoma. The results establish gemcitabine plus cisplatin as the standard first-line treatment option for this population. Sun Yat-Sen University Clinical Research 5010 Programme, Chinese National Natural Science Foundation project (grant numbers 81372502 and 81201917), the National High Technology Research and Development Program of China (863 program numbers 2012AA02A501 and 2012AA02A502), and the Natural Science Foundation of Guangdong (grant number S2013010016564).

Effects of integrating dynamic concept maps with Interactive Response System on elementary school students' motivation and learning outcome: The case of anti-phishing education

This study aimed to investigate the effects of integrating dynamic concept maps with Interactive Response System (IRS) on elementary school students' motivation and anti-phishing learning outcome. In the quasi-experimental design employed, 130 fifth-grade students were divided into three groups: the control group (traditional image-text), experimental group I (static concept maps), and experimental group II (dynamic concept maps). The results showed that the use of dynamic concept maps with IRS during anti-phishing education significantly increased students' learning self-efficacy when their initial self-efficacy was already high. For learners with low initial self-efficacy, the use of traditional image-text with IRS helped increase post-test self-efficacy. Learners' achievement in the dynamic concept maps group was significantly higher than that of the traditional image-text group. The findings suggest that the use of dynamic concept maps with IRS in the classroom has a positive impact on students' learning process. In addition, when implementing such strategies, it is important to consider students’ initial self-efficacy.

Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial

The combination of cobimetinib with vemurafenib improves progression-free survival compared with placebo and vemurafenib in previously untreated patients with BRAF(V600)-mutant advanced melanoma, as previously reported in the coBRIM study. In this Article, we report updated efficacy results, including overall survival and safety after longer follow-up, and selected biomarker correlative studies. In this double-blind, randomised, placebo-controlled, multicentre study, adult patients (aged ≥18 years) with histologically confirmed BRAF(V600) mutation-positive unresectable stage IIIC or stage IV melanoma were randomly assigned (1:1) using an interactive response system to receive cobimetinib (60 mg once daily for 21 days followed by a 7-day rest period in each 28-day cycle) or placebo, in combination with oral vemurafenib (960 mg twice daily). Progression-free and overall survival were primary and secondary endpoints, respectively; all analyses were done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01689519, and is ongoing but no longer recruiting participants. Between Jan 8, 2013, and Jan 31, 2014, 495 eligible adult patients were enrolled and randomly assigned to the cobimetinib plus vemurafenib group (n=247) or placebo plus vemurafenib group (n=248). At a median follow-up of 14·2 months (IQR 8·5-17·3), the updated investigator-assessed median progression-free survival was 12·3 months (95% CI 9·5-13·4) for cobimetinib and vemurafenib versus 7·2 months (5·6-7·5) for placebo and vemurafenib (HR 0·58 [95% CI 0·46-0·72], p<0·0001). The final analysis for overall survival occurred when 255 (52%) patients had died (Aug 28, 2015). Median overall survival was 22·3 months (95% CI 20·3-not estimable) for cobimetinib and vemurafenib versus 17·4 months (95% CI 15·0-19·8) for placebo and vemurafenib (HR 0·70, 95% CI 0·55-0·90; p=0·005). The safety profile for cobimetinib and vemurafenib was tolerable and manageable, and no new safety signals were observed with longer follow-up. The most common grade 3-4 adverse events occurring at a higher frequency in patients in the cobimetinib and vemurafenib group compared with the vemurafenib group were γ-glutamyl transferase increase (36 [15%] in the cobimetinib and vemurafenib group vs 25 [10%] in the placebo and vemurafenib group), blood creatine phosphokinase increase (30 [12%] vs one [<1%]), and alanine transaminase increase (28 [11%] vs 15 [6%]). Serious adverse events occurred in 92 patients (37%) in the cobimetinib and vemurafenib group and 69 patients (28%) in the vemurafenib group. Pyrexia (six patients [2%]) and dehydration (five patients [2%]) were the most common serious adverse events reported in the cobimetinib and vemurafenib group. A total of 259 patients have died: 117 (47%) in the cobimetinib and vemurafenib group and 142 (58%) in the vemurafenib group. The primary cause of death was disease progression in most patients: 109 (93%) of 117 in the cobimetinib and vemurafenib group and 133 (94%) of 142 in the vemurafenib group. These data confirm the clinical benefit of cobimetinib combined with vemurafenib and support the use of the combination as a standard first-line approach to improve survival in patients with advanced BRAF(V600)-mutant melanoma. F Hoffmann-La Roche-Genentech.

