Micafungin safe for children with Candida infections, new study says

December 30, 2013 – Daniel Benjamin, MD, MPH, PhD, and other researchers analyzed the findings of two phase I trials of the drug in children and infants.

The antifungal drug micafungin is safe for children with Candida infections, according to a new study led by the DCRI’s Daniel Benjamin, MD, MPH, PhD.

The study appears in a recent issue of The Pediatric Infectious Disease Journal.

Invasive candidiasis is a fungal infection that can occur when Candida yeasts enter the bloodstream. Although relatively uncommon among the general population, it is prevalent among hospitalized patients in the United States, including low–birth-weight and immunocompromised children. Although clinicians have successfully treated these infections with amphotericin B and fluconazole, amphotericin B’s side effects and the emergence of fluconazole-resistant strains of Candida have prompted a search for new therapies.

In this study, Benjamin and colleagues from Illinois and California sought to determine whether micafungin is an effective alternative to amphotericin B and fluconazole. Earlier studies have suggested that micafungin is safe for children, including those with life-threatening illnesses. To better evaluate the safety and effectiveness of the drug, the researchers analyzed patient data from two phase I, prospective, multicenter trials. The first study comprised 78 infants and adolescents aged 2–16 years. Children were grouped by weight at baseline to receive either 3 mg/kg or 4.5 mg/kg of micafungin, with a maximum daily dose of 150 mg. The population of the second study comprised 9 toddlers aged 4 months to less than 2 years. In this trial, all children received 4.5 mg/kg micafungin, with a maximum daily dose of 150 mg.

Most of the children in the first study (80 percent) experienced at least one adverse event, whereas all of the children in the second study experienced one or more adverse events. The most common adverse events were pyrexia, hypokalemia, and vomiting. Adverse events due to micafungin were less common, with only 28 children in the first study and 1 in the second study experiencing an adverse event related to the drug. The most common adverse events considered to be related to micafungin treatment were infusion-associated symptoms such as hypotension, hypertension and cyanosis, pyrexia, and hypomagnesemia. Four children in the first study died; three died during the study period and one after the end of the follow-up period. The micafungin pharmacokinetic profile was similar to that seen in other studies conducted in children, but different than that observed in adults.

Because micafungin-related adverse events were relatively uncommon and generally did not lead to discontinuation of treatment, the researchers concluded that once-daily 3 mg/kg and 4.5 mg/kg doses of micafungin are well tolerated in children and adolescents with proven, probable, or suspected Candida infection. Furthermore, the pharmacokinetic information obtained in these studies can be used to better calibrate the necessary dosage of the medication.

Creating a learning healthcare system; defining a new approach to clinical research

December 24, 2013 – Rob Califf, MD, talks about healthcare innovation in a recent DCRI Research Conference.

The future of clinical research and healthcare innovation, according to Rob Califf, MD, lies in innovating the way medical data is collected, stored, manipulated, and disseminated. In a presentation at a recent DCRI Research Conference, Califf, director of the Duke Translational Medicine Institute (DTMI), explained that traditional clinical research mythologies are quickly becoming too expensive to sustain, siloed, and out of touch with clinical practice. He used the presentation to highlight a few initiatives that are seeking to overcome these issues and move clinical research forward, including the National Health Institute’s (NIH) Health Care Systems Research Collaboratory and the Patient-Centered Outcomes Research Institute (PCORI) National Patient-Centered Clinical Research Network.

Califf explained that the disconnect between clinical research and practice has arisen from the belief that researchers don’t care about the welfare of their patients and think of them only as test subjects. Unfortunately, this has led to a breakdown in how patient data is stored, analyzed, and used to improve treatment. Furthermore, it is becoming increasingly difficult to translate basic or clinical observations into interventions that tangibly improve human health. Because of these transitional gaps and the increased cost of research, the number of discovered drugs that make it through the FDA’s clinical trial approval process has dropped exponentially over the past few decades.

“Things are terrible compared to what they could be and the cost of doing clinical research has skyrocketed beyond anything we can afford,” said Califf. “We need a system that produces reliable results at a reasonable price. This learning health care system would use computers to compile data from routine clinical care, which would then become the basis upon which we learn and accrue knowledge.”

