Click here to watch the Virtual Top 10 Clinical Research Achievement Awards!

The Clinical Research Forum is proud to announce the 2021 Top 10 Clinical Research Achievement Awards!  

These award-winning studies exemplify major advances resulting from the nation’s investment in research to benefit the health and welfare of its citizens, and reflect the influential work being conducted by investigators at nearly 60 research institutions and hospitals across the United States, as well as at partner institutions from around the world. All nominated studies were published in peer-reviewed journals during 2020.

The Top 10 were selected based on the degree of innovation and novelty involved in the advancement of science; contribution to the understanding of human disease and/or physiology; and potential impact upon the diagnosis, prevention, and/or treatment of disease.

New this year, the CR Forum will also be honoring Pfizer and Moderna for their work on the COVID-19 vaccines with the Clinical Research Forum Award for Extraordinary Impact on Health. This award honors extraordinary clinical and translational research that benefits all peoples and nations and exemplifies the promise of science and the scientific process to solve the huge problems of our time. A representative from both Pfizer and Moderna will be accepting these awards and presenting information on their research. More information can be found here.

Click here to view our 2021 Top 10 Clinical Research Achievement Awards Program!

At our Virtual Event on March 30, 2021, one study will receive the prestigious Herbert Pardes Clinical Research Excellence Award for the research study that best shows a high degree of innovation and creativity, advances science, and has an impact upon human disease, while two studies will receive additional recognition as Distinguished Clinical Research Awardees.

At our Virtual Event on March 30, 2021, three studies received further honors:

• ISCHEMIA Trial, nominated by Stanford University and represented by David Maron and Judith S Hochman received The Herbert Pardes Clinical Research Excellence Award. Named in honor of CR Forum board member Herbert Pardes for his profound impact on clinical research and academic medicine, this award, which comes with a $7,500 cash prize, is for the research study that best shows a high degree of innovation and creativity, advances science, and has an impact upon human disease.

• Integrating Global Health with the Microbiome, nominated by Washington University and represented by Dr. Jeffrey Gordon, and Selumetinib in Children with Inoperable Plexiform Neurofibromas, nominated by National Cancer Institute and represented by Dr. Brigitte Widemann both received Distinguished Clinical Research Achievement Awards, presented to the top two studies that show creativity, innovation, or a novel approach that demonstrates an immediate impact on the health and well-being of patients. Each study received a $5,000 cash prize.

The 2021 Top 10 Clinical Research Achievement Awardees are (in alphabetical order according to title):

Anti-Selig-8 Antibody for Eosinophilic Gastritis and Duodenitis -Evan Dellon, MD, MPH, Professor of Medicine, Division of Gastroenterology & Hepatology, University of North Carolina at Chapel Hill

• Eosinophilic gastrointestinal disorders are an under-recognized cause of gastrointestinal illness. Increasing in incidence for reasons that are unclear, eosinophilic GI disorders have no FDA-approved therapies. Dr. Dellon and his colleagues performed a randomized controlled trial of lirentelimab, an anti-Siglec-8 antibody, in patients with eosinophilic gastritis and duodenitis. This monoclonal antibody depletes eosinophils and inhibits mast cells, which are thought to be critical in the pathogenesis of these diseases. After four monthly infusions, patients receiving the monoclonal antibody had an 86 percent reduction in mean eosinophil counts from mucosal biopsies, compared to a nine percent reduction in controls. Additionally, treated patients experienced a 48 percent decrease in a standardized symptom score, compared to 22 percent in the placebo group. Both of these results were highly statistically significant.

  This study provides a potential therapeutic option for conditions afflicting thousands of patients, for whom other treatments were inadequate or too toxic for long-term use. It also provides proof-of-principle to advance our understanding of the pathogenesis of these conditions and their potential treatments. Given the significant challenges to treating EG and EoD, this study could significantly improve patient care.

