... Chronic effects of traumatic brain injury (TBI) can persist years after the initial injury, with profound effects on patient and family well-being. These effects and their connection to prior TBI can go unrecognized; striving to include patient and family voices in TBI ...

... Innovative clinical trial designs include adaptive, platform, and sequential multiple assignment randomized trials, and they can yield substantial operational and inferential efficiencies and improve patient centeredness. (Lewis)...

... Effective TBI therapies will likely be characterized by combination treatments, sequences of treatments, and treatments matched to specific patient subgroups. Innovative trial designs are well suited to measure treatment benefit for such therapies. (Lewis)...

... Clinical trial design challenges in the field of TBI are not unique, and much can be learned from the use of innovative trial designs in other fields. (Lewis)...

... 1 This list is the rapporteurs’ summary of points made by the individual speakers identified, and the statements have not been endorsed or verified by the National Academies of Sciences, Engineering, and Medicine. They are not intended to reflect ...

... The success of a clinical trial is characterized by efficiently and definitively answering the motivating question, regardless of whether that answer is positive or negative. (Lewis)...

... Many academics are unfamiliar with research and development (R&D) commercialization considerations, such as intellectual property issues, regulatory navigation, and industry nomenclature. ...

... Selective calpain-2 inhibitors block a pathway that leads to neuronal damage, and an identified blood biomarker reflects brain activation of this pathway, enabling determination of drug effectiveness. (Baudry)...

... Sex differences are at play in brain injury, demonstrated by variations seen between women and men in the recovery of cortical thickness and by a relationship identified between TBI outcome and the phase of menstrual cycle during which TBI occurred. (Adamson)...

... Research efforts should incorporate considerations regarding sex differences in TBI, adequate female sample size, and the increased comorbid mental health symptoms found in women with TBI, particularly those who sustained TBI from an assault. (Adamson)...

... Advances in biomarker discovery and their intersection with AI-based tools offer exciting new opportunities to design drugs for TBI. (Haskins)...

... The fifth session of the workshop featured a firsthand account from the father of a traumatic brain injury (TBI) survivor of her injury and the long-term ramifications on her and her relatives’ lives. The session then explored innovative clinical trial designs to increase learning ... efficiency in evaluating therapeutics for heterogeneous medical conditions such as TBI, (2) presenting an evolving evidence base for pharmacological and nonpharmacological therapies in TBI—including examples of ongoing clinical research—and future directions, and (3) highlighting challenges in ... academic research to therapeutic interventions, including regulatory and industry barriers. Ramon Diaz-Arrastia, professor at the University of Pennsylvania, moderated the session....

... new diagnostics that will not necessarily affect treatment. However, Diaz-Arrastia contended that the value that accurate diagnosis and prognosis brings to patients is itself of critical importance. Development and widespread buy-in and implementation of both diagnostic and ... strategies will involve the use of biomarkers to identify and enroll the patients best suited to participate in a given clinical trial. Prognostic or predictive biomarkers could aid in the selection process, he ... , and could also inform the particular therapy that specific patients are more likely to benefit from. Pharmacodynamic biomarkers could facilitate ... of optimal dose, timing, and duration of therapies. Diaz-Arrastia maintained that developing the suite of biomarkers needed in the TBI field will be an iterative process....

... A LIVED EXPERIENCE PERSPECTIVE...

... E. Wesley Ely, parent of a family member with TBI and professor and Grant W. Liddle endowed chair in medicine at Vanderbilt University School of Medicine, described how his daughter sustained TBI as a child and the decades of ramifications she and her family have experienced as a result. ...

... As I dipped my feet into the water, I sensed a flash of pink out of the corner of my eye and turned my head. A child was falling from the diving board, my child, 15 long feet toward the pavement below. I heard the thud as her head hit the ... , blood spilling, and watched her body crumple in on itself and flop unconscious over the edge into the pool. I plunged in and scooped her out, laying her gently on the hot cement like a broken bird. Her body was limp, but then reared up fighting me, flailing, seizing. And as ... slid inside a two-inch split in her skull, touching ragged edges of bone, a fracture. I knew this was how lives changed in an instant, a line in the sand marking before and after. I raged, banging my fists on the ground, screaming, “Why God, why?” As I lifted my eyes, I saw Kim standing frozen, ...