The NIH Collaboratory, wherein Califf represents the DCRI as a primary investigator for the coordinating center, will allocate funding over the next five years to a constellation of pragmatic clinical trials embedded within healthcare systems and involving electronic health records. The goal is to compile these trial best practices and guidelines into a comprehensive living textbook and online portal that has everything researchers need to know to conduct pragmatic health system-based clinical research using electronic records. This textbook will outline the most effective ways to use readily available clinical evidence, but at the same time reduce the cost of clinical research.

PCORI, a nonprofit research funding organization, shares a similar goal of improving clinical practice through the better implementation of evidence-based research. The organization has already approved 279 awards totaling more than $464.4 million to fund multi-center observational and interventional comparative clinical effectiveness research projects. PCORI has also recently approved development for PCORnet, which will be designed to integrate data available in 29 clinical research data networks. PCORnet will require participation by researchers, patients, and clinicians and represents that organization’s goal to advance the shift in clinical research from investigator-driven to patient-centered studies.

According to Califf, this shift towards using learning as part of healthcare delivery will take some time. He explained that as we move forward, the clinical research workflow will gradually transition into one defined by the transparency and reuse of data, research sites embedded in integrated health systems, and analyses conducted in a “reproducible research” environment. As these new processes are more widely accepted, Califf predicts that the gaps in the traditional clinical research models will fade away and that by making research a more collaborative and cumulative process the cost will plummet.

PCORI awards funds to Schanberg for new research network

December 23, 2013 – Schanberg’s project will be part of a national data network intended to improve the speed and efficiency of patient-centered comparative effectiveness research.

The DCRI’s Laura Schanberg, MD, has been approved for a funding award by the Patient-Centered Outcomes Research Institute (PCORI) to develop and expand a health data network that will be part of PCORnet, the National Patient-Centered National Clinical Research Network. Schanberg’s project, the Patients, Advocates and Rheumatology Teams Network for Research and Service (PARTNERS) Consortium data network, is one of 29 that were approved for a total of $93.5 million from PCORI last week to form this new national resource that aims to boost the efficiency of health research.

PARTNERS is designed to link patients, family members, advocacy groups, and other stakeholders in a network that will drive research on pediatric rheumatic diseases based on patient-centered scientific priorities and patient input. PARTNERS builds on the existing Childhood Arthritis and Rheumatology Research Alliance (CARRA) and Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN) registries, which together have enrolled almost 9,000 patients with pediatric rheumatic diseases.

Pediatric rheumatic diseases, such as juvenile idiopathic arthritis and childhood-onset systemic lupus erythematosus, are relatively uncommon but can be debilitating for patients. The cause of many of these illnesses remains unknown.

PCORI envisions PCORnet to be a secure, national data network that improves the speed, efficiency, and use of patient-centered comparative effectiveness research (CER). By integrating data available in the 29 individual networks, PCORnet aims to provide access to a large amount of diverse, nationally representative health information that can support a range of study designs. It will reduce the time and effort needed to launch new studies and focus research on questions and outcomes especially useful to patients and those who care for them.

Over the next two years, Schanberg and her team will use the PCORI funds to develop PARTNERS’ systems, work to standardize its data, and be part of the process to develop policies governing data sharing and security and protection of patient privacy. It also will build the network’s capacity to engage and recruit patients and other stakeholders interested in participating in research.

PCORI is an independent, non-profit organization established by Congress in 2010 to facilitate comparative effectiveness research (CER). The data network awards were among 82 funding awards totaling $191 million approved by PCORI’s board during a special meeting Tuesday. The board also approved $97.5 million in funding for 53 patient-centered CER studies.

Brennan receives funding award from PCORI

December 18, 2013 – The award, part of a $191 million project announced this week, will support research aimed at providing patients with more information about the effectiveness of various healthcare options.

The DCRI’s Matthew Brennan, MD, MPH, has received a new funding award from the Patient-Centered Outcomes Research Institute (PCORI) in collaboration with the Society of Thoracic Surgeons (STS) and the American College of Cardiology (ACC).