Ixmyelocel-T for patients with ischaemic heart failure: a prospective randomised double-blind trial

Ixmyelocel-T is an expanded, multicellular therapy produced from a patient's own bone marrow by selectively expanding two key types of bone marrow mononuclear cells: CD90+ mesenchymal stem cells and CD45+ CD14+ auto-fluorescent+ activated macrophages. Early phase clinical trials suggest that intramyocardial delivery of ixmyelocel-T might improve clinical, functional, symptomatic, and quality-of-life outcomes in patients with heart failure due to ischaemic dilated cardiomyopathy. We aimed to assess the safety and efficacy of catheter-based transendocardial injection of ixmyelocel-T cell therapy in patients with heart failure and reduced ejection fractions. In this randomised, double-blind, placebo-controlled phase 2B trial (ixCELL-DCM), patients from 31 sites in North America with New York Heart Association class III or IV symptomatic heart failure due to ischaemic dilated cardiomyopathy, who had left ventricular ejection fraction 35% or less, an automatic implantable cardioverter defibrillator, and who were ineligible for revascularisation procedures were randomly assigned (1:1) to receive ixmyelocel-T or placebo at the time of bone marrow aspiration and followed for 12 months. Randomisation was done through an interactive (voice/web) response system. The pharmacist, treating physician, and coordinator at each site were unblinded, but the the follow-up team was completely blinded. The primary endpoint was a composite of all-cause death, cardiovascular admission to hospital, and unplanned clinic visits to treat acute decompensated heart failure based on the blinded adjudication of an independent clinical endpoint committee. Primary efficacy endpoint analyses and safety analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01670981. Between April 2, 2013, and Jan 28, 2015, 126 participants were randomly assigned to receive either ixmyelocel-T (n=66) or placebo (n=60). 114 (90%) patients comprised the modified intention-to-treat population and 109 (87%) patients were included in the per-protocol primary efficacy analysis (58 in the ixmyelocel-T group and 51 in the placebo group). The primary efficacy endpoint was observed in 47 patients: 50 events in 25 (49%) of 51 patients in the placebo group and 38 events in 22 (38%) of 58 patients in the ixmyelocel-T group, which represents a 37% reduction in cardiac events compared with placebo (risk ratio 0·63 [95% CI 0·42-0·97]; p=0·0344). 41 (75%) of 51 participants in the placebo group had serious adverse events versus 31 (53%) of 58 in the ixmyelocel-T group (p=0·0197). To the best of our knowledge, ixCELL-DCM is the largest cell therapy study done in patients with heart failure so far. The transendocardial delivery of ixmyelocel-T in patients with heart failure and reduced ejection fraction due to ischaemic dilated cardiomyopathy resulted in a significant reduction in adjudicated clinical cardiac events compared with placebo leading to improved patient outcomes. Vericel Corporation.

Role of learning style preferences and interactive response systems on student learning outcomes

Learning style preferences are found influential in learning and academic achievement, and may explain how students learn. Additionally, technology has been proven effective in educational processes. Interactive response systems known also as clickers seem to increase student engagement, although studies on the direct effects of clickers on learning outcomes are limited. The purpose of this study is to determine whether student learning style plays a role in learning outcomes and whether some students benefit using interactive systems more than others. Learning outcomes are measured by critical thinking abilities, comprehension of subject knowledge, and effective decision-making abilities through problem/project-based learning practices. Based on the learning outcomes of students enrolled in operations management classes, business students with participant learning style were found to be high academic achievers and successful critical thinkers. Use of interactive response systems positively affected overall course performance and was instrumental in the comprehension of subject knowledge and problem-based learning practices. While participant learners benefited most from interactive response systems, independent learners' application and effective decision-making abilities were enhanced by the use of these systems.

