Trial Coordinators Research Articles

Abstract OT2-01-08: POSITIVE: A study evaluating pregnancy and disease outcome and safety of interrupting endocrine therapy for young women with endocrine responsive breast cancer who desire pregnancy (IBCSG 48-14/BIG 8-13)

Abstract Background Young breast cancer (BC) patients often face the disease before completing their family planning. The best available retrospective evidence suggests that pregnancy after BC does not negatively impact disease outcome in patients with endocrine sensitive BC and is safe for the offspring. However, given the need for prolonged adjuvant endocrine therapy for 5-10 years, it is not feasible to wait until completion of therapy in most of these women and thus there is a need to explore the safety of temporary interruption of endocrine therapy to allow pregnancy. To date, no definitive prospective study has been conducted in young women desiring future pregnancy. Trial Design Young patients with endocrine responsive early BC and pregnancy desire will interrupt endocrine treatment for up to 2 yrs to attempt pregnancy. As resumption of menses and conception depends on many factors, e.g. patient's age and adjuvant treatment received, the 2-yr interruption period is approximate, intended to include treatment wash-out (3 mos) conception (∼3-6 mos), delivery (∼9 mos), breast feeding (∼6 mos). Patients will be strongly advised to resume ET as soon as pregnancy attempts are concluded, and to complete 5-10 yrs ET at the local investigator discretion. Major Eligibility Criteria -Histologically-proven stage I-III endocrine-responsive BC. -Age ≥ 18 and ≤ 42 years at enrollment. -Adjuvant endocrine therapy (SERM alone, GnRH analogue plus SERM or AI) for ≥18 months but ≤30 months, stopped within 1 month prior to enrollment. -Patient wishes to become pregnant. -Premenopausal status at BC diagnosis. Specific Aim To assess the risk of BC relapse associated with temporary interruption of ET to permit pregnancy and to evaluate pregnancy success. Statistical Methods A true risk of BC recurrence of 2% per year is assumed for patients who do not interrupt endocrine treatment. With 500 patients enrolled in 4.0 yrs and an additional 1.6 yrs of follow up, there will be approximately 1600 patient-yrs of follow up and a median follow up of approximately 3 yrs at the time of the primary analysis, anticipated to occur 5.6 yrs after enrollment of the first patient. If the true risk of BC recurrence is 2% per yr, we anticipate 31 BC recurrences and an estimated 3-yr breast cancer free interval (BCFI) failure of 5.6% (95% CI 4.0% to 7.9%). Translational Research will investigate different ovarian function parameters; uterine evaluation; and circulating tumor DNA. FFPE tissue of the primary tumor will be collected to integrate different parameters related to biology of BC arising in young women. All material will be banked centrally. Psycho-oncological Companion Study on fertility concerns, psychological well-being and decisional conflicts is mandatory in the United States and open to interested centers elsewhere. Accrual: Target: 500; Actual: 4 (31 May 2015) Contact Information POSITIVE is conducted and sponsored by the International Breast Cancer Study Group. Alliance for Clinical Trials in Oncology is US sponsor for NCTN network. Contact Trial Coordinators at ibcsg48_positive@fstrf.org. Citation Format: Pagani O, Partridge A, Azim Jr HA, Peccatori FA, Ruggeri M, Sun Z. POSITIVE: A study evaluating pregnancy and disease outcome and safety of interrupting endocrine therapy for young women with endocrine responsive breast cancer who desire pregnancy (IBCSG 48-14/BIG 8-13). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-01-08.

Videoconferencing for site initiations in clinical studies: Mixed methods evaluation of usability, acceptability, and impact on recruitment

ABSTRACTBackground: A critical issue for multicentre clinical studies is conducting site initiations, ensuring sites are trained in study procedures and comply with relevant governance requirements before they begin recruiting patients. How technology can support site initiations has not previously been explored. Objective: This study sought to evaluate use of off-the-shelf web-based videoconferencing to deliver site initiations for a large national multicentre study. Methods: Participants in the initiations, including podiatrists, diabetologists, trial coordinators, and research nurses, completed an online questionnaire based on the System Usability Scale (SUS) (N = 15). This was followed by semi-structured interviews, with a consultant diabetologist, a trial coordinator, and three research nurses, exploring perceived benefits and limitations of videoconferencing. Results: The mean SUS score for the videoconferencing platform was 87.2 (SD = 13.7), suggesting a good level of usability. Interview participants perceived initiations delivered by videoconferencing as being more interactive and easier to follow than those delivered by teleconference. In comparison to face-to-face initiations, videoconferencing takes less time, easily fitting in with the work of staff at the local sites. Perceptions of impact on communication varied according to the hardware used. Conclusion: Off-the-shelf videoconferencing is a viable alternative to face-to-face site initiations and confers advantages over teleconferencing.