The award, part of more than $191 million in funding approved during a special PCORI Board of Governors meeting Tuesday, will support research aimed at providing patients with aortic valve heart disease, their families, and other healthcare stakeholders with more information about the effectiveness of various healthcare options so they can make better-informed decisions about their care. PCORI, an independent, non-profit organization, was established by Congress in 2010 to facilitate such research.

The funds will be distributed by PCORI to 82 projects across the country focused on the treatment of heart disease, cancer, obesity, chronic pain, diabetes, respiratory ailments, mental health disorders, and other conditions. Several projects will explore ways to support decision-making, reduce health disparities, and improve healthcare delivery systems.

Brennan’s project focuses on optimizing health outcomes in patients with symptomatic aortic valve disease. Aortic valve disease, which affects roughly 1 in 20 older patients, occurs when one of the heart’s valves is either too narrow or does not close properly. In either case, the condition can be extremely disabling and eventually result in death. Until recently most patients with severe aortic valve disease underwent surgery to replace the defective valve, but in 2011 the United States Food and Drug Administration approved a less invasive transcatheter procedure as an alternative to surgical valve replacement.

In his project, Brennan proposes to create an open-source, web-based resource of information for patients, their caregivers, and providers to help personalize the treatment of aortic valve disease. Central to the project is a comparison of “real-world” outcomes between patients who undergo surgical valve replacement and those who receive transcatheter valve replacement. The project will also entail the creation of two personalized tools: a decision tool to evaluate expected outcomes of surgical versus transcatheter valve replacement in patients who are eligible for both procedures, and a risk assessment tool for transcatheter valve replacement in patients who are not eligible for surgical valve replacement. To achieve these goals, Brennan will use registry data from the Society of Thoracic Surgeons and American College of Cardiology linked to Medicare administrative claims.

The goal, Brennan said, is to help match patients with the treatment that most closely aligns with their value systems and empower patients to participate actively in their own healthcare decisions.

“This award is a major win for both our patients with aortic valve disease and their community of caregivers,” he said. “The tools we develop will help both patients and clinicians personalize what should be a very personal treatment decision.”

Last year, PCORI sought proposals for projects to assess different treatment or prevention methods for the same condition, improve healthcare systems; communicate and distribute results from PCORI-funded projects, and eliminate or reduce ethnic and racial disparities in health care. In December 2012, PCORI announced the first round of 25 awards totaling more than $40 million over three years. In May, the organization announced another round of awards totaling $88.6 million to fund 51 research projects.

Study finds that clinical trials examining kidney disease may be inadequate and insufficient

December 12, 2013 – The DCRI’s Uptal Patel, MD analyzes the impact of nephrology clinical trials in the past few years.

In a study designed to assess the characteristics of nephrology clinical trials, researchers determined that trials focused on the growing population of patients with chronic kidney disease (CKD) may not be receiving the attention, funding, or efforts necessary to identify new therapies. The study recommends a concerted effort among government, industry, key stakeholders, and academia to increase the quality and quantity of clinical trials in this area.

CKD affects more than 10 percent of adults worldwide, and although CKD is associated with high morbidity, mortality, and costs, therapies are still not well studied. For this recent write-up, published online by the American Journal of Kidney Diseases, researchers examined more than 40,000 studies from the Clinical Trials Data Bank (ClinicalTrials.gov).

The analysis compared nephrology trials with other types of trials, including cardiology trials. Although many trial characteristics were similar between trial types or occasionally better in nephrology trials versus all others, nephrology trials were more likely to have some unfavorable study design characteristics, such as a large number of unblinded studies and a small number of studies with data monitoring committees. The study also found that funding for these trials came predominantly from non-government sources, although there were a large number sponsored by academic medical centers that likely receive government funding.

The study authors, including the DCRI’s Uptal Patel, MD (pictured right), and Rob Califf, MD, concluded that this lack of properly designed randomized clinical trials has led to delays in clinicians better understanding the lack of efficacy or harmful side-effects of some standard CKD treatments. They also explained that improvements in monitoring clinical trials are essential. An increase in the transparency in trial design, execution, and results may facilitate completion of a greater number of high-quality trials and lead to more effective therapies for patients with kidney disease.

Visit the Clinical Trials Transformation Initiative blog for more information about this study and related research.