Prevalent practice patterns in glaucoma: Poll of Indian ophthalmologists at a national conference.

Purpose:The aim of this study is to explore and compare the prevailing practice patterns in the diagnosis and management of glaucoma among subspecialists and general ophthalmologists in India.Materials and Methods:This is an interactive audience response system (ARS) based poll of ophthalmologists attending the annual conference of the Glaucoma Society of India in 2013.Results:The information was obtained from 379 ophthalmologists (146 glaucoma specialists, 54 nonglaucoma subspecialists, and 179 general ophthalmologists). The majority of polled ophthalmologists (236; 62%) had 10 or more years of experience in ophthalmology. The glaucoma specialists differed from nonglaucomatologists in their preference for Goldmann applanation tonometer (P < 0.01), four-mirror gonioscope (P < 0.01), Humphrey perimeter (P < 0.01), laser peripheral iridotomy in primary angle closure disease (P = 0.03), postiridotomy gonioscopy (P < 0.01), and usage of antifibrotic agents during filtering surgery (P < 0.01). Optical coherence tomography was the most preferred imaging modality and was utilized more often by the subspecialists than general ophthalmologists. The ophthalmologists also differed in their choice of antiglaucoma medications. More glaucoma specialists were performing surgery on children with congenital glaucoma (P < 0.01), implanting glaucoma drainage devices (P < 0.01), and using scientific journals to upgrade knowledge (P = 0.03) than the other ophthalmologists.Conclusions:This poll is the first of its kind in India, in its usage of the ARS, and in comparing the practice patterns of care for glaucoma among subspecialists and general ophthalmologists. It has revealed substantial diversity in a few areas among those who did and did not receive specialty training in glaucoma.

Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial

Isavuconazole is a novel triazole with broad-spectrum antifungal activity. The SECURE trial assessed efficacy and safety of isavuconazole versus voriconazole in patients with invasive mould disease. This was a phase 3, double-blind, global multicentre, comparative-group study. Patients with suspected invasive mould disease were randomised in a 1:1 ratio using an interactive voice-web response system, stratified by geographical region, allogeneic haemopoietic stem cell transplantation, and active malignant disease at baseline, to receive isavuconazonium sulfate 372 mg (prodrug; equivalent to 200 mg isavuconazole; intravenously three times a day on days 1 and 2, then either intravenously or orally once daily) or voriconazole (6 mg/kg intravenously twice daily on day 1, 4 mg/kg intravenously twice daily on day 2, then intravenously 4 mg/kg twice daily or orally 200 mg twice daily from day 3 onwards). We tested non-inferiority of the primary efficacy endpoint of all-cause mortality from first dose of study drug to day 42 in patients who received at least one dose of the study drug (intention-to-treat [ITT] population) using a 10% non-inferiority margin. Safety was assessed in patients who received the first dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00412893. 527 adult patients were randomly assigned (258 received study medication per group) between March 7, 2007, and March 28, 2013. All-cause mortality from first dose of study drug to day 42 for the ITT population was 19% with isavuconazole (48 patients) and 20% with voriconazole (52 patients), with an adjusted treatment difference of -1·0% (95% CI -7·8 to 5·7). Because the upper bound of the 95% CI (5·7%) did not exceed 10%, non-inferiority was shown. Most patients (247 [96%] receiving isavuconazole and 255 [98%] receiving voriconazole) had treatment-emergent adverse events (p=0·122); the most common were gastrointestinal disorders (174 [68%] vs 180 [69%]) and infections and infestations (152 [59%] vs 158 [61%]). Proportions of patients with treatment-emergent adverse events by system organ class were similar overall. However, isavuconazole-treated patients had a lower frequency of hepatobiliary disorders (23 [9%] vs 42 [16%]; p=0·016), eye disorders (39 [15%] vs 69 [27%]; p=0·002), and skin or subcutaneous tissue disorders (86 [33%] vs 110 [42%]; p=0·037). Drug-related adverse events were reported in 109 (42%) patients receiving isavuconazole and 155 (60%) receiving voriconazole (p<0·001). Isavuconazole was non-inferior to voriconazole for the primary treatment of suspected invasive mould disease. Isavuconazole was well tolerated compared with voriconazole, with fewer study-drug-related adverse events. Our results support the use of isavuconazole for the primary treatment of patients with invasive mould disease. Astellas Pharma Global Development, Basilea Pharmaceutica International.