Evaluation of the anti-SARS-CoV-2 humoral immune response in a cohort of COVID-19 convalescent individuals – Christian Gaebler, MD, Instructor in Clinical Investigation, Rockefeller University

• In April 2020, during the peak of the COVID-19 pandemic in New York City, Dr. Gaebler and his team studied blood samples collected by the Michel Nussenzweig laboratory at Rockefeller University from 149 volunteers who had recovered from COVID-19. While ~75 percent of the individuals had IgG antibodies to the SARS-CoV-2 spike protein and the receptor binding domain (RBD) on the spike protein, the majority generated relatively poor plasma SARS-CoV-2 neutralizing activity as judged by a pseudo virus neutralizing assay developed by Dr. Paul Bieniasz at Rockefeller. The team was also able to identify individual B cells that bound an RBD peptide, and thus could determine from the DNA sequences that antibodies produced by different people had structural similarities. Most importantly, as a prelude to developing monoclonal antibodies (mABs) for therapy and prevention of COVID-19 from the B cells from these patients, they found antibodies that were extremely potent in neutralizing authentic SARS-CoV-2. Moreover, these antibodies could be grouped into ones that can bind simultaneously to the RBD, making it possible to pair such antibodies in ways that will make it much harder for the virus to escape by mutating the RBD.

  This study lays the groundwork for a major potential addition to resources against the COVID-19 pandemic. At the same time, by rigorously analyzing the antibodies that neutralize the virus at the genetic level, it provides important information for assessing antibody responses to the many vaccines under development.

Genome-wide cell-free DNA mutational integration enables ultra-sensitive cancer monitoring – Dan Landau, MD, PhD,  Associate Professor of Medicine, Weill Cornell Medicine

• For many tumors, the chance of recurrence after initial treatment is quite high and scientists lack the ability to detect those recurrences early, when they are most treatable. Dr. Landau and his team identified that in solid tumor oncology, the need for advanced monitoring tools is extremely urgent. Dr. Landau and colleagues found that targeted sequencing approaches work only when circulating tumor DNA in blood samples includes sufficient fragments containing the targeted mutations yet in many cases, the tumor burden is much too low. In fact, standard targeted-sequencing techniques often miss small tumors that are evident on standard imaging scans. Even after cancer is diagnosed, medicine lacks sensitive tools to guide difficult therapeutic decisions such as adjuvant therapy. Sensitive cancer detection by blood biopsy can therefore transform care by enabling early detection and residual disease monitoring. Dr. Landau and his team replaced the prevailing paradigm of looking at a few DNA hotspots very thoroughly, with an innovative approach that detects minute amounts of tumor DNA by identifying mutations across the entire genome. The new method therefore involves the sequencing of all circulating DNA in a patient’s blood sample whole genome approach that boosts the effective sensitivity by one to two orders of magnitude. Thus, the novel DNA-sequencing strategy, powered by machine learning, may pick up even very low levels of tumor DNA in blood samples, potentially enabling the early detection of cancer recurrence after surgery or other treatments. The team demonstrated the method’s potential value with blood tests on patients who had melanomas, colorectal cancers and lung cancers.

  The results showed that the new technique can be used to detect blood-born tumor DNA even when it is much too sparse to be detected by existing methods, and many months or even years before recurrence is evident in imaging studies. This work will thus pave the way towards ultra-sensitive cancer detection, enabling transform cancer treatment in which therapeutic optimization is guided by real-time monitoring of tumor burden.