Biosimilar Trials in Developing Countries: Detecting and Eradicating Barriers to Patient Recruitment

Introduction:Biologic drugs are high-cost technologies that represent a challenge to the economic management of healthcare systems. Biosimilar drugs (BSD) are designed to be highly similar, in terms of safety, purity and efficacy to an existing licensed reference biologic drug (RBD). Furthermore, the use of BSD can reduce up to 35% of the cost of treatment compared to RBD, so the approval of BSD worldwide will strongly influence prescriptions, particularly in emerging markets. Previous studies have identified challenges regarding BSD prescription and patient recruitment in developing countries. Our goal was to identify potential barriers to patient accrual during biosimilar clinical trials (CT) in Brazil and propose solutions to enhance the process.Methods: A panel of specialists comprising investigators and site coordinators from 25 research sites in Brazil was invited to discuss recruitment barriers and related challenges in biosimilar trials. Participants were required to debate three open-ended questions. First: considering the biosimilar trial on rituximab, which are the main barriers/challenges to patient recruitment? Second: which aspects were determinant to an unsuccessful recruitment and why. Third: do the previous conclusions express my personal belief regarding the causes of the unsuccessful recruitment? Through a series of dynamic activities, problems were identified and collective solutions were proposed.Results: A group of 16 investigators, 23 clinical trial coordinators and 14 members of the sponsors' staff participated in the meeting. Investigators had a mean experience of 20 years of clinical practice and 15 years on clinical trial conduction. Criteria for unsuccessful recruitment and investigators' beliefs regarding the causes of low recruitment were consistent among the answers. Barriers, perceptions and possible solutions to improve patient recruitment in BSD trials are depicted on Figure 1. The main barriers for recruitment were distributed among different domains, including the biosimilar drug itself, limitations on the public healthcare system (PS) and established perceptions (status quo), among others. According to the panel the main issues are lack of information regarding BSD among patients and physicians and the negative attitude toward CT participation among patients. The lack of physicians' and patients' awareness regarding biosimilar development pathways was emphasized by all the panelists. Also, logistics played and important role in limiting patients' participation.Conclusions: The lack of information among patients and investigators was the main challenge regarding accrual in BSD trials, leading to negative attitudes towards CT in general by both patients and physicians. Providing information on BSD and CT to all players, as well as to society in general in fundamental in enhancing patient accrual and the comprehension on the benefits of participating in clinical studies. [Display omitted] DisclosuresCastilho:Libbs Farmacêutica: Employment. Almeida:Libbs Farmacêutica: Employment. Miyashiro:Libbs Farmacêutica: Employment.

Trials within trials of interventions to improve recruitment and retention: the experience of York Trials Unit

Results Of the 20 trials undertaken 8 were of interventions to enhance recruitment and 12 were of attrition reduction. For the recruitment strategies different information methods (6) were the most common with trial co-ordinator visit and different envelope colours being the other interventions. For the 12 attrition prevention trials 4 were of electronic reminders, 2 of newsletters, 4 were of post-it notes, 1 was of a free pen, and 1 was of offer of trial results. Currently, we have found that electronic reminders and participant newsletters for retention are effective and these are now being routinely included in our trials. Most of our trials were ‘unfunded’ and consequently the interventions tended to be inexpensive. The benefits of doing embedded trials include: improved knowledge and early publications for the trial co-ordinators. Some Chief Investigators can be hostile viewing them as a ‘nuisance’ but with discussion most reasonable investigators can be persuaded. Conclusion If all trials units did two ‘trials within a trial’ per year then the evidence base would be doubled within a year.

A better participant experience using sms for real time data collection

High quality, error free and complete data is the Holy Grail for healthcare researchers. Using SMS, researchers can build a data collection pathway which, when integrated with web technologies, can provide a dynamic data collection experience for each participant. It can highlight erroneous responses and missing data for correction by the participant and provide instant data delivery to the study team. The system can incorporate customisable reminders to improve overall data quality and completeness. By using a web front end, researchers can build a dynamic workflow of questions, presenting the next item based on previous responses, skipping to the next appropriate question or to the end if appropriate. This interactive approach reduces participants’ burden and gives a more seamless data collection experience. This data collection mechanism allows for responses to be available immediately for the study to review. The system provides a full audit trail of interactions with the participant. A dashboard enables the trial co-ordinator or data manager to visualise all the data collection points, identify non respondents and aid data cleaning in a timely fashion. Missing data or missed follow ups can then be followed up by a timely phone call and the data entered directly into the system. SMS data collection is being used in the SCOPiC Trial (HTA 12/201/09) of stratified care in Sciatica. It is proving to be a great contribution to efficient trial conduct. Testing with a user stakeholder group generated good, positive feedback.