Optimizing Electronic Capture of Clinical Outcome Assessment Data in Clinical Trials: The Case of Patient-Reported Endpoints.

For a number of compelling scientific, operational, and regulatory reasons, the use of electronic data capture is becoming the preferred means of collecting clinical outcome assessment (eg, patient-reported outcome [PRO]) data in clinical trials. Electronic PRO (ePRO) data collection leverages screen-based technologies (eg, handheld devices, tablet computers, and web-based systems) and telephone-based (eg, interactive voice response) systems. Data collection is routinely either site based (ie, clinical study site) or field based (eg, subject's home, school, or workplace). While tablet computers are often used for site-based PRO data collection, handheld devices have become the mainstay for ePRO data capture in field-based settings. The data collection devices are usually provisioned to the sites or subjects by an ePRO system provider contracted by the clinical trial sponsor. With site-based data collection, study staff are responsible for ensuring subject compliance with the protocol-driven data collection procedures, whereas with field-based data collection, the subject is responsible for compliance with the data entry requirements and sites are accountable for remotely monitoring the data for compliance. In addition to site and subject compliance issues, technology-related factors must be anticipated in order to adhere to the electronic PRO data collection plan. The objective of this paper is to describe study site-, subject-, and technology-related factors that may lead to deviations from the planned electronic collection of PRO data (eg, defaulting to paper-based data collection) and to provide recommendations aimed at preventing potential problems or quickly resolving problems once they occur.

Etirinotecan pegol (NKTR-102) versus treatment of physician's choice in women with advanced breast cancer previously treated with an anthracycline, a taxane, and capecitabine (BEACON): a randomised, open-label, multicentre, phase 3 trial

