IMPROVE trial: a randomized controlled trial of patient-controlled analgesia for sickle cell painful episodes: rationale, design challenges, initial experience, and recommendations for future studies.

BACKGROUND: The hallmark of sickle cell disease (SCD) is pain from a vaso-occlusive crisis. Although ambulatory pain accounts for most days in pain, pain is also the most common cause of hospitalization and is typically treated with parenteral opioids. The evidence base is lacking for most analgesic practice in SCD, particularly for the optimal opioid dosing for patient-controlled analgesia (PCA), in part because of the challenges of the trial design and conduct for this rare disease. PURPOSE: The purpose of this report is to describe our Network's experiences with protocol development, implementation, and analysis, including overall study design, the value of pain assessments rather than 'crisis' resolution as trial endpoints, and alternative statistical analysis strategies. METHODS: The Improving Pain Management and Outcomes with Various Strategies (IMPROVE) PCA trial was a multisite inpatient randomized controlled trial comparing two PCA-dosing strategies in adults and children with SCD and acute pain conducted by the SCD Clinical Research Network. The specified primary endpoint was a 25-mm change in a daily average pain intensity using a Visual Analogue Scale, and a number of related pain intensity and pain interference measures were selected as secondary efficacy outcomes. A time-to-event analysis strategy was planned for the primary endpoint. RESULTS: Of 1116 individuals admitted for pain at 31 participating sites over a 6-month period, 38 were randomized and 4 withdrawn. The trial was closed early due to poor accrual, reflecting a substantial number of challenges encountered during trial implementation. LIMITATIONS: While some of the design issues were unique to SCD or analgesic studies, many of the trial implementation challenges reflected the increasing complexity of conducting clinical trials in the inpatient setting with multiple care providers and evolving electronic medical record systems, particularly in the context of large urban academic medical centers. LESSONS LEARNED: Complicated clinical organization of many sites likely slowed study initiation. More extensive involvement of research staff and site principal investigator in the clinical care operations improved site performance. During the subsequent data analysis, alternative statistical approaches were considered, the results of which should inform future efficacy assessments and increase future trial recruitment success by allowing substantial reductions in target sample size. CONCLUSIONS: A complex randomized analgesic trial was initiated within a multisite disease network seeking to provide an evidence base for clinical care. A number of design considerations were shown to be feasible in this setting, and several pain intensity and pain interference measures were shown to be sensitive to time- and treatment-related improvements. While the premature closure and small sample size precluded definitive conclusions regarding treatment efficacy, this trial furnishes a template for design and implementation considerations that should improve future SCD analgesic trials.

Toward reconciling instantaneous roadside measurements of light duty vehicle exhaust emissions with type approval driving cycles.

A method is proposed to relate essentially instantaneous roadside measurements of vehicle exhaust emissions, with emission results generated over a type approval driving cycle. An urban remote sensing data set collected in 2008 is used to define the dynamic relationship between vehicle specific power and exhaust emissions, across a range of vehicle ages, engine capacities, and fuel types. The New European Driving Cycle is synthesized from the remote sensing data using vehicle specific power to characterize engine load, and the results compared with official published emissions data from vehicle type approval tests over the same driving cycle. Mean carbon monoxide emissions from gasoline-powered cars ≤ 3 years old measured using remote sensing are found to be 1.3 times higher than published original type approval test values; this factor increases to 2.2 for cars 4-8 years old, and 6.4 for cars 9-12 years old. The corresponding factors for diesel cars are 1.1, 1.4, and 1.2, respectively. Results for nitric oxide, hydrocarbons, and particulate matter are also reported. The findings have potential implications for the design of traffic management interventions aimed at reducing emissions, fleet inspection and maintenance programs, and the specification of vehicle emission models.

Opioid patient controlled analgesia use during the initial experience with the IMPROVE PCA trial: a phase III analgesic trial for hospitalized sickle cell patients with painful episodes.

Opioid analgesics administered by patient-controlled analgesia (PCA)are frequently used for pain relief in children and adults with sickle cell disease (SCD) hospitalized for persistent vaso-occlusive pain, but optimum opioid dosing is not known. To better define PCA dosing recommendations,a multi-center phase III clinical trial was conducted comparing two alternative opioid PCA dosing strategies (HDLI­higher demand dose with low constant infusion or LDHI­lower demand dose and higher constant infusion) in 38 subjects who completed randomization prior to trial closure. Total opioid utilization (morphine equivalents,mg/kg) in 22 adults was 11.6 ± 2.6 and 4.7 ± 0.9 in the HDLI andin the LDHI arms, respectively, and in 12 children it was 3.7 ± 1.0 and 5.8 ± 2.2, respectively. Opioid-related symptoms were mild and similar in both PCA arms (mean daily opioid symptom intensity score: HDLI0.9 ± 0.1, LDHI 0.9 ± 0.2). The slow enrollment and early study termination limited conclusions regarding superiority of either treatment regimen. This study adds to our understanding of opioid PCA usage in SCD. Future clinical trial protocol designs for opioid PCA may need to consider potential differences between adults and children in PCA usage.