... Ely’s daughter was taken by ambulance to the Vanderbilt Emergency Department where scans revealed that she had fractures on both sides of her skull that extended through her foramen magnum (the ... the skull through which the spinal cord passes). After several days in a neuro intensive care unit (ICU), doctors told Ely that his daughter was fine and would fully recover. Noting that he is an intensivist and his wife is a pathologist, Ely remarked that for years providers—including those in ... and neurosurgical services—assured them that their daughter was...

... perplexed 25 years ago by patients who faced persisting issues after being discharged from the ICU, including unemployment, broken relationships, and suicidal ideation. Studying postintensive care syndrome and Alzheimer’s disease and related dementia, he described being unaware that his daughter ...

... Ely described how the post-TBI challenges his daughter faced placed significant stress on both her and the family, reflecting that she had strived and struggled to find her place in the world. Ely described witnessing his daughter’s hardships as a brutal experience for a father, commenting that ... his perspective the precarious situations, decision-making choices, personal struggles, and job, mental, and physical health challenges she encountered took a toll on the entire family. His marriage suffered and he spent years suppressing his pain, focusing ... on a need to control his life and career. In the past 5 years, he noted that he has become active in Al-Anon—a spiritual but nonreligious program for people with a loved one ... with addiction—and reflected that his involvement with the Forum on Traumatic Brain Injury led to his understanding that his daughter has chronic TBI. At a forum meeting shortly after its creation, he realized the long-term effects from his daughter’s TBI and ... into tears in the meeting room. He recounted his shock at realizing that so many years had passed without understanding the full entity that his daughter and family were contending with. Ely stated his hope that forum efforts will address long-term—not just acute� ... �TBI and consider the ways that patients, families, spouses, and others suffer in facing the challenges of TBI. He remarked that people directly affected by TBI must be given a voice, because in the absence of ...

... at the University of California, Los Angeles, explored the benefits of innovative clinical trial designs before outlining various design types and examples of studies using innovative designs (such as those discussed in Berry et al., 2015; Woodcock and LaVange,...

... 2017; Butler et al., 2018, Kidwell and Almirall, 2023, and other sources).2 Underscoring the hardships described by Ely, he stated his hope that more effective therapies for the treatment of TBI will be ... and that this will lead to changed narratives for the patients and their families in the minutes, days, weeks, and decades after injury. Similar to many complex therapeutic areas, numerous challenges face later stage development (i.e., phases II and III3) and ... of new treatments for TBI. He remarked that many of the concepts pertinent to acute TBI treatments also apply to diagnostics, rehabilitation, and long-term therapy....

... Highlighting the complexity and heterogeneity of the TBI patient population and injuries as key challenges, Lewis noted that most TBI treatments are not effective and fail when tested in clinical trials. Effective therapies are ... by (1) combinations of treatments, (2) sequences of treatments, in which decisions within the sequence are dependent on individual patient responses, and (3) therapies matched to specific responding subsets of patients identified by biomarkers, imaging patterns, electroencephalography (EEG), clinical ... been slowed by a disconnection between typical trial design—which tends to be overly simple with questions distilled down to a single focus—and care delivery and characteristics of the patient population, both of which are highly complex, Lewis asserted....

... unique about the clinical trial design challenges in the field of TBI in comparison to other fields. The statistical models are agnostic to disease and operate the same across diseases, yet the diffusion of innovation advances in the field of TBI has been slow. In bringing innovative clinical trial ...

... 2 Lewis noted that his academic and employment relationships include the County of Los Angeles Department of Health Services, David Geffen School of Medicine at UCLA, and Lundquist Institute for Biomedical Innovation, as well as Berry Consultants LLC, which works in adaptive trial design. He ...