Oxygen Biotherapeutics selects the DCRI to conduct phase III trial of levosimendan

December 13, 2013 – John Alexander, MD, and Rajendra Mehta, MD, are the lead investigators.

Oxygen Biotherapeutics, Inc., a pharmaceutical company focused on developing drugs for the acute care market, today announced that it has selected the DCRI to conduct the phase III trial of the company’s newly acquired compound, levosimendan. The DCRI will serve as the coordinating center and Drs. John Alexander and Rajendra Mehta as lead investigators for the phase III trial.

Levosimendan is a calcium sensitizer developed for intravenous use in hospitalized patients with acutely decompensated heart failure. The treatment is currently approved in more than 50 countries for this indication. The United States Food and Drug Administration (FDA) has granted Fast Track status for levosimendan for the reduction of morbidity and mortality in cardiac surgery patients at risk for developing Low Cardiac Output Syndrome (LCOS). In addition, the FDA has agreed to the phase III protocol design under Special Protocol Assessment (SPA), and provided guidance that a single successful trial will be sufficient to support approval of levosimendan in this indication.

Oxygen Biotherapeutics recently acquired the North American rights to develop and commercialize levosimendan from Phyxius Pharma. It was discovered and developed by Orion Pharma, Orion Corporation of Espoo Finland.

John Kelley, CEO for Oxygen Biotherapeutics and former co-founder of Phyxius Pharma commented on this agreement: “We are extremely pleased to have an organization with the skill and expertise in conducting clinical trials that DCRI possesses as our partner. They have been responsible for managing a number of major cardiac surgery trials in the last decade, so their knowledge of this area of medicine is invaluable to us. At Phyxius Pharma, we worked with DCRI for the past three years to develop the clinical program for levosimendan. They played a key role in designing the phase III protocol that has been approved by the FDA under SPA.”

According to the scientific literature, LCOS occurs in 5-10 percent of cardiac surgery patients, and is associated with a 10 – 15 fold increase in mortality. There is no drug currently approved for the prevention or treatment of LCOS. The trial will study if levosimendan administered before and during surgery will reduce the incidence of LCOS and associated morbidity and mortality. There is substantial scientific evidence for the use of levosimendan in cardiovascular surgery, with over 25 published articles in peer reviewed journals and evidence of mortality reduction in some cardiac surgery trials of more than 50 percent.

The trial will be conducted in approximately 50 major cardiac surgery centers in North America. The trial will enroll patients undergoing coronary artery bypass grafts (CABG) and/or mitral valve surgery who are at risk for developing LCOS. The trial will be a double blind, randomized, placebo controlled study seeking to enroll 760 patients. It is expected that enrollment will begin in the third quarter of 2014, and will take approximately 18 months to complete. More details on the specifics of the trial will be released shortly.

John Alexander, MD, MHS, director of Cardiovascular Research for the DCRI, said about the announcement: “We are excited to be continuing our work on levosimendan and to move forward with the conduct of this innovative trial. The prevention of complications after high-risk cardiac surgery is clearly an area of unmet medical need. Our recent analysis of the work that has been published on levosimendan to date indicated a benefit to high-risk cardiac surgery patients at risk for developing LCOS. This next phase of research will be important to determine whether those results are verified in a large study.”

Program encourages regional cooperation in the treatment of heart attack patients

December 12, 2013 – Akshay Bagai, MD, MHS, outlines the goals and logistics surrounding the Mission: Lifeline STEMI Systems Accelerator initiative.

The Regional Systems of Care Demonstration Project: Mission: Lifeline STEMI Systems Accelerator is a national educational outreach initiative designed to improve and expedite care for heart attack patients. The program draws upon guidelines from the American Heart Association (AHA) and American College of Cardiology (ACC) with an aim to improve use and timeliness of reperfusion therapy and to improve clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI). Early reperfusion can lead to significantly lower mortality rates in heart attack patients, and regional coordination is essential in this effort to improve the care process.

A recent article published online by the American Heart Journal outlines the parameters and goals of the Mission: Lifeline STEMI Systems Accelerator program and highlights its importance for improved patient care. Lead author Akshay Bagai, MD, MHS, collaborated with the DCRI’s Hussein Al-Khalidi, PhD; Matthew Sherwood, MD; Daniel Muñoz, MD; Mayme Roettig, RN, MSN; James Jollis, MD; and Christopher Granger, MD.