Automated summaries of serious adverse events in the hepatitis C antiviral long-term treatment against cirrhosis trial.

BACKGROUND: Even though adverse event (AE) collection and official accounting are mandatory for clinical trials, there are limited detailed guidelines specifying how to summarize the event for reporting in a timely and expeditious manner. This article details the AE and serious adverse event (SAE) reporting summary developed for a large multi-center National Institutes of Health (NIH)-sponsored clinical trial. PURPOSE: To review and analyze the large volume of AE data reported by 10 sites (806 SAEs and 19,034 AEs from August 2000 to May 2007) the automated SAE summary was developed. It was designed to ensure timeliness and clarity in the complex process of AE review and reporting. METHODS: The AE and SAE case report forms (CRFs) as well as the automated SAE summary were developed within a database management system developed by the Data Coordinating Center (DCC) which allowed for web-based data entry at the DCC and 10 sites and offered immediate overall and site-specific reports accessible by the DCC, site, and NIH project staff. RESULTS: The automated SAE summary pulled data from multiple CRFs to create a succinct and informative summary and allowed for prompt and easy reporting to the regulatory agencies. The summary was adaptable to the needs of reviewers because of the availability of multiple search options.

Cyclist casualty severity at roundabouts - To what extent do the geometric characteristics of roundabouts play a part?

INTRODUCTION: In general, priority junctions are converted into roundabouts to increase capacity and reduce vehicle accidents. However, previous research has indicated that roundabouts are dangerous for vulnerable users, especially cyclists. METHOD: This paper investigates which design factors influence cyclist casualty severity at give way (non-signalized) roundabouts with mixed traffic, using the UK STATS19 National dataset of cyclist casualties. First, the correlation matrix was generated to observe the relationship between variables. Second, dimension reduction was applied to geometric design variables in order to reduce the number of variables and generate the factors. Finally, the binary logistic regression method, with serious and slight casualties as dependent variables, was applied in three steps. The first Binary Logistic Regression Model (BLRM) included speed limit, sociodemographic, and meteorological conditions. The variables in the second BLRM consisted of geometric design variables. The third BLRM included the factors that were generated by dimension reduction. RESULTS: The correlation matrix revealed that the number of lanes on approach and half width on approach were statistically significantly correlated, while the variables, such as geometric design (entry path radius, number of arms, number of flare lanes on approach, type of roundabout and number of circulating lanes), sociodemographic (casualty gender and age), speed limit and meteorologically related factors (daylight, weather and road surface condition), did not show any statistical significance. From the dimension reduction process, two main factors were identified, including Approach Capacity (Factor 1) and Size of Roundabout (Factor 2), and they were subsequently used as independent variables in the logistic regression analysis. The subsequent BLRMs showed that a higher speed limit reduces the safety for cyclists at roundabouts. The probability of a serious casualty increases by approximately five times (odds ratio 4.97) for each additional number of lanes on approach and by 4% (odds ratio 1.04) with a higher entry path radius. It was also found that Factor 2 (Approach Capacity) increases the casualty severity (odds ratio 1.86) for cyclists at roundabouts. Practical applications: While this research studied roundabouts in the UK, the methodological approach and statistical analysis techniques are applicable to other countries and the findings are likely to be of value to decision makers worldwide.

Completeness and Accuracy of Local Clinical Registry Data for Children Undergoing Heart Surgery.

BACKGROUND: Data routinely captured in clinical registries may be leveraged to enhance efficiency of prospective research. The quality of registry data for this purpose has not been studied, however. We evaluated the completeness and accuracy of perioperative data within congenital heart centers' local surgical registries. METHODS: Within 12 Pediatric Heart Network (PHN) sites, we evaluated 31 perioperative variables (and their subcategories, totaling 113 unique fields) collected via sites' local clinical registries for submission to The Society of Thoracic Surgeons Database, compared with chart review by PHN research coordinators. Both used standard STS definitions. Data were collected on 10 subjects for 2 to 5 procedures/site and adjudicated by the study team. Completeness and accuracy (agreement of registry data with medical record review by PHN coordinator, adjudicated by the study team) were evaluated. RESULTS: A total of 56,500 data elements were collected on 500 subjects. With regard to data completeness, 3.1% of data elements were missing from the registry, 0.6% from coordinator-collected data, and 0.4% from both. Overall, registry data accuracy was 98%. In total, 94.7% of data elements were both complete/non-missing and accurate within the registry, although there was variation across data fields and sites. Mean total time for coordinator chart review per site was 49.1 hours versus 7.0 hours for registry query. CONCLUSIONS: This study suggests that existing surgical registry data constitute a complete, accurate, and efficient information source for prospective research. Variability across data fields and sites also suggest areas for improvement in some areas of data quality.

Processes to manage analyses and publications in a phase III multicenter randomized clinical trial.

