TRANSFORM-HF team pioneers new type of clinical trial

January 2, 2019 – One of the first DCRI studies of its kind could become a model for the future.

Heart failure patients have a tendency to accumulate excess fluid in the body, which can lead to debilitating symptoms such as shortness of breath and swelling. Loop diuretic medication, aims to prevent accumulation of this fluid and is the cornerstone treatment for heart failure signs and symptoms. With more than six million Americans affected by heart failure, and about one million hospitalized every year, a new DCRI study called TRANSFORM-HF will directly compare two well-known diuretics – furosemide and torsemide – to determine which is the most effective.

At the same time, the trial’s innovative design could change the way medical research is developed and managed for years to come. Investigators hope that TRANSFORM-HF, which began this summer, will live up to its name – that its innovative approach will transform the clinical trial experience for researchers, site staff, and patients.

“This is one of the first contemporary heart failure studies to significantly streamline the trial process in many important ways,” said Robert Mentz, MD, (pictured) co-principal investigator on the study. “It’s designed to have a lighter touch than most heart failure trials and reduce the burden on everyone involved. We’re striving to surpass traditional rates of site activation and patient enrollment.”

TRANSFORM-HF is being led by the DCRI team and Eric Velazquez at Yale University as well as the National Heart, Lung, and Blood Institute, which recently awarded both institutions grants for the Clinical Coordinating Center (CCC) and Data Coordinating Center (DCC). The primary endpoint is all-cause mortality. Secondary endpoints include patient-reported quality of life and hospitalizations.

The trial was designed to improve the clinical research experience for site coordinators and patients at enrolling hospitals. The study has a projected enrollment of 6,000 patients at approximately 50 sites in the U.S. over the next three years. Enrollment criteria are very broad so that those with both low ejection fraction (weak hearts) and normal ejection fraction (stiff hearts) may enroll. Patients are randomized to either furosemide or torsemide as the study drug, but medication dose and frequency are determined by the patient’s usual medical team.

To date, no large, definitive clinical trial has determined which loop diuretic— furosemide or torsemide—is best, and neither American College of Cardiology nor American Heart Association HF guidelines provides a specific recommendation.

“With slow enrollment across many recent heart failure trials, we’ve been in a particularly challenging time for this kind of research,” Mentz said. “So a key aim was to make TRANSFORM-HF as streamlined as possible for site staff as well as patients, many of whom are elderly and might not otherwise enroll because of the burden of participating in a traditional trial.”

TRANSFORM-HF also aims to streamline data collection and enroll a broad representative population of heart failure patients.

During TRANSFORM-HF, heart failure patients admitted to the hospital are enrolled and randomized equally between the two diuretics before discharge, and then continued on that diuretic as part of their daily care after they return home. While most trials require patients to come to the clinic for extra visits, patients in TRANSFORM-HF follow up per usual care with their normal care teams—there are no extra visits.

Instead, study follow-up is coordinated by the DCRI call center, with patients receiving a 15-minute phone call 30 days into the study and then every six months for up to 36 months, asking scripted questions about medication use, quality of life, and hospitalizations. This “televisit” process saves patients the time, effort, and expense of the extra clinic visits usually required from conventional studies. Hospital records and the National Death Index also will be used to gather follow-up information.

“We knew that if questions were to be answered, TRANSFORM-HF needed to be a really large study in addition to being simple, decentralized, and patient-centered,” said Kevin Anstrom, PhD, co-principal investigator at the trial’s DCC. “There was no way we could do this study with the traditional model.”

“We worked closely with sites on the trial design and the processes to enroll patients and collect patient data,” said Eric Eisenstein, DBA, another co-principal investigator at the DCC. “And because the trial is essentially embedded in the patient’s usual care with their healthcare providers, nothing changes for them –we’re not impacting how they’re otherwise treated. Fewer moving parts lowers trial costs and makes it much easier for everyone in the study.”

According to Eisenstein, investigators also wanted to focus on minimizing the amount of data collected throughout the trial, by, for example, limiting the detail of case report forms. They wanted to optimize the process without sacrificing data quality or the study’s scientific validity, he said.