New options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor that prolongs exposure to, but reduces the toxicity of, SN38 (the active metabolite of irinotecan). We assessed whether etirinotecan pegol is superior to currently available treatments for patients with previously treated, locally recurrent or metastatic breast cancer. In this open-label, multicentre, randomised phase 3 study (BEACON; BrEAst Cancer Outcomes with NKTR-102), conducted at 135 sites in 11 countries, patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline, a taxane, and capecitabine (and two to five previous regimens for advanced disease) were randomly assigned (1:1) centrally via an interactive response system to etirinotecan pegol (145 mg/m(2) as a 90-min intravenous infusion every 3 weeks) or single-drug treatment of physician's choice. Patients with stable brain metastases and an Eastern Cooperative Oncology Group performance status of 0-1 were eligible. Randomisation was stratified with a permuted block scheme by region, previous eribulin, and receptor status. After randomisation, patients and investigators were aware of treatment assignments. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01492101. Between Dec 19, 2011, and Aug 20, 2013, 852 patients were randomly assigned; 429 to etirinotecan pegol and 423 to treatment of physician's choice. There was no significant difference in overall survival between groups (median 12·4 months [95% CI 11·0-13·6] for the etirinotecan pegol group vs 10·3 months [9·0-11·3] for the treatment of physician's choice group; hazard ratio 0·87 [95% CI 0·75-1·02]; p=0·084). The safety population includes the 831 patients who received at least one dose of assigned treatment (425 assigned to etirinotecan pegol and 406 to treatment of physician's choice). Serious adverse events were recorded for 128 (30%) patients treated with etirinotecan pegol and 129 (32%) treated with treatment of physician's choice. Fewer patients in the etirinotecan pegol group had grade 3 or worse toxicity than those in the treatment of physician's choice group (204 [48%] vs 256 [63%]; p<0·0001). The most common grade 3 or worse adverse events were diarrhoea (41 [10%] in the experimental group vs five [1%] in the control group), neutropenia (41 [10%] vs 125 [31%]), and peripheral neuropathy (two [<1%] vs 15 [4%]). Three patients in the etirinotecan pegol group died of treatment-related adverse events (pneumonia, myelodysplastic syndrome, and acute renal failure) and two in the treatment of physician's choice group (neutropenic sepsis and septic shock). This trial did not demonstrate an improvement in overall survival for etirinotecan pegol compared to treatment of physician's choice in patients with heavily pre-treated advanced breast cancer. The toxicity profile noted in the etirinotecan pegol group differed from that in the control group. In view of the frequency of cross-resistance and overlapping toxicities noted with many available drugs and the need for effective drugs in highly refractory disease, etirinotecan pegol may warrant further research in some subgroups of patients. Nektar Therapeutics.

Evaluation of interactive teaching for undergraduate medical students using a classroom interactive response system in India

BackgroundThe classical didactic lecture has been the cornerstone of the theoretical undergraduate medical education. Their efficacy however reduces due to reduced interaction and short attention span of the students. It is hypothesized that the interactive response pad obviates some of these drawbacks. The aim of this study was to evaluate the effectiveness of an interactive response system by comparing it with conventional classroom teaching. MethodsA prospective comparative longitudinal study was conducted on 192 students who were exposed to either conventional or interactive teaching over 20 classes. Pre-test, Post-test and retentions test (post 8–12 weeks) scores were collated and statistically analysed. An independent observer measured number of student interactions in each class. ResultsPre-test scores from both groups were similar (p = 0.71). There was significant improvement in both post test scores when compared to pre-test scores in either method (p < 0.001). The interactive post-test score was better than conventional post test score (p < 0.001) by 8–10% (95% CI-difference of means – 8.2%–9.24%–10.3%). The interactive retention test score was better than conventional retention test score (p < 0.001) by 15–18% (95% CI-difference of means – 15.0%–16.64%–18.2%). There were 51 participative events in the interactive group vs 25 in the conventional group. ConclusionsThe Interactive Response Pad method was efficacious in teaching. Students taught with the interactive method were likely to score 8–10% higher (statistically significant) in the immediate post class time and 15–18% higher (statistically significant) after 8–12 weeks. The number of student–teacher interactions increases when using the interactive response pads.

Constructing a Multimedia Mobile Classroom Using a Novel Feedback System

In the conventional classroom, many obstacles hinder interaction between an instructor and students, such as limited class hours, fixed seating, and inadequate time for meetings after class. This work develops a novel multimedia mobile classroom feedback system (MMCFS) that instantly displays students' responses, such as class-related questions or answers to questions on a quiz, on the instructor's computer. This system reinforces interaction between instructors and students and improves learning efficiency. Its features are as follows: 1) automatic attendance checking; 2) in-class real-time evaluation; 3) improved willingness of students to raise questions; 4) immediate grade enquiring; 5) cross-platform functionality; 6) a virtual mobile classroom; 7) data integrity; 8) low construction cost; 9) group learning; and 10) learning process recording. This system uses a client-server and three-tiered architecture models as its framework. When a class is in progress, the instructor only requires a notebook computer with a web browser, while students need a mobile phone or equivalent mobile devices with built-in Java Platform, Micro Edition (J2ME) and wireless support. A web server and the rear-end database can be located outside the classroom when network connections are available. Attendance checking, conducting quizzes, instant question inquiring, and grade inquiring are the four primary functions of the system. A questionnaire is applied to evaluate system's interactivity, mobility, and functionality. The 105 subjects comprised two classes of undergraduate students. The questionnaire addresses interactivity, mobility, and functionality. Its purpose was to compare the proposed system and the interactive response system (IRS). Experimental results show that the proposed system has superior interactivity, mobility, and functionality.