... 3 In clinical research, phase I studies involve a small number of participants and aim to understand the safety of a treatment and help identify dosage, while phase II studies explore its efficacy and side effects. Phase III studies are late-stage trials to test efficacy in ...

... run on a specific disease, as if the disease determines the performance of a clinical trial design. Another common question is whether the U.S. Food and Drug Administration (FDA) approved a drug or device evaluated in the trial, given that when FDA denies clearance, this is typically because of the ...

... area of uncertainty. For instance, when researchers are not confident about the dose, patient population, or proper outcome measure to use in a test, and the option they select does not yield satisfactory answers, they may anticipate making a choice that they later regret. These areas of anticipated ...

..., rather than running separate trials for each treatment being evaluated. Inferential efficiencies involve making better use of the available data and can include adaptive designs and response-adaptive randomization. He explained that response-adaptive randomization randomizes patients ...

... Adaptive designs have prespecified rules for using incoming data to modify trial characteristics, such as randomization ratios, sample size, or enrollment criteria. Trial characteristics are modified to mitigate the risk of failure, to improve treatment of ... within the trial, and to achieve statistical efficiency to reach a conclusion as early as possible, whatever the conclusion may be. He noted that time to information is ... in an adaptive trial, and an outcome measure must become rapidly available to provide stimulus for the trial’s response. For many acute and medium-term TBI treatments, the outcomes are known fairly early because differences in patient groups and recovery trajectories are at focus, rather ...

... Presenting recent examples of adaptive trial designs in practice, Lewis summarized two trials in ischemic and hemorrhagic stroke. In a trial evaluating thrombectomy for patients with large vessel occlusion stroke,4 researchers were uncertain whether a size ... to the treatment, at which point they would narrow the trial. Researchers found that the therapy worked broadly across the patient population, and the trial adaptation of narrowing the population was never needed because the full population saw benefit....

...) (Pradilla et al., 2024). In this trial, investigators were uncertain whether the therapy would work equally well in anterior basal ganglia locations and in lobar locations for ICH. As the trial progressed, the algorithm found that the benefit of the therapy seemed to be located only in those patients ... lobar locations of ICH. Instead of potentially ending with a failed trial, researchers ceased enrolling patients with a basal ganglia location and went on to demonstrate tremendous benefit in the responding subpopulation of patients with lobar...

... 4 This was the Diffusion-Weighted Imaging or Computed Tomography Perfusion Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo (DAWN trial)....

... the platform trial to a sports stadium hosting multiple games in that the stadium does not have to be rebuilt for each match. Treatments enter and exit the platform and are evaluated against one another and against the control or standard of care, thereby generating tremendous operational ...

... of TBI patients during initial resuscitation. Lewis explained that a platform trial might begin with the investigation of three agents: A, B, and C versus control (see Figure 5-1). Researchers may stop testing one or more agents if they find the treatment harmful or futile. Should one of the ... arms perform better than the control, the trial is not ended and restarted from the beginning; instead, the better therapy now becomes the standard of care, and the trial can continue....

... believe that platform trials are only used in oncology, but this design has been used in trials for a variety of conditions, including COVID-19 and amyotrophic lateral sclerosis, Lewis stated. He commented that the fear generated by the COVID-19 pandemic made people more receptive to innovation ... clinical trial design, which accelerated use of these approaches during the pandemic. The National Institute of Neurological Disorders and Stroke has initiated a major effort to launch a multicenter adaptive platform trial in acute ischemic stroke....

... Platform trials have multiple potential efficiencies that can be categorized as structural efficiencies, adaptations, and statistical approaches. He specified that because multiple therapies are used for patients during the acute postinjury period of TBI, multiple ... to compare neuroprotectants—or hemostatic treatments, in the case of hemorrhage indicated by computed tomography (CT)—would conduct factorial randomization in which the patient would be randomized to one option within each of the domains of...

... FIGURE 5-1 Depiction showing potential features of a platform trial design. A, B, and C represent potential treatments being investigated through the trial. During the trial, treatment C is found to be ineffective or harmful and is ... . Treatment B is found to be better than the initial control or standard of care (SOC). Treatment B then becomes the new standard of care against which performance of other treatments is evaluated. D and E represent new treatment arms that may join the ongoing trial....