Mission: Lifeline STEMI Systems Accelerator is led by the DCRI in partnership with the AHA. In 17 major metropolitan regions across the United States, program leaders work with care providers to develop an analytical plan to evaluate the impact of implementing regional STEMI-care systems on both care processes and clinical outcomes, including reperfusion times and in-hospital mortality. Since percutaneous coronary intervention (PCI) is the preferred method of reperfusion, getting patients to PCI-capable hospitals is a key part of these plans.

The largest barrier to success for this initiative is the high level of competition that is common among hospitals throughout the country. Treating heart attack patients is highly profitable for hospitals that provide cardiovascular services, and so often time and opportunity can be wasted as emergency medical services providers attempt to navigate complicated referral networks tied to traditionally entrenched interhospital and physician relationships.

To overcome the reluctance of these regional care providers to collaborate with their competitors, the program relies on a number of evidence-based standard protocols and also puts a strong emphasis on the collection and distribution of data at each stage of system implementation. The involvement and resources provided by the AHA are also essential in encouraging interhospital collaboration.

DCRI named data coordinating center for new pulmonary fibrosis patient registry

December 11, 2013 – Kevin Anstrom, PhD, will be the principal investigator for the registry’s coordinating center.

The Pulmonary Fibrosis Foundation (PFF) announced today that the DCRI has been chosen as the data coordinating center for the newly launched PFF Patient Registry.

The Registry will eventually be the largest database of pulmonary fibrosis (PF) patient records with the furthest demographic reach in the country. It will provide data essential for improving the understanding of the epidemiology, incidence, prevalence, natural history, and other clinical characteristics of PF. The Registry will use consistent data gathering methodology so that the information obtained will be useful to all clinicians and researchers seeking to better understand the disease and develop new therapies for PF.

“We are proud to be a central part of such an important initiative,” said DCRI Director Eric Peterson, MD, MPH. “The PFF Patient Registry extends the DCRI’s commitment to PF research. We are pleased to be part of a national effort to collect data that is often critical for developing more effective treatments for PF.”

Kevin Anstrom, PhD, will serve as principal investigator for the coordinating center, and Rex Edwards will serve as project leader. The Registry plans to enroll its first patient by November of 2014.

The PFF also announced the launch of the PFF Care Center Network, an alliance of medical centers across the country working on a standardized, multidisciplinary approach to patient care. All the pilot sites of the Care Center Network will participate in the Registry. A principal investigator at each Network site will work with a team of allied health professionals to enroll PF patients into the Registry. The DCRI will host and maintain the PFF Patient Registry, and they will oversee the implementation of the Registry.

Pulmonary fibrosis is a condition in which the lung tissue becomes thickened, stiff, and scarred. In most cases, there is no known cause and the disease is called idiopathic pulmonary fibrosis (IPF). IPF affects approximately 132,000 to 200,000 individuals in the United States, and approximately 38,000 individuals in the European Union. In the United States the annual mortality is estimated to be 40,000 with an average survival of only 2–3 years from the time of diagnosis. There is no cure for IPF, and there is no approved treatment for IPF in the United States.

Targeted investment in palliative care at local level can improve access to end-of-life care

December 10, 2013 – Amy Abernethy, MD, and other researchers found that funding strategies focused on a local level may be more effective than those targeting statewide change.

Targeted investment in hospice and palliative care at the local level can lead to improved access to end-of-life care service, according to a study by the DCRI’s Amy Abernethy, MD, and other Duke researchers.

The study was published in a recent issue of the Journal of Pain and Symptom Management.

Although earlier research has indicated that palliative care improves quality of life and reduces spending, the United States still lacks a national model for developing palliative care models, expanding service delivery, and establishing financing mechanisms. As such, systems of palliative care (including hospice care) in the country have developed in an ad hoc fashion, often differing from one locality to another. Palliative and hospice care in the United States typically fall into one of four categories:  hospital-based palliative care, community-based palliative care, community-based hospice care, and inpatient hospice care. Patients may receive one or more of these types of care during their treatment.

