A clinical trials consortium

Consensus on clinical treatment protocols – with patient outcome benefits. The opportunity to gather and produce treatment protocols (standard operating procedures, SOPs) by consensus of the trauma and burn centers participating in the program produced significant improvements in survival and a reduction in morbidity for blunt-injured patients.

• Glue Grant investigators created ten SOPs for severe blunt trauma and these were individually published as a series in the J Trauma and Acute Care Surgery. The trauma SOPs have been adopted for use in several large federally funded clinical trials.  In addition, the investigators developed SOPs for severe burn injury and published the SOPs in the J Burn Care and Research. PubMed PMID numbers: 16361929; 16688078; 16832253; 16917462; 17351437; 17414328; 18073622; 18090028; 18849816; 19077651; 19077652; 19667895)
• With the implementation of the SOPs together with external audit of SOP compliance, the mortality rate for the severe blunt trauma patients was reduced by 50% (22% vs. 11%) over the course of the seven-year study. PMID number: 22470077
• In comparing our mortality with APACHE II and TRISS-predicted rates or with the National Trauma Data Bank patients from over 2.4 million NTDB records, the observed mortality in the Glue Grant cohort was dramatically better than predicted by APACHE II across all quintiles and based on TRISS, markedly improved in those patients from the most critically ill quintile. PMID number: 22470077
• When comparing the survival results of patients from the burn centers in the Glue Grant with those approximately 200,000 inpatients reported to the National Burn Repository, the patients in the Glue Grant study had a statistically significant 29% survival benefit in comparison to the patients reported in the NBR. PMID number: 24722222

Capability to enroll sufficient numbers of critically ill patients of all ages. The patient research core of the program functioned as originally envisioned to provide the large-scale collaborative research project with clinical, physiological, pathophysiological, and outcomes data together with biological samples to support the analysis and interpretation of the numerous phenotypic, proteomic, and genomic alterations and interactions in patients with severe injury-induced, innate immune and particularly inflammatory responses.  The quality of the samples in the critically ill patients from emergency departments and intensive care units in terms of proteomics and genomics is of excellent quality and as good as one can achieve in a laboratory under highly controlled model studies. Our twelve Level I trauma and burn centers enrolled more than 2,600 patients and controls for the Glue Grant studies: blunt trauma 494, burns 484, epidemiology 1,633, and controls 199.

The Glue Grant studies enrolled children with burn injuries while the trauma studies were limited to those age 16 years or older.  The investigators uncovered distinct genomic differences that at least partly point to the immaturity of a child’s immune system.  The analysis revealed that 21% of the genes were age-specific and principally involved the differential expression of mitochondrial and immunoglobulin genes that were responsive to burn injuries in pediatric versus adult burn patients (PMID number: 20479259). These new findings in the body’s response to burn injury in children versus adults support further investigations of therapeutic options targeting specific age groups.  Furthermore, the Glue Grant’s technology developments in the field of microfluidics for blood sampling have direct relevance to the pediatric patient in that the new technology enables clinicians to obtain highly enriched information from increasingly smaller blood volumes as seen in children.

Capacity to form new questions and hypotheses. The Glue Grant was a discovery-based science program and even after 12 years, investigators are uncovering exciting, potentially clinically important observations that are leading to new questions and hypotheses.  These “discoveries” are not only coming from the Glue Grant investigators, but also from the program’s Consortium Members and scientific community who have recognized the potential value of this vast experimental data.

The program’s overall strategy is to sustain the infrastructure as well as the resources, tools, and analytical methodologies developed in the Glue Grant through funding collaborations with other federal funding agencies, industry, and foundations.  In 2013, we were recruited by a consortium led by Puget Sound Blood Center (PSBC) to lead the “Inflammation and Vascular Research Core” for a UM1 Multi-Component Research Project Cooperative Agreement through the NHLBI Trans-Agency Research Consortium for Trauma-Induced Coagulopathy (TACTIC).   Also in 2013, the Glue Grant investigators participated in a U54 grant application with Lawrence Livermore National Laboratory as the PI for the application of novel methods of supercomputing for biomedical data analysis.  Although these applications were not funded, the Glue Grant investigators have established new working relationships with the scientists and engineers at PSBC and LLNL and are fully committed to exploring future large initiatives within NHLBI, NIGMS, and DARPA.

Attractiveness of a clinical trials consortium.  A by-product of the Glue Grant program is the creation of an infrastructure than can be leveraged with federal agencies, foundations, and industry partners to promote the development of clinical trials in the fields of trauma and burns.  Unlike other medical communities including cancer, heart disease, arthritis, and diabetes wherein the NIH serves as the cornerstone for important clinical research, this infrastructure does not exist in trauma.  The major obstacles to industry-sponsored clinical trials in trauma and burns have been essentially eliminated with the creation of this clinical trials consortium:

• The institutions and participating investigators are well established centers with a proven track record for enrollment in studies of critically ill patients
• The treatment methods are standardized to reduce the impact on the genomic and proteomic responses
• The institutional review board process is streamlined with uniform protocols and consent forms
• A well-defined, homogeneous, critically ill patient cohort has been identified for study

Federal agencies or industry leaders with an interest in the inflammatory process could gain important new knowledge from clinical trials in injury, including the identification of important, fundamental biological mechanisms associated with improved patient outcomes.

Use of genomic profiles and markers for prognostics. As an extension of our program contributions for the future, the Glue Grant investigators have organized several “post-Glue” grant applications applying our new knowledge and methodologies.  The funded projects include a NIGMS R01 for the project “Bedside genomics in severe trauma” to optimize a statistical model for the prediction of clinical recovery and a R34 grant for “Planning a multi-center trial of interferon-gamma in trauma patients.” The 2014 planning grant supported the development of the rationale and design of a new interventional clinical trial entitled “Prospective randomized trial of interferon-gamma in severe trauma” to be submitted to NIGMS in February 2015.

The proposed clinical trial is the next logical step to carry the Glue Grant forward in an effort to take the descriptive discovery science obtained from the Glue Grant and apply it to several of the most pressing issues confronting the management of the trauma patient.  Of interest has been the recent observation that different clinical trajectories over several weeks can be identified with changes in gene expression measured in the first 24 hours after injury.  In particular, Glue Grant investigators have identified 63 blood leukocyte genes whose expression in the first 24 hours could distinguish those patients who were destined to have a complicated clinical course and organ failure.  This subset of patients, who will likely have a protracted clinical course based on their early leukocyte transcriptome, might benefit from interventional therapies with biological-response modifiers.

The current project takes the bold and innovative next step to use a prognostic biomarker based upon the leukocyte genomic response to trauma determined in the first 24 hours post-injury to prospectively predict clinical trajectories (uncomplicated versus complicated patient groups).  Our overarching hypothesis is that immunological interventions can improve clinical outcomes in a subset of severely injured patients, but the challenge is to identify those patients prospectively, and to intervene with the appropriate biological-response modifier at the correct time.  It is possible, if not likely, that the exogenous addition of interferon might improve the genomic signature or profile, and that this improvement in the genomic profile might be associated with improvements in the patient’s outcome.

When successful, the clinical trial will be the first of its kind to combine a prospective, defensible biomarker-based entry criterion with a clinically appropriate biologic therapy to evaluate its efficacy in a subgroup of patients expected to have a complicated clinical course and recovery.

Contact

Ronald Tompkins, MD, ScD	Ronald Maier, MD	David Herndon, MD	Lyle Moldawer, PhD
617-726-3447	206-744-3299	409-770-6731	352-265-0494

Visit the Glue Grant program website

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