Because investigators are not “dealing with an investigative product where we don’t know the side effects, this kind of comparative study lends itself well to a streamlined model,” said Mary Creed, MSN, associate director of DCRI’s clinical operations.

“That said, we still have the challenge of keeping the study foremost in patients’ minds and helping to prevent dropout, particularly without the in-person site visits. But simple strategies such as wallet cards in English and Spanish and refrigerator magnets should be helpful.”

TRANSFORM-HF is an exception to traditional HF trials where so few patients qualify, according to DCRI Fellow Stephen Greene, MD.

“Most heart failure trials have many exclusion and inclusion criteria, so only a small percentage of patients seen in general practice qualify,” he said. “TRANSFORM-HF is different – the vast majority of patients seen in everyday practice are going to be eligible. This will help the enrollment rate, and importantly, will also generate trial results that will apply to the at-large heart failure community.”

“Loop diuretics are such an incredibly common heart failure therapy that we really need to know if there is a best one to use,” said Greene. “We owe it to the scientific community, and to our patients, to know the best loop diuretic for heart failure patients.”

Other DCRI contributors on TRANSFORM-HF include Ingrid Jones, Sharon Settles, Varsha Gajjar, Wendy Johnson, Joshua D. Lance, Vivian Thompson, Tina Harding, Amanda Harrington, Kristi Prather, Carol Pereira, Rochelle Suffern, and Shelby Morgan.

AHA 2018: DCRI founder Robert Califf honored with Braunwald Mentoring Award

November 11, 2018 – The award is given to physicians who demonstrate excellence in mentoring young academic clinicians.

The American Heart Association (AHA) has awarded DCRI founder and former FDA Commissioner Robert M. Califf, MD, the 2018 Eugene Braunwald Award for Academic Mentoring. The award, which is given to physicians who demonstrate a consistent track record of outstanding mentorship of young academic physicians, was presented to Califf Sunday at the AHA’s annual meeting in Chicago.

For Califf, who is currently the director of Duke Forge, vice chancellor for health data science, and Donald F. Fortin Professor of Cardiology at the Duke University School of Medicine, the award recognizes a commitment to teaching and mentoring that has been a recurring theme throughout a four-decade career as a cardiologist, researcher, teacher, and public servant.

With the exception of an internal medicine residency at the University of California – San Francisco and two years serving as Deputy Commissioner and then Commissioner of the FDA, almost all of Califf’s career, including his time as an undergraduate and medical student, has been spent at Duke University. But despite his long association with Duke, Califf remains keenly aware that learning and mentoring are to be found in many places.

“Mentoring is a two-way street,” said Califf, noting that some of the most profound lessons of his career have been imparted outside of academia.

Although perhaps best known as a leading figure in cardiovascular clinical trials and as the founding director of the DCRI, Califf also taught and mentored multiple generations of academic physicians at Duke, incorporating continuous learning and teaching into the fabric of the institution he helped create. In addition to mentoring individual learners, Califf also contributed to the creation of innovative training curricula, including the DCRI Research Fellowship Training Program and the University of North Carolina-Duke Collaborative Postdoctoral Training Program.

“Without question, he is the single most important influence in my professional development as both a cardiovascular clinician and a cardiovascular clinical researcher,” said Robert Harrington, MD, chair of the Department of Medicine at Stanford University and incoming AHA president. Harrington, who spent more than two decades at Duke as a cardiologist and clinical researcher, first met Califf in 1990 upon arriving at Duke to begin a cardiology fellowship.

“He has an amazing ability to push people into areas where they are not yet accomplished, to step back and let them run a bit on their own, but to always be available when things don’t work out,” Harrington continued, noting that Califf’s mentoring style helped trainees to grow into true colleagues.

His extensive contributions as mentor at Duke were honored in 2012 with the Duke Clinical Research Mentoring Award, and the DCRI’s award given to faculty for outstanding mentorship of fellows is named in honor of Califf. Among the numerous clinicians and researchers, and academic leaders that Califf mentored are Harrington and the Chair of the 2018 Scientific Sessions, Eric Peterson, MD, MPH, – both of whom also followed Califf in the role of director of the DCRI.