Integrating Global Health with the Microbiome – Jeffrey Gordon, MD, Dr. Robert J. Glaser Distinguished University Professor, Washington University

• Despite childhood malnutrition being the leading cause of death among those under five years old, current interventions have had limited success addressing this global heath challenges that is not due to food insecurity alone. This highlights the need for a more comprehensive understanding of mechanisms underlying malnutrition. One testable hypothesis is that proper assembly of the gut microbial community (microbiota), beginning at birth, is linked to healthy growth of infants and children. The role of the small intestinal microbiota is particularly enigmatic in part because of the difficulty in obtaining samples. Environmental enteric dysfunction (EED) is a disease of the small intestine characterized by a reduction in its absorptive area and chronic inflammation of the bowel wall. Most attempts to diagnose EED have relied on non-validated fecal and/or blood biomarkers. To examine the role of the small intestinal microbiota in the pathogenesis of EED and its relationship to stunting, 12-18 month-old Bangladeshi children who were stunted and failed a standard nutritional intervention underwent endoscopy to characterize their duodenal microbiota. The results revealed that duodenal levels of 14 different bacteria, present in >80 percent of children with biopsy-confirmed EED, were positively correlated with their stunting and gut inflammation.  

  Furthermore, when young germ-free mice were colonized with duodenal bacteria cultured from these children, they developed features of EED in their small intestines. Together, these results provide evidence of a causal link between the small intestinal microbiota, EED and stunting, and identify new (microbial) therapeutic targets.

  The study of the duodenal microbiome and undernutrition reclassifies our understanding of gut physiology in children with stunted growth. The authors identify the duodenal microbiome as a plausible causal factor underlying stunting and pinpoints specific strains capable of transmitting enteropathy in a mouse model. Moreover, their proteomic analysis identified a swath of potential biomarkers and mechanistic drivers of stunted growth.

ISCHEMIA Trial- David Maron, MD, Professor of Medicine, Stanford University School of Medicine; Judith Hochman, MD, Professor of Medicine, NYU Grossman School of Medicine

• Ischemia of the heart occurs when cholesterol deposits narrow heart arteries and reduce blood flow to the heart muscle. Ischemia can cause chest pain, also known as angina. It is common for people who develop chest pain to have a stress test, however, it is not clear how best to treat patients with ischemia who have abnormal results on a stress test. For this reason, the ISCHEMIA trial compared two standard treatments, invasive and conservative, to learn which is better. The invasive approach involves cardiac catheterization, a procedure to take movies of the heart arteries, where then narrowed heart arteries can either be opened with a balloon and metal tubes called stents, or heart surgery can bypass the narrowed artery. The invasive approach also includes medicines (aspirin and cholesterol-lowering drugs) and lifestyle changes (like eating healthy food, exercising, and not smoking). The conservative approach involves treatment with medicines and lifestyle changes only.

  More than 5,000 people from 37 countries participated in the trial. Half were assigned to the invasive group and half were assigned to the conservative group. After an average of three years of follow-up, there was no overall difference between groups in major events like heart attack and death. People with angina (chest pain) who were assigned to the invasive treatment group had less angina, which improved their quality of life. With this information, patients and their doctors now understand that doing invasive procedures does not reduce the chances of a heart attack or dying, but does improve symptoms.

  The trial highlights the importance of using a validated instrument to assess patient-reported anginal symptoms, and provides critical information to use in shared decision-making between physician and patient when deciding whether or not to manage the disease with revascularization. Such decisions affect more than 9 million patients in the U.S. with stable angina, only one-third of whom take aspirin, statin, and beta-blocker (part of optimal medical therapy). This research has the potential to improve the management of millions of patients around the world.

Kisspeptin in the Evaluation of Delayed Puberty -Stephanie Seminara, MD, Professor of Medicine, Massachusetts General Hospital; Yee-Ming Chan, MD, PhD, Assistant Professor of Pediatrics, Boston Children’s Hospital; Margaret Lippincott, MD, Instructor in Medicine, Massachusetts General Hospital

• Delayed puberty affects over two percent of children, and most children with delayed puberty have a condition called constitutional delay, a self-limited condition in which puberty is late to start but, once started, proceeds normally. However, some children with delayed puberty have a problem called idiopathic hypogonadotropic hypogonadism (IHH) and require medical treatment to go through puberty. Currently, there is no way to determine in advance which children have constitutional delay and which have IHH. As a result, children with IHH often experience significant delays in starting treatment, as they are often assumed to have constitutional delay and advised to wait for a puberty that will never come.