In this study, Abernethy and her colleagues sought to determine whether targeted investments in hospice and palliative care contribute to increasing access to and use of these services. “Targeted investments,” as defined by the researchers, are funds distributed in a way intended to generate a specific outcome. To answer this question, they examined how access to hospice and palliative care programs was affected by private philanthropic funding for the development of these services in North Carolina. The source of funding was the Duke Endowment, a 501(c)(3) nonprofit charitable foundation. The foundation has awarded more than $9.3 million since 2000 to help build inpatient and residential hospice facilities and to develop palliative care programs in the southeastern United States, including more than $5.4 million awarded to existing organizations in North Carolina.

The researchers measured access to end-of-life services by the death service ratio (DSR), defined as the proportion of people who died and were served by hospice for at least one day before death. The DSR was calculated by the Carolinas Center for Hospice and End of Life Care, an association representing more than 100 hospice providers in North Carolina (NC) and South Carolina.

During the study period (2003–2009), 28 of the 100 NC counties received funding from the Duke Endowment to support development of community-based hospice and palliative care. In NC, the average DSR increased from 20.7 percent in 2003 to 35.8 percent in 2009 (a 55 percent increase). In 2009, 82 of 100 NC counties had a DSR below the US average (41.6 percent). The researchers also found significant associations between county population and DSR, and between receipt of philanthropic funding and DSR. On average, funded counties had a DSR that was 2.63 percentage points higher than unfunded counties.

These findings, the researchers concluded, suggest that the DSR is a useful measure of access to hospice care and that funding strategies that seek to maximize local (i.e., county-level) returns on investment may be more effective than one seeking to maximize statewide returns.

DCRI Informatics manuscript named one of the best papers of 2012

December 9, 2013 – The paper recognized in the IMIA yearbook highlights the methodology they used to make the ClinicalTrials.gov data easier to analyze.

The editorial board for the 2013 International Medical Informatics Association (IMIA) yearbook recently named a DCRI analysis of ClinicalTrials.gov as one of the best medical informatics papers of 2012.

Asba Tasneem, PhD, was the lead author for the paper, “The database for aggregate analysis of ClinicalTrials.gov and subsequent regrouping by clinical specialty.” The DCRI’s Laura Aberle, Hari Ananth, Swati Chakraborty, Karen Chiswell, PhD, Brian McCourt, and Ricardo Pietrobon, MD, were co-authors.

ClinicalTrials.gov was originally designed as a resource for researchers, patients, and patient advocates to help them find trials of interest that were enrolling patients or seeking to add more sites. Since it was created, the registry has grown into a repository with information on more than 153,000 clinical trials from around the world. Despite the significant amount of data, it was not in a format that could be easily used in analyses.

The researchers aggregated the data from the registry,created 18 different specialty data sets that were further subdivided into specific diseases (for example, endocrinology would include thyroid conditions and diabetes), and then developed a downloadable Oracle database that makes it simpler to study specific types of trials. The paper recognized in the IMIA yearbook highlights the methodology they used to make the ClinicalTrials.gov data easier to analyze.

The tool they developed has already been used as the basis for more in-depth analyses. For example, Califf used the tool to compare government funding versus industry funding for cardiology, oncology, and mental health trials.

During the creation of the tool, the DCRI team found discrepancies between data that researchers are legally required to submit about their trials and what was actually uploaded to the registry. Because ClinicalTrials.gov does not mandate completion of many fields that are legally required in order to register a trial, the DCRI researchers found gaps in information across specialties. For example, many trials did not include information on data monitoring committees, even though trials likely used them.

“The work we did with ClinicalTrials.gov to create this tool was interesting and complex, and hopefully it will have an impact for years to come on how people use the data,” said Tasneem. “I feel very fortunate to have been part of such an exciting project.”

This work is part of the Clinical Trials Transformation Initiative’s State of Clinical Trials project. The paper, The Database for Aggregate Analysis of ClinicalTrials.gov(AACT) and Subsequent Regrouping by Clinical Specialty, was published in PLOS One in May 2012. A link to the paper and other publications using the AACT database are available on the CTTI website.