... an individual patient regimen. He explained that this approach allows the individual patient to yield information on how best to control hemorrhage and on the effectiveness of the neuroprotectant, thereby fundamentally accelerating the speed with which both therapeutic areas can be evaluated. Lewis ...

... FIGURE 5-2 Depiction of a multifactorial platform trial. In this example, treatment options in two different therapeutic areas, neuroprotection and hemostasis, are studied. Each patient receives one treatment option from each area. For example, the depicted patient receives as their regimen both ... drug A (NP A) and a hemostatic treatment. Other patients will receive different regimens. Such a trial design accelerates evaluation of treatments in these two ...

... by comparing results on interleukin-6 antagonists, anticoagulation in seriously ill patients, anticoagulation in noncritically ill patients, and in other areas (Goligher et al., 2021; Gordon et al., 2021; McQuilten et al., 2023)....

... Sequential Multiple Assignment Randomized Trial Design...

... Sequential multiple assignment randomized trials (SMART) are specifically designed to evaluate sequences of therapies in which the treatment choice at each randomization point is ... on the patient’s response to prior therapy, Lewis explained. In a SMART, a patient is randomized between available options for initial management. Some patients will respond well to the therapies they are assigned to, whereas others will ... . The patients that fail to respond to their assigned therapy are randomized between alternative secondary or second-line treatments. He highlighted a SMART design that rigorously evaluates the overall effectiveness of ... separate treatment algorithms (Kidwell and Almirall, 2023). Lewis stated that this design could be applied to address variability in patient response to treatments received over time to ...

... Benefits and Common Pitfalls...

... Lewis presented a table of the various types of adaptive and platform trials and their potential benefits in terms of how well each type meets specific innovative trial design goals (see Table 5-1)....

... Lewis explained that each approach has strengths, and the use of an individual therapy in an innovative trial often improves the participant’s prospect of benefit. These approaches could reduce the ... question), but the size of gains varies between approaches. Lewis explained that these designs offer the prospect of operational efficiencies, and the SMART design is particularly useful in evaluating the longitudinal trajectories of care influenced by patient response....

... information. For example, a company unsure about the optimal dose, population, outcome, or responding subset for a therapy might consult with experts and then misconstrue expert opinion as fact....

... NOTES: SMART = sequential multiple assignment randomized trial. The table compares features of innovative trial designs, particularly in comparison to a standard approach evaluating one treatment ... question (reducing the risk of trial failure), have the potential to answer the question using fewer numbers of patients (inferential efficiency) and greater operational efficiency, and can be used to evaluate combinations of therapies or different sequences of treatments. See text for explanations ...

... because the treatment does not work, he remarked. Lastly, he underscored that phase II trials should be designed with phase III considerations in mind. For instance, a phase II trial design can aid in determining the predictive probability of phase III success. All too often, the design of phase II ...

... The design of clinical trials in TBI can be improved by learning and incorporating progress from therapeutic development in other fields, Lewis summarized. Adaptive trials, platform trials, and SMART can yield ... operational and inferential efficiencies and improve patient-centeredness, he asserted. Underscoring that particular trial designs have tremendous potential to accelerate the evaluation of TBI ... to the specific threats to a particular evaluation program’s success. Lewis emphasized that success of a trial is characterized by efficiently and definitively...

... PANEL ON PHARMACOLOGICAL AND NONPHARMACOLOGICAL TREATMENT...

... of academic investigators with entrepreneurial interests, Diaz-Arrastia noted challenges engaging large pharmaceutical companies in TBI research and development, and shared that the panel features speakers from small biotech companies to share progress, barriers, and limitations they have ... in their work and highlight opportunities for collaboration moving forward....