  The key biological innovation of this study was recognizing that giving a child with delayed puberty a dose of the hormone kisspeptin provides a glimpse into the future for that child. Kisspeptin is a key reproductive hormone that activates the reproductive endocrine system (the system of hormones that causes puberty to occur). Before the onset of puberty, the body produces little kisspeptin, and the reproductive endocrine system is relatively quiescent. The start of puberty is marked by increasing production of kisspeptin, and by the end of puberty the reproductive endocrine system reaches adult levels of function. In children with IHH, the reproductive endocrine system does not function properly, and puberty never occurs. However, in a child for whom puberty has not yet started and the reproductive endocrine system is still inactive, it can be impossible to determine whether the reproductive endocrine system is intact or not. By giving a dose of kisspeptin as part of a diagnostic test, the study was able to mimic the kisspeptin that the body would produce during puberty and thereby assess the integrity of the reproductive endocrine system. A normal response to kisspeptin would indicate that the reproductive endocrine system can function properly given the right stimulus and would predict eventual pubertal entry. In contrast, inability to respond to kisspeptin would indicate dysfunction of the reproductive endocrine system and would allow a diagnosis of IHH.

  In this study, the children with delayed puberty who responded to kisspeptin all later entered puberty, demonstrating that their reproductive endocrine system was intact and that the kisspeptin-stimulation test could reveal this future potential. Conversely, the children who did not respond to kisspeptin did not enter puberty, demonstrating that the kisspeptin-stimulation test could also reveal when the reproductive endocrine system could not function properly.

  The kisspeptin-stimulation test cleanly distinguished children with constitutional delay from those with IHH. This major advance will allow children with IHH to receive prompt diagnosis and treatment and children with constitutional delay to receive appropriate reassurance.

Remdesivir in COVID 19–John Beigel, MD, Associate Director for Clinical Research, National Institute of Allergy and Infectious Disease, NIH

• More than 53 million children and adults have COVID-19 infections throughout the world. Although several therapeutic agents have been evaluated for the treatment of COVID-19, no antiviral agents have yet been shown to be effective. Dr. John Beigel and his team of researchers conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults who were hospitalized with COVID-19 and had evidence of lower respiratory tract infection. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only. A total of 1,062 patients underwent randomization. In an analysis that used a proportional-odds model with an eight-category ordinal scale, the patients who received remdesivir had a median recovery time of 10 days, as compared with 15 days among those who received placebo.

  The team’s data showed that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with COVID-19 and had evidence of lower respiratory tract infection. This study resulted in the first FDA-approved therapeutic for COVID-19, paving the way for more treatment options and greater access.

Ruxolitinib for treatment of vitiligo - David Rosmarin, MD, Assistant Professor of Dermatology, Tufts Medical Center

• Vitiligo is a disease of depigmentation, where the immune system kills off the pigment cells, causing white spots on the body. Despite its high prevalence in about 0.5 to 2 percent of the population, not a single medication is currently FDA approved to repigment patients who suffer from vitiligo. Dr. Rosmarin and his team are helping meet the clinical need for reliable vitiligo treatments. Involving 26 centers in 18 states across the U.S., the study presents solid evidence for the efficacy and safety of a topical formulation of the Janus kinase (JAK) inhibitor, ruxolitinib.

  The team compared the use of a topical JAK inhibitor with that of a placebo cream, conducting the largest randomized controlled study every done in vitiligo. The results showed that after one year of use of the medication, about half of the patients achieved 50 percent or more repigmentation for the whole body. Since the pathogenesis of the disease is superficial within the skin, a topical delivery system can be used instead of a systemic oral treatment, with a goal of minimizing side effects. Furthermore, JAK inhibition can also have pro-melanocytic effects which may counteract a further problem in the pathogenesis of vitiligo.