Textual inference for eligibility criteria resolution in clinical trials

Clinical trials are essential for determining whether new interventions are effective. In order to determine the eligibility of patients to enroll into these trials, clinical trial coordinators often perform a manual review of clinical notes in the electronic health record of patients. This is a very time-consuming and exhausting task. Efforts in this process can be expedited if these coordinators are directed toward specific parts of the text that are relevant for eligibility determination. In this study, we describe the creation of a dataset that can be used to evaluate automated methods capable of identifying sentences in a note that are relevant for screening a patient’s eligibility in clinical trials. Using this dataset, we also present results for four simple methods in natural language processing that can be used to automate this task. We found that this is a challenging task (maximum F-score=26.25), but it is a promising direction for further research.

P200 A facility to enable high-quality, time-efficient evaluations of diagnostics for stis

<h3>Background/introduction</h3> Control of STIs is challenged by inadequate access to prompt diagnosis and treatment for patients and partners. Novel point-of-care diagnostics have real potential to address some of these challenges but their robust evaluation, and hence utility, is hampered by the ethics and regulatory landscape that confronts industry and academia. <h3>Aim(s)/objectives</h3> To develop a diagnostics and clinical facility to deliver high-quality, time-efficient diagnostic evaluations for STIs. <h3>Methods</h3> A multi-institutional and disciplinary group (<i>e</i>STI²) including clinical, public health and social scientists, microbiologists, clinicians, trial coordinators, and North American and European regulatory expertise was established. An ‘overarching’ ethics, favourable costing, and regulatory framework was carefully developed and put in place to enable any new diagnostic evaluation involving residual and/or additional-to-routine patient-consented samples to start promptly without requiring lengthy ethics applications. Strong working relationships with <i>multiple</i> GUM clinics were developed to overcome the potential for clinic fatigue, and Good Clinical Laboratory Practice Standard Operating Procedures were enabled. <h3>Results</h3> Since February 2012, the network has conducted several evaluations with both academia and industry, spanning initial ‘proof of concept’ projects using residual samples, multi-site diagnostic evaluations involving &gt;800 additional-to-routine patient samples completed in four months, and service evaluations of CE-marked assays. A diagnostic evaluation to support an application for regulatory approval will be taking place in 2015. <h3>Discussion/conclusion</h3> The development of a diagnostic facility for STIs that fast-tracks high quality diagnostic evaluations is feasible and has potential for supporting promising diagnostic technologies towards NHS adoption.

P199 Neoadjuvant systemic therapy for breast cancer: a survey of Australian and New Zealand specialists

P199 Neoadjuvant systemic therapy for breast cancer: a survey of Australian and New Zealand specialists N. Zdenkowski *, P. Butow, G.B. Mann, S. Fewster, C. Beckmore, R. Isaacs, F.M. Boyle. Trials Coordination Department, Australia and New Zealand Breast Cancer Trials Group, Waratah, Australia, University of Sydney, Sydney, Australia, University of Melbourne, Melbourne, Australia, MidCentral Regional Cancer Treatment Service, Palmerston North, New Zealand

Cancer patients' acceptability of incorporating an epidemiology questionnaire within a clinical trial.

Understanding the influence or impact of epidemiological factors on cancer outcomes in clinical trials can broaden our knowledge of disease, trial populations and therapeutic effects thus leading to improved patient care. However, there is a lack of data on cancer patients' compliance with an epidemiology questionnaire in the context of a clinical trial. Cancer patients were provided with a hypothetical scenario and surveyed regarding their willingness and preferences to complete an epidemiology questionnaire if incorporated into a cancer therapy trial. Patient compliance with completing a voluntary epidemiology questionnaire and trial coordinators perceptions therein were separately determined in the NCIC Clinical Trials Group HN.6 clinical trial, an ongoing randomized phase III trial comparing two first-line treatment regimens in patients with locoregionally advanced head and neck cancer. Of 617 cancer patients from community, academic and tertiary cancer centres, the majority were willing to complete an epidemiology questionnaire either unconditionally (45%), or provided it did not inconvenience them (31%); 4% would refuse. Patients preferred shorter questionnaires of 30-50 questions requiring 10-20 min to complete, administered over 1-3 sessions. Patients were less willing, but still compliant, to answer questions relating to sexual history (71%) and annual household income (66%) relative to other questions (>90%). Eighteen percent thought that the questionnaire should be mandatory, with 31% believing that they may benefit personally from such research. In the HN.6 trial, compliance averaged 94.8% per question. Cancer patients are very willing to complete epidemiology questions in clinical trials.

The impact of registration of clinical trials units: the UK experience.