... Daniel Laskowitz, professor of neurology and therapeutic lead of neuroscience medicine at the Clinical Research Institute at Duke University, said that he has dedicated his career to acute brain ... as an attending physician in the neuro-ICU and in preclinical research. Stating his frustration at the slow pace of therapeutic development, he recalled the absence of nonsurgical treatments to ... TBI patients in the 1990s, when he began practice. This lack of therapeutics necessitated challenging conversations with patients and caregivers, and he described being haunted by the decisions families faced in determining whether to withdraw care from their children or continue life support. ... outcomes motivated Laskowitz to create a translational laboratory to develop new therapies and clinically relevant models. Three decades later, TBI treatment remains limited after surgical stabilization, he said. Despite increased insight into ...

... the genetics of recovery following brain injury. His time spent in the ICU demonstrated that two patients could share the same injury, demographics, and mechanism of injury, yet one would be discharged from the hospital and the other would die from severe cerebral edema. This variability in response ... focus on the polymorphisms of apolipoprotein E (apoE), a protein involved in the metabolism of fats that is associated with Alzheimer’s disease and that influences inflammation, excitotoxic injury, and outcome. Since it does not cross the blood–brain barrier, apoE is not a therapeutic that can ... administered peripherally, he clarified. Laskowitz and colleagues have spent approximately 30 years working to move from signal transduction to cell culture in an effort to make the...

... protein receptor region a druggable target. They developed a product that has progressed through phase I and is currently in phase II trials....

... therapies in TBI that aim to protect against excitotoxicity or neuroinflammation. Acknowledging that advancing from cell culture to animal modeling and through FDA review and approval processes is necessarily a time-intensive process, he stated that several common pressure points can hinder progress. ... property (IP) issues can hinder translation, he said, noting that academics typically approach research through a process of obtaining grants and publishing research, but public disclosure can preclude potential commercialization opportunities....

... Additionally, generating interest in funding therapeutics is challenging, and Laskowitz remarked that the absence of large pharmaceutical company representation at this workshop reflects that challenge. After many efforts to ... regulatory pathway is not merely a process, but rather it is a strategy to stimulate commercial interest in a product. He remarked that the Clinical and Translational Science Award grant at Duke University provided Laskowitz with access to a regulatory expert who explained the importance of ... . Assisting Laskowitz in mapping out a strategy, the expert explained how the therapeutic outlet feeds into FDA Investigational New Drug studies and drives the ultimate therapy forward....

... reflect a broad skill set involving communication with companies, IP issues, and regulatory navigation that is not traditionally taught in medical school, said Laskowitz. Academics can use resources to fill such knowledge gaps and advance stalled, yet promising, developing therapies. He noted that he ...

... viable commercialization strategy, said Laskowitz. Stating his gratitude for the infrastructure created via efforts such as the Transforming Research and Clinical Knowledge in TBI study, he credited such research for allowing drugs he is developing to reach phase II trials. Laskowitz added that TBI ... are incredibly challenging and require an infrastructure of harmonized MRI protocols and biomarker protocols that may not be readily available to many academic investigators and small businesses....

... Michel Baudry, founder and chief scientific advisor at NeurAegis and professor at the Western University of Health Sciences, stated that he has been researching the enzyme calpain for 45 years. In 1986, his ... for the treatment of neurodegeneration, but this effort did not yield effective therapies. Four decades of research have led Baudry to understand that previous trials of calpain inhibitors failed because selective calpain-2 inhibitors are needed. In 2016, he started a company, NeurAegis, to ... calpain-2 inhibitors as neuroprotective drugs. Baudry explained that selective calpain-2 inhibitors block a pathway that leads to neuronal damage and death. A blood biomarker has been identified that reflects brain activation of this pathway, making it possible to test whether the drug is working ... biomarker remains elevated for several days, which enables researchers to determine the appropriate dose, the time window for initiating treatment, and the treatment duration. Baudry was optimistic that clinical trials would begin in 2025....

... faced in developing this therapy. Given that research on preventing neurodegeneration with calpain inhibitors began in 1986, convincing those within and beyond the scientific community that his company has identified a novel, unique pathway that leads to neuronal damage and can be blocked by selective ... NIH support, but he secured funding for his preclinical work from the U.S. Department of Defense (DoD). He remarked that pharmaceutical companies and venture capitalists have lost interest in supporting TBI work because all potential TBI treatments have failed. Describing the struggle of securing ...