Safety, tolerability, and efficacy of PBT2 in Huntington's disease: a phase 2, randomised, double-blind, placebo-controlled trial

PBT2 is a metal protein-attenuating compound that might reduce metal-induced aggregation of mutant huntingtin and has prolonged survival in a mouse model of Huntington's disease. We aimed to assess the safety, tolerability, and efficacy of PBT2 in patients with Huntington's disease. In this 26-week, randomised, double-blind, placebo-controlled trial, adults (≥25 years old) with early-stage to mid-stage Huntington's disease were randomly assigned (1:1:1) by a centralised interactive response system to once daily PBT2 250 mg, PBT2 100 mg, or placebo. Randomisation was stratified by site with a block size of three. Participants, carers, the steering committee, site investigators, study staff, and the study sponsor were masked to treatment assignment. Primary endpoints were safety and tolerability. The safety population consisted of all participants who were randomly assigned and had at least one dose of study drug. The principal secondary endpoint was cognition, measured by the change from baseline to week 26 in the main composite Z score of five cognitive tests (Category Fluency Test, Trail Making Test Part B, Map Search, Symbol Digit Modalities Test, and Stroop Word Reading Test) and scores on eight individual cognitive tests (the five aforementioned plus the Trail Making Test Part A, Montreal Cognitive Assessment, and the Speeded Tapping Test). The intention-to-treat population comprised participants who were randomly assigned and had at least one efficacy assessment after administration of study drug. This trial is registered with ClinicalTrials.gov, NCT01590888. Between April 18, 2012, and Dec 14, 2012, 109 participants were randomly assigned to PBT2 250 mg (n=36), PBT2 100 mg (n=38), or placebo (n=35) at 19 research centres in Australia and the USA. 32 (89%) individuals on PBT2 250 mg, 38 (100%) on PBT2 100 mg, and 34 (97%) on placebo completed the study. Six serious adverse events (acute coronary syndrome, major depression, pneumonia, suicide attempt, viral infection, and worsening of Huntington's disease) occurred in five participants in the PBT2 250 mg group, three (fall with subdural haematoma, suicide attempt, and hospital admission for stabilisation of Huntington's disease) occurred in two participants in the PBT2 100 mg group, and one (increasing aggression) occurred in a participant in the placebo group. The site investigators deemed all, except the worsening of Huntington's disease, as unrelated to study drug. 32 (89%) participants on PBT2 250 mg, 30 (79%) on PBT2 100 mg, and 28 (80%) on placebo had at least one adverse event. Compared with placebo, neither PBT2 100 mg (least-squares mean 0·02, 95% CI -0·10 to 0·14; p=0·772) nor PBT2 250 mg (0·07, -0·05 to 0·20; p=0·240) significantly improved the main composite cognition Z score between baseline and 26 weeks. Compared with placebo, the Trail Making Test Part B score was improved between baseline and 26 weeks in the PBT2 250 mg group (17·65 s, 0·65-34·65; p=0·042) but not in the 100 mg group (0·79 s improvement, -15·75 to 17·32; p=0·925); neither dose significantly improved cognition on the other tests. PBT2 was generally safe and well tolerated in patients with Huntington's disease. The potential benefit on executive function will need to be confirmed in a larger study. Prana Biotechnology Limited.

Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study

Persistent eosinophilic airway inflammation in asthma increases the risk of exacerbations. In a phase 2b dose-ranging study, we aimed to assess the efficacy and safety of benralizumab, an anti-interleukin 5 receptor α monoclonal antibody that depletes blood and airway eosinophils, in adults with uncontrolled eosinophilic asthma. We did a randomised, controlled, double-blind, dose-ranging phase 2b study. Eligible participants were adults aged 18-75 years with uncontrolled asthma using medium-dose or high-dose inhaled corticosteroids and longacting β agonists, with two to six exacerbations in the past year. Current or former smokers were excluded. We used the ELEN index (an algorithm to predict elevated sputum eosinophils) or baseline fraction of exhaled nitric oxide to stratify patients by eosinophilic status, and with an interactive web-voice response system randomly assigned eosinophilic individuals in a 1:1:1:1 ratio to receive placebo, 2 mg benralizumab, 20 mg benralizumab, or 100 mg benralizumab, and non-eosinophilic individuals in a 1:1 ratio to receive placebo or 100 mg benralizumab. Study drugs were given as two subcutaneous injections every 4 weeks for the first three doses, then every 8 weeks, for 1 year. Patients, treating physicians, and study investigators were masked to treatment allocation. The primary endpoint was annual exacerbation rate in eosinophilic individuals after 1 year of follow-up. Analysis was by modified intention to treat. This study was designed with a two-sided α of 0·2 and powered at 78% for the primary outcome in the eosinophilic population. This study is registered with ClinicalTrials.gov, number NCT01238861. Between Jan 3, 2011, and March 6, 2012, we randomly assigned 324 eosinophilic individuals to placebo (n=80) or benralizumab 2 mg dose (n=81), 20 mg dose, (n=81), or 100 mg dose (n=82), and 285 non-eosinophilic individuals to 100 mg benralizumab (n=142, 140 included in analysis) or placebo (n=143, 142 included in analysis). In eosinophilic individuals, benralizumab reduced exacerbation rates compared with placebo in the 100 mg group (0·34 vs 0·57, reduction 41%, 80% CI 11 to 60, p=0·096) but not in the 2 mg group (0·65 vs 0·57, difference -9%, 80% CI -59 to 26, p=0·781) or the 20 mg group (0·37 vs 0·57, reduction 36%, 80% CI 3 to 58, p=0·173). In patients with a baseline blood eosinophil cutoff of at least 300 cells per μL, exacerbation rates in the benralizumab 20 mg group (n=70) and 100 mg group (n=97) were lower than in the placebo group (n=83; 0·30 vs 0·68, reduction 57%, 80% CI 33 to 72, p=0·015 for 20 mg dose; 0·38 vs 0·68, difference 43%, 80% CI 18 to 60, p=0·049 for 100 mg dose). Our findings suggested that benralizumab 20 mg and 100 mg resided at the dose-response plateau. Treatment-emergent adverse events occurred in 277 (72%) of 385 participants receiving any benralizumab dose compared with 143 (65%) of 221 receiving placebo. Nasopharyngitis (44 [11%] patients receiving benralizumab vs 13 [6%] patients receiving placebo) and injection site reactions (60 [16%] vs eight [4%]) occurred more frequently with benralizumab than with placebo. Benralizumab at 20 mg and 100 mg doses seemed to reduce asthma exacerbations in adults with uncontrolled eosinophilic asthma and baseline blood eosinophils of at least 300 cells per μL, possibly due to targeting of the interleukin 5 receptor rather than interleukin 5 ligand. Further investigation of benralizumab treatment in phase 3 studies is warranted. MedImmune.

Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial

Many patients with acromegaly do not achieve biochemical control despite receiving high doses of the first-generation somatostatin analogues octreotide or lanreotide. In the PAOLA trial, we aimed to assess the efficacy and safety of two different doses of the somatostatin analogue pasireotide long-acting release compared with active control (octreotide or lanreotide) in patients with inadequately controlled acromegaly. In a multicentre, randomised, phase 3 trial, we enrolled eligible patients aged 18 years or older with acromegaly who were inadequately controlled (5-point, 2 h mean growth hormone concentration >2·5 μg/L and insulin-like growth factor 1 [IGF-1] concentration >1·3 times the upper normal limit) and had received 30 mg octreotide long-acting repeatable or 120 mg lanreotide (Somatuline Autogel; Ipsen, UK) as monotherapy for 6 months or longer. We randomly assigned patients in a 1:1:1 ratio with an interactive voice-web response system to receive 40 mg pasireotide long-acting release once every 28 days for 24 weeks, 60 mg pasireotide long-acting release once every 28 days for 24 weeks, or continued treatment with octreotide or lanreotide (active control). Patients were stratified according to previous treatment (octreotide or lanreotide) and growth hormone concentrations at screening (2·5-10 μg/L and >10 μg/L). Patients and study investigators were not masked to study drug assignment but were masked to pasireotide dose allocation. The primary endpoint was number of patients achieving biochemical control, defined as mean growth hormone concentration less than 2·5 μg/L and normalised IGF-1 concentration. Efficacy analyses were based on intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01137682. Between Dec 17, 2010, and Aug 6, 2012, 198 patients were enrolled and randomly assigned to pasireotide 40 mg (n=65), pasireotide 60 mg (n=65), or active control (n=68) groups. At 24 weeks, ten (15%) patients in the pasireotide 40 mg group and 13 (20%) patients in the pasireotide 60 mg group achieved biochemical control, compared with no patients in the active control group (absolute difference from control group 15·4%, 95% CI 7·6-26·5, p=0·0006 for pasireotide 40 mg group, 20·0%, 11·1-31·8, p<0·0001 for pasireotide 60 mg group). The most common adverse events were hyperglycaemia (21 [33%] for treatment with 40 mg pasireotide, 19 [31%] with 60 mg pasireotide, and nine [14%] with active control), diabetes (13 [21%], 16 [26%], and five [8%]), and diarrhoea (ten [16%], 12 [19%], and three [5%]); most were grade 1 or 2 in severity. Serious adverse events were reported in six (10%) patients in the pasireotide 40 mg group, two (3%) in the pasireotide 60 mg group, and three (5%) in the active control group. Pasireotide provides superior efficacy compared with continued treatment with octreotide or lanreotide, and could become the new standard pituitary-directed treatment in patients with acromegaly who are inadequately controlled using first-generation somatostatin analogues. Novartis Pharma AG. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation.

Using Clickers to Enhance Student Learning in Mathematics

The purpose of this study was to determine how to integrate technology into mathematics classes using clickers in the high school setting. The ability to integrate technology into instruction is a current requirement for mathematics teachers in the United States; however, students have been traditionally taught to solve equations using pencils and paper. In addition to leveraging an understanding of the impact that using interactive Student Response System (SRS) have in helping students learn mathematics, this study also aimed to examine its effect on Special Education and English Language Learner (ELL) student learning outcome. 47 high school students who were enrolled in Geometry class were selected to participate in this study. Pre-tests and post-tests were conducted with both the trial and contrast groups of the study. The trial group contained all of the students in one period of Geometry class in which clickers were integrated into the classroom instruction. The contrast group contained all of the students in the same subject as the trial group but did not use clickers. The key elements of the study included having the technology available to the trial group throughout the entire learning process, having consistent participant groups, and having equal access to the materials presented to both groups. Based on the summative and informal assessment test scores, completion rates of class work and the teacher’s observations, the research team concluded that for the students in the trial group, the use of clickers did improve the student learning outcome and class participation in mathematics compared to the contrast group. The test scores of Special Education and ELL students in both groups were also assessed for the clickers’ impact on these students’ learning. The results showed that the use of clickers had a positive impact as these students gained better test scores. These results align with the current research regarding technology integration in mathematics. Factors affecting the effective integration of technology such as teachers’ use of clickers, types of questions teachers should ask and depth of technology integration will be discussed.