Over the last decade, the United Kingdom has invested significant resources in its clinical trial infrastructure. Clinical research networks have been formed, and some general oversight functions for clinical research have been centralised. One of the initiatives is a registration programme for Clinical Trials Units involved in the coordination of clinical trials. An international review panel of experts in clinical trials has been convened for three reviews over time, reviewing applications from Clinical Trials Units in the United Kingdom. The process benefited from earlier work by the National Cancer Research Institute that developed accreditation procedures for trials units involved in cancer trials. This article describes the experience with the three reviews of UK Clinical Trials Units which submitted applications. This article describes the evolution and impact of this registration process from the perspective of the current international review panel members, some of whom have served on all reviews, including two done by the National Cancer Research Institute. Applications for registration were invited from all active, non-commercial Clinical Trials Units in the United Kingdom. The invitations were issued in 2007, 2009 and 2012, and applicants were asked to describe their expertise and staffing levels in specific areas. To ensure that the reviews were as objective as possible, a description of expected core competencies was developed and applicants were asked to document their compliance with meeting these. The review panel assessed each Clinical Trials Unit against the competencies. The Clinical Trials Unit registration process has evolved over time with each successive review benefiting from what was learned in earlier ones. The review panel has seen positive changes over time, including an increase in the number of units applying, a greater awareness on the part of host institutions about the trials activity within their organisations, more widespread development of Standard Operating Procedures in key areas and improvements in information technology systems used to host clinical trials databases. Key funders are awarding funds only to registered units, and host institutions are implementing procedures and structures to ensure improved communication between all parties involved in trials within their organisation. The registration process developed in the United Kingdom has helped to ensure that trials units in the United Kingdom are compliant with regulatory standards and can meet acceptable standards of quality in their conduct of clinical trials. There is an increased awareness among funders, host institutions and Clinical Trials Units themselves of the required competencies, and communication between all those involved in trials has increased. The registration process is an effective and financially viable way of ensuring that objective standards are met at a national level.

A pilot randomized controlled trial of a post-discharge program to support emerging adults with type 1 diabetes mellitus transition from pediatric to adult care.

There is a paucity of randomized controlled trials (RCT) examining transition from pediatric to adult care in type 1 diabetes mellitus (T1DM). This study aimed to determine if transition in T1DM is more effective with a comprehensive transition program (CTP) compared with standard clinical practice (SCP). This RCT recruited as young people left pediatric diabetes services. The trial co-ordinator provided CTP participants with standardized telephone communication support at week 1, and 3, 6, and 12 months post-discharge from pediatric care. SCP participants were briefly contacted at 6 and 12 months post-discharge to confirm transfer status; they received no other post-discharge contact as per usual practice. At 12 months, the primary outcomes were engagement and retention in the adult service and secondary outcomes included hemoglobin A1c (HbA1c), diabetes-related hospitalizations, microvascular complication appearance, and global self-worth. Most CTP participants (11/14) and all SCP (12/12) participants (P = 0.2) transferred to an adult diabetes service; the median time to transfer was 14-15 wk. Overall, participants' frequency of adult diabetes service visits was sub-optimal but their retention in adult care was high. The only group difference was a higher HbA1c at baseline and follow-up in the CTP group. However, a general linear model found that follow-up HbA1c increased by 1.2% for each percentage increase in baseline HbA1c [95% confidence interval (0.4, 1.9; P = 0.01)], independent of treatment group. Despite the challenges in recruiting adequate numbers, these findings provide valuable insights for future T1DM transition RCTs that are needed to build a more solid evidence-base in this field.

Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial

Most patients with extensive stage small-cell lung cancer (ES-SCLC) who undergo chemotherapy, and prophylactic cranial irradiation, have persistent intrathoracic disease. We assessed thoracic radiotherapy for treatment of this patient group. We did this phase 3 randomised controlled trial at 42 hospitals: 16 in Netherlands, 22 in the UK, three in Norway, and one in Belgium. We enrolled patients with WHO performance score 0-2 and confirmed ES-SCLC who responded to chemotherapy. They were randomly assigned (1:1) to receive either thoracic radiotherapy (30 Gy in ten fractions) or no thoracic radiotherapy. All underwent prophylactic cranial irradiation. The primary endpoint was overall survival at 1 year in the intention-to-treat population. Secondary endpoints included progression-free survival. This study is registered with the Nederlands Trial Register, number NTR1527. We randomly assigned 498 patients between Feb 18, 2009, and Dec 21, 2012. Three withdrew informed consent, leaving 247 patients in the thoracic radiotherapy group and 248 in the control group. Mean interval between diagnosis and randomisation was 17 weeks. Median follow-up was 24 months. Overall survival at 1 year was not significantly different between groups: 33% (95% CI 27-39) for the thoracic radiotherapy group versus 28% (95% CI 22-34) for the control group (hazard ratio [HR] 0.84, 95% CI 0.69-1.01; p=0.066). However, in a secondary analysis, 2-year overall survival was 13% (95% CI 9-19) versus 3% (95% CI 2-8; p=0.004). Progression was less likely in the thoracic radiotherapy group than in the control group (HR 0.73, 95% CI 0.61-0.87; p=0.001). At 6 months, progression-free survival was 24% (95% CI 19-30) versus 7% (95% CI 4-11; p=0.001). We recorded no severe toxic effects. The most common grade 3 or higher toxic effects were fatigue (11 vs 9) and dyspnoea (three vs four). Thoracic radiotherapy in addition to prophylactic cranial irradiation should be considered for all patients with ES-SCLC who respond to chemotherapy. Dutch Cancer Society (CKTO), Dutch Lung Cancer Research Group, Cancer Research UK, Manchester Academic Health Science Centre Trials Coordination Unit, and the UK National Cancer Research Network.