... Nonpharmacological Therapies and Sex Differences in TBI...

... Maheen Mausoof Adamson, clinical professor at the Stanford School of Medicine, director of research at the Women’s Operational Military Exposure Network Center of Excellence, and senior scientist for ...

... and the difficulty she encountered in obtaining FDA approval for its use in mild and moderate TBI patients, an approval process that required EEG and MRI evidence to proceed. Noting progress in the field, she stated that the Stanford neuromodulation therapy trial is currently demonstrating ... 90 percent remission from major depressive disorder, and this technique is now also being used in TBI patients in the VA system. This accelerated treatment uses functional neuronavigation, and Adamson noted ...

... Adamson is particularly interested in sex differences in brain injury and other health conditions. Conducting a matched-sample analysis to examine behavioral symptomology differences within the polytrauma population, ... found that women experienced more psychiatric symptoms, more vertigo, and—despite being more educated—more unemployment than their male counterparts. Prior research has reported that MRI-based analysis of cross- ... cortical thickness in men and women with and without brain injury revealed that women’s cortical thickness did not return to original size to the same degree as that of men. She emphasized ... these differences are unrelated to treatment. Noting presentations during the workshop on TBI related to blast exposure, sports, and falls, Adamson underscored that TBI also occurs within the polytrauma population and among those experiencing violence and sexual trauma, an issue ... is understudied. Thus, associated post-traumatic stress disorder, depression, and other symptoms can manifest differently in women than in men. She questioned whether researchers have considered how to integrate such aspects into ...

... small sample sizes (Oberman et al., 2020). These findings highlight the need for personalized, precision treatment for people with TBI, depression, and pain. She described cortical differences between men and women and stated that recent research has revealed that women who sustain TBI in the luteal ... is high, have worse outcomes than women in their follicle phase. Furthermore, the realizable electric field in women shows differences in the cortex and in gray and white matter from that in men. Adamson emphasized that female hormones play a role in mechanisms of TBI and they must be taken into ...

... Efforts are needed to incorporate considerations of these factors into studies and increase sample sizes to optimize treatment for women, particularly those who have survived intense environmental exposures, said Adamson. She ...

... and dedicating time to attending multiple and sequential appointments can be difficult. On the other hand, shorter and more innovative therapy trials can be more expensive—and thus, less accessible in a different way—as a result of the higher costs of the cutting- ... development relating to up-scaling from clinical trials to commercialization. She stated that additional education in industry development concepts and approaches (i.e., minimum viable product) could help researchers understand what’s needed to commercialize new therapies....

... Biomarkers and Biologics...

... William Haskins, chief executive officer and cofounder of Gryphon Bio and Owl Therapeutics, shared that 2 decades ago he applied his Ph.D. in proteomics to biomarker discovery in TBI before shifting his focus to drug ... . Approximately 6 years ago, he and Kevin Wang founded Gryphon Bio to apply their combined learnings on developing novel diagnostics and therapeutics to improve patients’ lives. Drawing on his perspective as a chemist, designing the best drugs possible for TBI patients is incredibly ... , Haskins said. Dramatic improvements in diagnostic and therapeutic technologies for drug development have been made over the past 20 years and include advances in biomarker discovery and testing platforms and new therapeutic modalities, including biologics such as monoclonal, bispecific, and ...

... During his career, Haskins has led drug development teams for antibodies, bispecific antibodies, antibody drug conjugates, and gene therapies. Attention to repurposing drugs approved for other indications for applicability to TBI is warranted, he said, and development of ... drug design, Haskins noted that Google DeepMind developed the AlphaFold AI system to predict three-dimensional structures of proteins. Generative AI and large language models are now being used to virtually dock libraries of small molecules to these theoretical protein structures and select lead ... . Haskins expressed his excitement about current opportunities to bring new therapeutic modalities to TBI and, combined with new diagnostic tools for blood biomarker testing, improve the safety and efficacy of novel medicines for TBI patients....