  The study offers strong evidence for a new understanding of the specific immune system mechanisms that cause vitiligo. The tested compound is already being used to treat the disorder.  Based on this work, there are now multiple studies in earlier development evaluating JAK inhibitors for the treatment of vitiligo. The study has also helped to establish a pathway and trial design for others to follow to be able to determine if a vitiligo treatment is effective.

Selumetinib in Children with Inoperable Plexiform Neurofibromas - Brigitte Widemann, MD, Deputy Director, Center for Cancer Research, National Cancer Institute

• Neurofibromatosis type 1 (NF1), is a progressive genetic disorder that affects 1 out of 3,000 individuals. One of the most devastating problems in NF1 is the development of tumors, plexiform neurofribomas, that typically grow in very young children. These tumors can cause compression of the airway, blindness, difficulty moving, disfigurement, and pain, which is difficult to control. In some cases, they can transform to an aggressive form of cancer. Unfortunately, for most patients, surgical removal is not feasible and there is no effective medical treatment for patients with NF1.

  Dr. Widemann’s team conducted phase I/II clinical trials of selumetinib, a specific MEK inhibitor, in children with inoperable plexiform neurofibromas, which were causing clinical problems such as pain, disfigurement and motor weakness. After a series of negative prior clinical trials with targeted therapies, selumetinib demonstrated unprecedented preclinical and clinical activity in NF1 plexiform neurofibromas. Selumetinib resulted in partial responses in 74 percent of patients and a progression free survival of 84 percent after three years on treatment.

  The team observed tumor shrinkage in the majority of patients, which was unprecedented compared to previous clinical trials. In addition, and most importantly, the majority of patients experienced improvement in pain, quality of life, or function and thus direct clinical benefit.

  Due to Dr. Widemann’s pivotal and pioneering work, selumetinib was approved by the Food and Drug Administration, and is now available as the first treatment to help children with NF1 across the United States.

The CENTAUR Trial for ALS- Sabrina Paganoni, MD, PhD, Co-Director Neurological Clinical Research Institute, Massachusetts General Hospital

• ALS (Amyotrophic Lateral Sclerosis) is a fatal neurodegenerative disease. The lifetime risk of getting ALS is 1 in 400 and most ALS patients only live 2-4 years. The CENTAUR trial is the first trial to demonstrate positive effects of an investigational product on both functional outcomes and survival in people with ALS. ALS remains a uniformly fatal disease and the two FDA-approved medications only produce modest benefits.

  Dr. Paganoni and her team tested a new drug called AMX0035 in the CENTAUR trial. AMX0035, is a combination of two molecules (Sodium Phenylbutyrate and Taurursodiol) that each target a different molecular mechanism underlying ALS, endoplasmic reticulum stress and mitochondrial dysfunction, respectively. When combined in a fixed ratio in cell culture models of neurodegeneration they were found to have synergistic effects. The CENTAUR trial was the first trial to test this combination in people with ALS. Participants who took AMX0035 retained physical functions and lived longer than those who received placebo. Depending on the individual this could mean the difference between walking independently or needing an assistive device, or being able to feed themselves independently or needing a feeding tube. The team was able to see treatment effect in a relatively short period of time (6 months). In addition, when the team followed trial participants for up to three years, they saw that patients who were originally assigned to AMX0035 lived longer than those who were given placebo (their risk of death was 44 percent lower).

  The results of this trial are currently being used to support a New Drug Application in several territories including the United States. This is the first time that a new drug is shown to have positive effects on both physical function and survival in ALS.

The Top 10 Awardees will be honored at the Top Ten Clinical Research Achievement Awards Virtual Event on March 30, 2021. In addition, winning researchers will receive complimentary registration and present their work at the 2021 Translational Science Virtual Meeting.

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