Site-specific predictors of successful recruitment to a perinatal clinical trial.

With large collaborations needed to reach sample size requirements for relatively rare events, a major challenge for multi-centre clinical trials is efficiency of recruitment at individual sites. We used data from an international, multi-centre, randomised trial of preterm prelabour rupture of membranes to assess any impact on recruitment following the introduction of a new Clinical Trial Agreement and to identify site-specific predictors of recruitment to the trial for the purpose of targeting future recruitment sites and strategies. The outcome measure was recruitment rate per 10,000 births, and according to this, an average recruitment rate was determined. Factors that were considered potentially predictive of recruitment above the average rate were classified according to three broad themes: 'ethics and regulatory requirements', 'characteristics of site investigators' and the 'research culture' at the collaborating site. Data were analysed using contingency tables and logistic regression modelling. At 31 January 2009, following the introduction of the Clinical Trial Agreement, 39 centres had obtained ethics approval to commence recruitment, and 38 centres had enrolled at least one woman. Time to first recruit ranged from 25 days to 584 days. Recruitment rates ranged from 0.18 to 6.0 per 10,000 births (mean 1.71/10,000 births) per month. Factors most associated with above-average recruitment rate were the following: implementation of a clearly defined 'system' of recruitment, engagement of other staff, time from ethics approval to first recruit and provision of a dedicated trial coordinator. A delay of greater than 3 months in approval of the new Clinical Trial Agreement had an effect which extended into the third year of the trial. Characteristics that were indicative of the presence of a 'system' were the best predictors of recruitment. It may be more effective to limit recruitment sites and focus resources on those sites where investigators are engaged with trial processes and have adequate resources and structures to support them.

Early referral to specialist nephrology services for preventing the progression to end-stage kidney disease.

Early referral of patients with chronic kidney disease (CKD) is believed to help with interventions to address risk factors to slow down the rate of progression of kidney failure to end-stage kidney disease (ESKD) and the need for dialysis, hospitalisation and mortality. We sought to evaluate the benefits (reduced hospitalisation and mortality; increased quality of life) and harms (increased hospitalisations and mortality, decreased quality of life) of early versus late referral to specialist nephrology services in CKD patients who are progressing to ESKD and RRT. In this review, referral is defined as the time period between first nephrology evaluation and initiation of dialysis; early referral is more than one to six months, whereas late referral is less than one to six months prior to starting dialysis. All-cause mortality and hospitalisation and quality of life were measured by the visual analogue scale and SF-36. SF-36 and KDQoL are validated measurement instruments for kidney diseases. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2012; Issue 1) which contains the Cochrane Renal Group's Specialised Register; MEDLINE (1966 to February 2012), EMBASE (1980 to February 2012). Search terms were approved by the Trial Search Co-ordinator. Randomised controlled trials (RCTs), quasi-RCTs, prospective and retrospective longitudinal cohort studies were eligible for inclusion. Two authors independently assessed study quality and extracted data. Events relating to adverse effects were collected from the studies. No RCTs or quasi-RCTs were identified. There were 40 longitudinal cohort studies providing data on 63,887 participants; 43,209 (68%) who were referred early and 20,678 (32%) referred late.Comparative mortality was higher in patients referred to specialist services late versus those referred early. Risk ratios (RR) for mortality reductions in patients referred early were evident at three months (RR 0.61, 95% CI 0.55 to 0.67; I² = 84%) and remained at five years (RR 0.66, 95% CI 0.60 to 0.71; I² = 87%). Initial hospitalisation was 9.12 days shorter with early referral (95% CI -10.92 to -7.32 days; I² = 82%) compared to late referral. Pooled analysis showed patients referred early were more likely than late referrals to initiate RRT with peritoneal dialysis (RR 1.74, 95% CI 1.64 to 1.84; I² = 92%).Patients referred early were less likely to receive temporary vascular access (RR 0.47, 95% CL 0.45 to 0.50; I² = 97%) than those referred late. Patients referred early were more likely to receive permanent vascular access (RR 3.22, 95% CI 2.92 to 3.55; I² = 97%). Systolic blood pressure (BP) was significantly lower in early versus late referrals (MD -3.09 mm Hg, 95% CI -5.23 to -0.95; I² = 85%); diastolic BP was significantly lower in early versus late referrals (MD -1.64 mm Hg, 95% CI -2.77 to -0.51; I² = 82%). EPO use was significantly higher in those referred early (RR 2.92, 95% CI 2.42 to 3.52; I² = 0%). eGFR was higher in early referrals (MD 0.42 mL/min/1.73 m², 95% CI 0.28 to 0.56; I² = 95%). Diabetes prevalence was similar in patients referred early and late (RR 1.05, 95% CI 0.96 to 1.15; I² = 87%) as was ischaemic heart disease (RR 1.05, 95% CI 0.97 to 1.13; I² = 74%), peripheral vascular disease (RR 0.99, 95% CI 0.84 to 1.17; I² = 90%), and congestive heart failure (RR 1.00, 95% CI 0.86 to 1.15; I² = 92%). Inability to walk was less prevalent in early referrals (RR 0.66, 95% CI 0.51 to 0.86). Prevalence of chronic obstructive pulmonary disease was similar in those referred early and late (RR 0.89, 95% CI 0.70 to 1.14; I² = 94%) as was cerebrovascular disease (RR 0.90, 95% CI 0.74 to 1.11; I² = 83%).The quality of the included studies was assessed as being low to moderate based on the Newcastle-Ottawa Scale. Slight differences in the definition of early versus late referral infer some risk of bias. Generally, heterogeneity in most of the analyses was high. Our analysis showed reduced mortality and mortality and hospitalisation, better uptake of peritoneal dialysis and earlier placement of arteriovenous fistulae for patients with chronic kidney disease who were referred early to a nephrologist. Differences in mortality and hospitalisation data between the two groups were not explained by differences in prevalence of comorbid disease or serum phosphate. However, early referral was associated with better preparation and placement of dialysis access.