... Approaches to TBI Heterogeneity and Inclusion Criteria...

... Uzma Samadani, founder of Oculogica and neurosurgeon at the Minneapolis Veterans Administration Medical Center, expressed hope that innovative trial design will be an effective mechanism to ... the heterogeneity of TBI and avoid grouping patients with varied pathophysiology together, a practice that contributes to failed trials. She remarked that clinical trials often ... brain injury with Glasgow Coma Scale (GCS) scores and perhaps positive CT scans and use the Glasgow Outcome Scale-Extended (GOSE) to measure outcomes. Samadani asked how to facilitate a shift toward more refined inclusion criteria ... outcome measures. Laskowitz agreed that GCS scores have limited usefulness in stratifying patients and commented that a new series of trials will include multiple inclusion criteria, including neurologic score, initial radiographic data, and a tissue ...

... setting is not required to qualify a predictive biomarker. For instance, researchers could enroll a broad population of patients with TBI and perform baseline biomarker assessment. Even if the biomarker assay requires time to run in a research laboratory, patients could be treated in the ... , and researchers could meld the outcome and response data with the biomarker data once it becomes available. Measuring the biomarker at baseline aids in assessing the effectiveness of the ... and assessing the heterogeneity of the treatment effect. Even if a biomarker does not yet have feasible clinical application because of the time required ...

... Baudry emphasized that multiple mechanisms are known to be engaged after TBI, including neuronal death, axonal damage, inflammation, and a number of molecular events. Heterogeneous outcomes do not negate that a core set of mechanisms are generally involved after TBI. The target he and ... colleagues have identified, selective calpain-2, is useful because it becomes engaged very early after trauma, remains activated for several days, and a blood biomarker that reflects brain activation of this pathway is identified, he said. The ability to monitor the level of this blood biomarker...

... a selected drug works as intended. He anticipates being able to determine both the dose required for complete prevention of biomarker increase and the duration needed to maintain prevention of pathway activation. In animals, treatment lasting 1 week post-trauma results in optimal neuroprotection,...

... Leslie Wise, chief executive officer at EvidenceMatters, asked how a biomarker that is not yet standard of care—even one cleared by FDA—can be used to determine treatment that will then be reimbursed by payers. In her experience, payers want to ... results from classic randomized controlled trials (RCT) to prove efficacy and legitimize a causal relationship, even if the trials are conducted with small populations. Stating her appreciation for adaptive trial designs, Wise ... that payers first want results from RCTs before expanding to adaptive designs....

... Lewis clarified that every innovative trial design he discussed is an RCT; they are all randomized designs. Lewis replied that the rules of inference and determining causality do not differ between (a) a traditional single intervention, (b) ... , fixed sample size trials, and (c) adaptive trials. Rules are in place for fixed sample and adaptive trial design types regarding randomization, baseline measurements, and accounting for various causal pathways to patient outcomes. He noted that a traditional approach to clinical ... often involves a 2-year startup period, concluding a trial, and waiting 2 years before starting the next trial, and that this process is inherently inefficient. Adaptive trial designs provide mechanisms to mitigate some of these sources of inefficiency by allowing ...

... No therapeutic trials in TBI have succeeded, and extraordinary clinical need exists, which should fuel a desire throughout the field to be as...

... 5 In 2019, the FDA provided guidance on the use of adaptive designs in clinical trials for drugs and biologics (FDA, 2019). These adaptive trial mechanisms may include terminating a trial before completion due to futility or efficacy, re-estimating ... power, enriching the target population of enrolled participants, selecting across multiple treatment arms, revising allocation ratios used for randomization, and identifying the most appropriate endpoint measure (Kaizer et al., 2023)....

... said. He added that methods of increasing efficiency are also available during the early phase of development. The basic ground rules of the evidence and the statistical characteristics of that evidence to demonstrate patient population and estimated treatment effect are known, he reiterated. ... regulatory history around evaluating diagnostic and therapeutic products is established, Lewis added....