During Califf’s remarks at the award presentation, he also issued a call to service. Noting that amid deep cultural and political division the United States is currently experiencing significant health challenges that threaten to erode hard-won gains in life expectancy and quality of life, he challenged his audience to continue to engage with the wider world outside of academic medicine.

“Keeping our heads down in our respective academic or clinical foxholes will not solve the daunting problems that we face both as health professionals and as members of society,” Califf said. “We must work together to re-envision and change the ways that we work to achieve better health outcomes.”

EASD 2018: Albiglutide superior to placebo in reducing MACE risk

October 2, 2018 – The results of the Harmony Outcomes study were published simultaneously in The Lancet.

GSK and the DCRI today announced publication of positive results from the Harmony Outcomes study, which assessed the cardiovascular (CV) safety and efficacy of albiglutide, a GLP-1 receptor agonist, in patients with type 2 diabetes and CV disease. Results were presented at the annual meeting of the European Association for the Study of Diabetes with simultaneous publication in The Lancet.

The study was initiated in July 2015 and GSK remained committed to completing it following an announcement in July 2017 of GSK’s intention to cease further R&D, manufacturing and sales activity for albiglutide (Tanzeum/Eperzan®). Prior studies of GLP-1 receptor agonists when used in patients with diabetes and CV disease had provided inconsistent results regarding the potential benefit, and GSK believed that the data generated from this study could contribute important new evidence to the field.

Adrian Hernandez

Harmony Outcomes was a randomized, double-blind, placebo-controlled study to assess the effect of albiglutide on major adverse CV events in 9,463 patients with type 2 diabetes and cardiovascular disease which took place at 610 sites in 28 countries. Patients were randomized to the addition of once-weekly subcutaneous injection of albiglutide 30mg (potentially increasing to 50 mg) or matching placebo in addition to standard care.

It was hypothesized that albiglutide would be noninferior to placebo for the primary outcome of first occurrence of cardiovascular death, myocardial infarction, or stroke. The study continued until  611 or more confirmed primary outcome events (CV death, myocardial infarction, or stroke) occurred over a median follow-up of at least 1.5 years.

The primary outcome showed that albiglutide, administered subcutaneously once-weekly in 9,463 patients over a median period of 1.6 years, was superior to placebo in reducing the risk of major adverse cardiovascular events (MACE) by 22 percent (95 percent confidence interval [CI] 10 percent to 32 percent) when used in addition to standard of care in patients with type 2 diabetes and cardiovascular disease (p<0.0001 for non-inferiority; p=0.0006 for superiority). MACE occurred in 7.1 percent (N=338) and 9.0 percent (N=428) of patients receiving albiglutide and placebo in addition to standard of care, respectively. Overall, the number of patients who would need to be treated with albiglutide to prevent one event over a median of 1.6 years was 50.

The incidence of acute pancreatitis was  less than 1 percent (10 patients for albiglutide; 7 patients for placebo), as was the incidence of pancreatic cancer (6 patients for albiglutide; 5 patients for placebo). No events of medullary thyroid carcinoma were observed, and other serious adverse events did not differ significantly between the two groups.

“This large cardiovascular outcome trial has shown impressive results for albiglutide in lowering the risk of major adverse cardiovascular events and adds important evidence that certain GLP-1 receptor agonists can improve cardiovascular outcomes,” said the DCRI’s Adrian F. Hernandez, MD, MHS, Duke’s vice dean for clinical research. “Despite the need for treatments to manage these events, there was uncertainty about the cardiovascular effects of GLP-1 receptor agonists as a class due to mixed results from previous studies. We are fortunate that all involved maintained their commitment to participants to complete the trial, which helps address this knowledge gap for patients and clinicians alike on the role of GLP-1 receptor agonists in diabetes.”

“We would like to thank all the investigators and patients who participated in this study,” said GSK’s John Lepore, senior vice president, R&D pipeline. “Harmony Outcomes was an important study for us to complete to generate new data and insights about the role of the GLP-1 receptor agonist class in the management of patients with diabetes and cardiovascular disease.  GSK continued to invest in this study following a decision last year to cease all other activities on albiglutide, and we continue to explore opportunities to divest this medicine to a company with the right expertise and resources to realize its full potential for patients.”



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CV Research at ACC.19

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