Organizational update: American Heart Association Stroke Council.

This report represents the Spring 2014 update of the Stroke Council. Much has happened in the past 6 months, and we want to particularly focus on the new strategic plan for the American Heart Association (AHA)/American Stroke Association (ASA) and new research opportunities within the AHA/ASA. Each Stroke Council Update starts with restating our 2020 Goals: By 2020 to improve the cardiovascular health of all Americans by 20% while reducing deaths from cardiovascular diseases and stroke by 20%. To reach this goal, the AHA/ASA has worked hard, with input from throughout the organization, to craft the next detailed strategic plan for the entire AHA/ASA, including the strategic plan for the ASA that will be distributed throughout the organization in the upcoming months. One issue became apparent while reviewing the strategic plan for AHA/ASA: stroke rehabilitation and recovery are not emphasized currently in the Strategic Plan for the AHA as they deserve. In part, this reflects more limited research data and metrics available for assessing the effect of various approaches to stroke recovery compared with extensive research and public data about cardiac rehabilitation. Our stroke strategic plan must prioritize increasing engagement and advocacy for stroke recovery and rehabilitation. For example, in March, Congress passed another temporary fix to the Medicare therapy caps. They extended the exceptions process for 1 additional year (through March 31, 2015). This process allows stroke survivors on Medicare to get more outpatient therapy than the $1920 caps allow but only if their healthcare provider jumps through additional hoops to get those services covered. Although this short-term fix is good and is a direct result of advocacy from many stroke-related organizations, a long-term fix to Medicare therapy caps is paramount, and advocacy by all of us will be needed to ensure a long-term solution. …

Clinical research potential in Victorian hospitals: the Victorian clinician researcher needs analysis survey

The 2012 McKeon Review highlighted the role of clinician researchers in patient based research and the need to foster this capacity. While anecdotal evidence suggests that clinician researchers are under threat and underfunded, Australian data on barriers and enablers of clinician-led research are scant. To describe (i) characteristics of clinician researchers; (ii) for research-active clinicians: areas of research, barriers/enablers of research and factors associated with funding success; and (iii) for research-inactive clinicians: enablers of future research. An online survey distributed through the Bio21 Cluster to clinicians (doctors, nurses, allied health professionals) in 15 Victorian hospitals between November 2011 and January 2012. Seven hundred and seventy of 1027 (75%) of respondents were research-active and were more likely to be male, medical doctors, aged 45-54 years, to work full-time and have a higher degree (all P < 0.01). Of clinicians with a higher degree, 28% were research-inactive. Clinicians identified protected research time (50%), designated research space (42%), clinical trial coordinators (35%), institutional funding (34%) and mentoring (33%) as critical enablers of research. Research-inactive clinicians identified protected research time as the key enabler of future research. To realise recommendations in the McKeon Review, hospitals and research bodies will need to protect research time and provide space and funding. Engaging research-inactive clinicians will build research capacity.