... diagnostics that would require payer approval once the patient is treated; that would constitute a third step after biomarker identification and testing the therapeutic. Haskins commented that different questions are at play in these steps. Laskowitz maintained that researchers need to ...

... Kristy Arbogast, R. Anderson Pew Distinguished Chair of Pediatrics at Children’s Hospital of Philadelphia, noted that most of the trials discussed so far were for ... in which people have moderate and severe TBI and asked if trials for people with milder forms of TBI involve unique challenges or opportunities. Baudry remarked that the selective calpain-2 pathway ... studied is the same for both mild and severe TBI, and thus the selective calpain-2 inhibitor drug being developed is neuroprotective for all severity levels. Underscoring Ely’s discussion of his ... ’s symptoms and the length of time before they emerged, Adamson highlighted the need to determine how to acquire data from patients experiencing chronic symptoms, as ... biomarker is yet available to indicate TBI years after injury. She remarked that GCS scores and self-reported, evidence-based forms on TBI can be used to this end. Researchers can also use addenda to gather data on more focused issues related to ... partner violence, military sexual trauma, or other aspects. Adamson stated that pulling various components together and understanding the variables, including potentially social determinants of health, can make RCTs more powerful....

... not vary from disease to disease. Likewise, the process of making inferences about treatment effects does not change for mild TBI versus severe TBI. However, time to information is very important in innovative trial design, he specified. Treatment intended to mitigate or prevent TBI ramifications that ...

... trials that feature lengthy time to information. Such situations offer fewer and different opportunities for efficiency, Lewis explained, than those in which the symptom targeted for intervention becomes available in a short time ...

... Frederick Korley, professor at the University of Michigan, noted that cardiology therapies were typically developed in more severe cases and then over time were tested for effectiveness on lower severity levels. However, given that TBI pathophysiologies can differ, Korley asked whether an ... focus on patients with more clear-cut evidence of structural injury and structural pathology could lead to more successful trial designs in the future. Lewis replied that the ideal selection of injury or illness severity ... that which enables more efficient learning. He stated that this determination involves understanding the pathophysiology, the severity level most likely to demonstrate successful effect, and the response of the population in terms of the outcome ... from one disease or condition to another, Lewis said that this determination can be informed by the current work developing TBI outcome measures and biomarkers and in understanding patient population recovery trajectories....

... Phase II Design and Endpoints...

... example, a choice may involve using a 1-month Glasgow Outcome Scale-Extended (GOSE) assessment, a 6-month GOSE assessment, a given biomarker test, and/or other measures. Lewis replied that the purpose of a phase II program is to determine whether and how to run a phase III program. A well-designed ... researchers should assess whether to continue or to stop testing a therapy, he explained. For example, early phase II may involve proof of concept and target engagement, and researchers should accept when a treatment fails and return to the proverbial drawing board rather than assume the trial ... is to blame, Lewis stated. However, the best result of a phase II study is a quantitative prediction of probability of phase III success, and late phase II work necessitates enrolling the same patients with the same treatment and measuring the same outcome, he offered. Thus, the concept of ... II endpoints is fundamentally flawed from the perspective that the purpose of phase II is to indicate whether and how to run phase III, said Lewis. He remarked...

... clinical trials in which the registration endpoint is a 6-month neurologic outcome, the Modified Rankin Scale can be used at hospital discharge and at 1 month to reduce the uncertainty regarding whether the individual patient will return for the 6-month assessment. Emphasizing that the ... between proximate endpoints and longer-term endpoints can be determined—but not assumed—Lewis remarked that using proximate endpoints can enable the phase II trial to ...

... A participant commented that a major cause of secondary injury in TBI is neuroinflammation and asked about the use of nutritional interventions or neurosteroids to help address neuroinflammation. Diaz-Arrastia remarked on emerging research in ... area, including studies on omega-3 fatty acids and B vitamins. The wide availability and lack of label claims for these therapies pose a challenge in recruitment and other aspects of research, he said. Noting the potential for deeper ...