BACKGROUND: The timely publication of findings in peer-reviewed journals is a primary goal of clinical research. In clinical trials, the processes leading to publication can be complex from choice and prioritization of analytic topics through to journal submission and revisions. As little literature exists on the publication process for multicenter trials, we describe the development, implementation, and effectiveness of such a process in a multicenter trial. METHODS: The Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial included a data coordinating center (DCC) and clinical centers that recruited and followed more than 1,000 patients. Publication guidelines were approved by the steering committee, and the publications committee monitored the publication process from selection of topics to publication. RESULTS: A total of 73 manuscripts were published in 23 peer-reviewed journals. When manuscripts were closely tracked, the median time for analyses and drafting of manuscripts was 8 months. The median time for data analyses was 5 months and the median time for manuscript drafting was 3 months. The median time for publications committee review, submission, and journal acceptance was 7 months, and the median time from analytic start to journal acceptance was 18 months. CONCLUSIONS: Effective publication guidelines must be comprehensive, implemented early in a trial, and require active management by study investigators. Successful collaboration, such as in the HALT-C trial, can serve as a model for others involved in multidisciplinary and multicenter research programs. TRIAL REGISTRATION: The HALT-C Trial was registered with clinicaltrials.gov (NCT00006164).

Exploring the processes governing roadside pollutant concentrations in urban street canyon.

This paper describes an in-depth analysis to investigate the huge variation in the measured roadside air-pollutant concentrations of carbon monoxide and nitrogen dioxide in terms of the traffic flow levels, the orientation of the street to the prevailing wind, the wind speed, temperature and barometric pressure. The work has attempted to develop generic parameters that can be applied to other urban areas. However, in the absence of a measure of congestion at the site in Palermo (Italy), the methodological approach proposed used the simultaneous noise measurements, in units of decibels (B), to help parameterise a generic congestion indicator in terms of the traffic flow. The potential transferability of the approach was demonstrated for a site in Marylebone Road, London (UK), given the similarity of the two study sites, canyon shape, traffic characteristics and road orientation. The results showed that, within the range of data available, noise levels could be used as a proxy for flow change on the shoulders of the peak hour and hence congestion and a generic relationship with factors statistically significant at 99% confidence allows roadside concentrations due to traffic to be estimated with a regression coefficient of R(2) = 0.73 (R = 0.85). The research demonstrates that whilst there are indeed underlying relationships that can explain the roadside concentrations based on traffic and meteorological conditions, evidence is presented that confirms the complexity of the physical and chemical processes that govern roadside concentrations.

Clinical trial implementation and recruitment: lessons learned from the early closure of a randomized clinical trial.

BACKGROUND: The NHLBI-sponsored Sickle Cell Disease Clinical Research Network (SCDCRN) conducted a multi-center, acute intervention randomized clinical trial of two methods of Patient Controlled Analgesia for acute pain. This trial was terminated early due to low enrollment. We analyzed the perceived barriers and recruitment difficulties as reported by the coordinators and principal investigators. METHODS: Participating sites completed a missed eligibility log of subjects admitted in pain crisis throughout the study and a survey at the end of the trial. The survey covered site-specific factors, policies, and procedures in study implementation, recruitment strategies, and eligibility factors. The New England Research Institutes (NERI) collected de-identified surveys from 31 respondents at 29 of 31 participating sites. RESULTS: From December 2009 to June 2010, 1116 patient encounters for SCD and pain occurred at participating institutions: 38 subjects were enrolled (14 pediatric and 24 adults) and 34 completed the trial, below the projected 278 subjects. Fourteen sites enrolled subjects and seventeen did not. Recruitment barriers included insufficient staff, subject ineligibility or in too much pain to consent, competing protocols, and concerns regarding pain control. Recruitment methods were referrals from urgent care, SCD clinics and in house databases. No use of media or outside physicians was reported. CONCLUSION: We identified multiple barriers to patient accrual including short duration of enrollment period, protocol design, complex dosing schedule, requirement for staff availability during week-end and after hours, multiple departments' involvement, protocol acceptance, eligibility criteria, competing protocols, and limited staff. Each of these areas should be targeted for intervention in order to plan and conduct successful future clinical trials.

Change-point detection of gaseous and particulate traffic-related pollutants at a roadside location.

An 8-year (1998-2005), hourly data set of measurements of NOx, NO2, PM10, PM2.5, and PMcoarse (defined as PM(2.5-10)) from a busy roadside location in central London has been analyzed to identify important change-points in the time series using a cumulative sum (CUSUM) technique. Randomization methods were used to estimate the uncertainty level associated with the change-points with uncertainty intervals derived using a bootstrap approach. The results show that there is a clear change-point increase for NO2 coinciding with the introduction of the London congestion-charging in February 2003 (95% confidence interval from January-March 2003). At this time there was both an increase in bus numbers and buses fitted with catalyzed diesel particulate filters, which increase direct emissions of NO2. A highly statistically significant change-point was also observed for PMcoarse (95% confidence interval from December 2002-February 2003), which also occurred close to the time of the congestion charge introduction and is most closely related to the increase in bus flows. The increase in PMcoarse at this time has largely compensated for reductions in the concentration of PM2.5, such that the concentration of PM10 has remained almost constant. Comparing the 2 years before and after the introduction of congestion charging, the increment in NO2 above background increased from 22 to 34 ppb and PMcoarse increased from 4 to 9 microg m(-3). These results could have important implications for meeting European air quality standards that currently set limits for PMlo rather than PM2.5.