Abstract OT3-2-06: TREND: A randomized phase II clinical trial evaluating the endocrine activity and efficacy of neoadjuvant degarelix versus triptorelin in premenopausal patients receiving letrozole for locally advanced endocrine responsive breast cancer (IBCSG 41-13)

Abstract Background The TREND trial compares endocrine activity of neoadjuvant triptorelin (Trip) and degarelix (Deg) in premenopausal patients receiving letrozole for primary endocrine responsive breast cancer. Recent studies suggest that combined neoadjuvant endocrine therapy with GnRH analogues and aromatase inhibitors (AIs) is effective for a selected group of premenopausal patients; degarelix, a GnRH antagonist, may induce faster ovarian suppression compared with other GnRH analogues. Trial Design This randomized phase II trial compares Trip and Deg in terms of time to optimal ovarian function suppression (OFS). The primary endpoint is defined as time from the first injection of Trip or Deg to the first assessment of centrally assessed 17-β-estradiol (E2) level in the range of optimal ovarian function suppression (≤2.72 pg/mL or ≤10 pmol/L) during the 6 cycles of neoadjuvant treatment. All patients receive 6 28-day cycles of neoadjuvant therapy: Trip: 3.75mg i.m. on day 1 of each cycle; Deg: 240mg s.c. cycle 1 day 1 and 80mg s.c. cycles 2-6 day 1. All patients receive 2.5mg/day continuous letrozole for all 6 cycles. Secondary endpoints include tolerability, Ki67 changes, preoperative endocrine prognostic index (PEPI) score, and best overall disease response. Major Eligibility Criteria • Premenopausal status confirmed (E2 &amp;gt; 54 pg/mL (or above 198 pmol/L) within 14 days of randomization • Histologically confirmed invasive breast cancer • ER and PgR &amp;gt; 50% of the cells and HER2-negative • No hormonal treatment in previous 2 months • No GnRH analogue, SERM or AI within 12 months prior to randomization • Normal hematologic, renal, liver and cardiac function Specific Aim To compare the endocrine activity of neoadjuvant Deg and Trip in premenopausal patients also receiving letrozole. Statistical Methods Randomized patients receiving at least one injection in both arms will be included in primary analysis. The primary endpoint will be evaluated in both treatment arms using stratified two-sample log-rank test (two-sided Type I error) with age as stratification factor. Assuming accrual of 25 patients per treatment arm (2 patients/month over approx. 24 months), the trial will have at least 90% power to detect a targeted or pre-specified difference in time to optimal OFS. Kaplan Meier method will be used to estimate distribution of the primary endpoint. Accrual: Target: 50 (Arm A: 25; Arm B: 25); Present: 0 Translational research A tumor block from the diagnostic core biopsy and one from final surgery will be collected and banked for central review and future translational research. Patient Reported Symptoms (PRS) PRS scores will be measured at baseline, day 1 of cycles 2 and 4 and prior to surgery. E2 will be correlated with the PRS scores. Individual endocrine symptoms (FACT-ES) will be summarized over time. Contact Information The TREND trial is conducted and sponsored by the International Breast Cancer Study Group (IBCSG). Contact Dr. Rudolf Maibach, IBCSG Coordinating Center, Bern, Switzerland, rudolf.maibach@ibcsg.org, or the Trial Coordinators at ibcsg41_TREND@fstrf.org. Pharmaceutical Support: Ferring. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-2-06.

Abstract OT3-1-02: The SNAP trial: Schedules of nab-paclitaxel in metastatic breast cancer, International breast cancer study group (IBCSG 42-12) and breast International group (BIG 2-12)

Abstract Background The SNAP trial aims to improve the tolerability of prolonged chemotherapy administration by studying alternative treatment schedules, while preserving and possibly improving treatment efficacy. Trial Design Randomized phase II study (1:1:1 randomization) evaluates each of 3 treatment arms versus a historical reference to determine whether any of the three are worthy of further investigation. All patients will begin with 3 cycles of nab-Paclitaxel 150 mg/m2 days 1,8,15 every 28 days. Maintenance nab-Paclitaxel will be given every 28 days until disease progression: (A) 150 mg/m2 days 1, 15, (B) 100 mg/m2 days 1, 8, 15, (C) 75 mg/m2 days 1, 8, 15, 22. Major Eligibility Criteria • Histologically or cytologically confirmed HER2-negative metastatic (stage IV) breast cancer • No prior chemotherapy for metastatic breast cancer • Measurable or non-measurable, but radiologically evaluable, disease according to RECIST 1.1 criteria • Either ER-positive or ER-negative disease. Patients with ER-positive disease must be endocrine resistant, defined as having failed at least one prior endocrine therapy for breast cancer, or must be candidates for first-line chemotherapy • Normal hematologic, renal, liver and cardiac functions • No peripheral neuropathy grade 2 or higher Specific Aim To evaluate the efficacy of three different schedules of nab-Paclitaxel for first-line treatment of metastatic breast cancer, measured by progression-free survival (PFS), using the historical reference of PFS for docetaxel. Statistical Methods The primary efficacy endpoint of PFS will be evaluated among each of the three treatment arms separately, in three independent tests, and compared to the historic PFS of first-line docetaxel. Assuming the median PFS of docetaxel is 7 months and the median PFS of a new regimen is 10 months, with 76 patients in each arm, and an accrual rate of 8 patients per month for an accrual period of 30 months plus 12 months additional follow-up, the study will have 88% power to detect an improvement in PFS in a new regimen relative to docetaxel, using a one-sample log-rank test at the one-sided significance level of 0.05. The target number of events per group is 63. The sample size of 80 patients per arm assumes a 5% drop out rate. Accrual Target: 240; Present: 1 (June 1, 2013) Related Research Translational research will investigate the prognostic role of putative markers SPARC and caveolin determined in FFPE tumor tissue from primary surgery and, if available, from metastatic biopsy. Material will be banked centrally. Quality-of-life assessments will be conducted to explore the change in QL over time until treatment discontinuation by LASA scales for physical well-being, mood, coping effort, overall treatment burden, appetite, tiredness, hair loss and feeling sick (nausea/vomiting). Sensory neuropathy will be assessed by the 4-item subscale of the FACT/GOG-Ntx. The SNAP trial is a collaboration through the Breast International Group (BIG). For more information about SNAP contact Dr. Rudolf Maibach, IBCSG Coordinating Center, Bern, Switzerland, rudolf.maibach@ibcsg.org, or the Trial Coordinators at ibcsg42_SNAP@fstrf.org. Pharmaceutical Support Celgene; Sponsor: IBCSG. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-1-02.

Assessing the challenges of multi‐scope clinical research sites: an example from NIH HIV/AIDS clinical trials networks

Large-scale, multi-network clinical trials are seen as a means for efficient and effective utilization of resources with greater responsiveness to new discoveries. Formal structures instituted within the National Institutes of Health (NIH) HIV/AIDS Clinical Trials facilitate collaboration and coordination across networks and emphasize an integrated approach to HIV/AIDS vaccine, prevention and therapeutics clinical trials. This study examines the joint usage of clinical research sites as means of gaining efficiency, extending capacity, and adding scientific value to the networks. A semi-structured questionnaire covering eight clinical management domains was administered to 74 (62% of sites) clinical site coordinators at single- and multi-network sites to identify challenges and efficiencies related to clinical trials management activities and coordination with multi-network units. Overall, respondents at multi-network sites did not report more challenges than single-network sites, but did report unique challenges to overcome including in the areas of study prioritization, community engagement, staff education and training, and policies and procedures. The majority of multi-network sites reported that such affiliations do allow for the consolidation and cost-sharing of research functions. Suggestions for increasing the efficiency or performance of multi-network sites included streamlining standards and requirements, consolidating protocol activation methods, using a single cross-network coordinating centre, and creating common budget and payment mechanisms. The results of this assessment provide important information to consider in the design and management of multi-network configurations for the NIH HIV/AIDS Clinical Trials Networks, as well as others contemplating and promoting the concept of multi-network settings.

Inconsistencies in quality of life data collection in clinical trials: a potential source of bias? Interviews with research nurses and trialists

Background Patient-reported outcomes (PROs), such as health-related quality of life (HRQL) are increasingly used to evaluate treatment effectiveness in clinical trials, are valued by patients, and may inform important decisions in the clinical setting. It is of concern, therefore, that preliminary evidence, gained from group discussions at UK-wide Medical Research Council (MRC) quality of life training days, suggests there are inconsistent standards of HRQL data collection in trials and appropriate training and education is often lacking. Our objective was to investigate these reports, to determine if they represented isolated experiences, or were indicative of a potentially wider problem. Methods And Findings We undertook a qualitative study, conducting 26 semi-structured interviews with research nurses, data managers, trial coordinators and research facilitators involved in the collection and entry of HRQL data in clinical trials, across one primary care NHS trust, two secondary care NHS trusts and two clinical trials units in the UK. We used conventional content analysis to analyze and interpret our data. Our study participants reported (1) inconsistent standards in HRQL measurement, both between, and within, trials, which appeared to risk the introduction of bias; (2), difficulties in dealing with HRQL data that raised concern for the well-being of the trial participant, which in some instances led to the delivery of non-protocol driven co-interventions, (3), a frequent lack of HRQL protocol content and appropriate training and education of trial staff, and (4) that HRQL data collection could be associated with emotional and/or ethical burden. Conclusions Our findings suggest there are inconsistencies in the standards of HRQL data collection in some trials resulting from a general lack of HRQL-specific protocol content, training and education. These inconsistencies could lead to biased HRQL trial results. Future research should aim to develop HRQL guidelines and training programmes aimed at supporting researchers to carry out high quality data collection.