Evolution of the Strategies to Innovate Emergency Care Clinical Trials Network (SIREN)

TY - JOUR

T1 - Evolution of the Strategies to Innovate Emergency Care Clinical Trials Network (SIREN)

AU - Beam, Daren M.

AU - Brown, Jeremy

AU - Kaji, Amy H.

AU - Lagina, Anthony

AU - Levy, Phillip D.

AU - Maher, Patrick J.

AU - Yadav, Kabir

AU - Vogel, Jody A.

N1 - Funding Information: Currently, 2 funded studies are active in SIREN. These include the Hyperbaric Oxygen Brain Injury Treatment Trial (HOBIT) and the Brain Oxygenation Optimization in Severe Traumatic Brain Injury, Phase III Trial (BOOST-3). The HOBIT trial is a randomized, phase 2, adaptive, dose-finding clinical trial designed to evaluate optimization of hyperbaric oxygen treatment protocols to improve neurologic outcomes in acute severe traumatic brain injury. This multicenter study will randomize patients with acute severe traumatic brain injury into adaptive treatment arms of various hyperbaric treatment pressures. The study will be broadly applicable to both multiplace and monoplace chamber centers. The ultimate goal of the investigation is to determine whether an optimized dose in a subsequent phase 3 trial should be initiated according to the optimized hyperbaric oxygen treatment protocol demonstrating a greater than 50% likelihood of showing an improvement in 6-month outcomes after severe traumatic brain injury. HOBIT was conceived before SIREN was funded, was awarded in June 2018, and is currently actively enrolling. BOOST-3 was the first study designed after SIREN was funded and was awarded by NINDS through the U01 mechanism. This randomized, multicenter, single-blind, 2-arm, phase 3 trial is designed to determine the effectiveness of 2 approaches to monitoring and guided therapy on neurologic outcomes in severe traumatic brain injury. The study compares a guided tiered treatment algorithm to changes in intracranial pressure with a guided tiered treatment algorithm in response to both intracranial pressure and brain tissue oxygen monitoring. All patients will have both intracranial pressure and brain tissue oxygen monitored, but in the intracranial pressure arm alone, brain tissue oxygenation will be masked to the treating clinicians. BOOST-3, like HOBIT, is funded through the NINDS U01 mechanism and the previous BOOST II trial was funded through a Research Project Grant (R01) from NINDS. The award was issued in June 2018 and multiple sites are anticipated to start enrollment in June 2019. Dr. Barsen from the University of Michigan is project leader for BOOST-3 and Dr. Gaylan Rockswold of Hennepin Healthcare Research Institute is the project leader for HOBIT. Both of these actively funded studies are supported through the NINDS U01 mechanism. Currently, there are not yet any funded studies through the UG3/UH3 mechanism. The strength of SIREN is clearly demonstrated in both HOBIT and BOOST-3. The initial phase 2 trial of hyperbaric oxygen in treatment of patients with traumatic brain injury did not demonstrate a favorable outcomes difference between control and treatment with a dichotomized Glasgow Outcome Scale. The Data Coordinating Center was asked to reanalyze the initial phase 2 data after Progesterone for Traumatic Brain Injury: Experimental Clinical Treatment demonstrated that patients with traumatic brain injury and an initial Glasgow Coma Scale score of 7 to 8 and a Marshall score on computed tomography greater than or equal to 2 had a favorable outcome 55% of the time. 15 Eliminating this subset of patients and including only patients with higher severity of traumatic brain injury showed a 78% favorable outcome in the treatment group over the control group, but the sample size was too small to show significance. Second, by using a sliding dichotomized Glasgow Outcome Scale, the Data Coordinating Center found there was a more favorable outcome in 12.7% of the treatment group. The analysis by the Data Coordinating Center was integral and facilitated the current new adaptive phase 2 trial to evaluate hyperbaric oxygen treatment schedule, and parameters before a phase 3 efficacy trial. As stated previously, BOOST II was an R01 feasibility study that was stopped short of the planned sample size after successful demonstration of the primary outcome in a smaller sample than initially planned. The central hub of the Clinical Coordinating Center allows BOOST-3 access to a more diverse network of emergency departments (EDs) than NETT. The strength of the Clinical Coordinating Center is shown in the participation of 46 different sites before the start of enrollment. The Data Coordinating Center’s ability to help design adaptive trials and analyze data combined with the expansive access of participating centers from the Clinical Coordinating Center shows the potential of the SIREN network to conduct rigorous multicenter investigations to improve emergency care and patient outcomes. Although no new trials are being proposed in NETT, 2 clinical trials were initiated in the NETT and have completed enrollment. These trials include the Established Status Epilepticus Treatment Trial and the Stroke Hyperglycemia Insulin Network Effort. Funding Information: Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist. Supported, in part, by the Agency for Healthcare Research and Quality (Dr. Vogel; K08 HS023901). Funding Information: Unlike traditional NIH-funded research networks, but similar to other recent NINDS-funded clinical trial networks, SIREN itself was not provided the funding needed to complete any clinical trials as part of the infrastructure awards. Rather, trial-specific funds must be competed for and awarded on their own merit in competition with all other NIH applications. Although the SIREN Data and Clinical Coordinating Centers receive modest infrastructure funding from the NIH, the budget is lean and covers only basic administrative costs. Therefore, trial funding is expected to arise from funded clinical trial grants that are typically cooperative (U) awards. Two mechanisms for grant applications have been developed. Within NINDS, the investigator applies using the U01 mechanism. 21 Briefly, the U01 is a Research Project Cooperative Agreement similar to an R01 but with much more direct involvement of the NIH in the conduct of the research. It is used when substantial programmatic involvement is anticipated between the awarding institute and center. The NHBLI uses a UG3/UH3 mechanism, which is a single grant composed of 2 phases. 22 In the first UG3 phase, the project and principal investigator are funded for 1 year and must meet predetermined milestones. It is during this period that the principal investigator confirms the study team (eg, other sites from SIREN) and begins to enroll patients to determine whether the recruitment and retention strategies that were set forth in the grant are feasible and achievable. This allows the principal investigator to tune study processes in this year, if needed, to ensure that the preplanned milestones will be completed. Only UG3 projects that have met the scientific milestones and feasibility requirements may transition to the UH3 phase. If the grant is successful in the UG3 portion, the UH3 phase will be supported and can be awarded for up to 5 years. Both the U01 and UG3/UH3 mechanisms use trial budgeting, based on a per-patient enrollment amount. The process for sharing funding between hubs and spokes for per-patient payments should be negotiated between the hub and spoke contractually. Because of the many factors that need to be considered to determine the appropriate budget, the project principal investigators should work closely with the Clinical Coordinating Center.

PY - 2020/3

Y1 - 2020/3

UR - http://www.scopus.com/inward/record.url?scp=85074340522&partnerID=8YFLogxK

U2 - 10.1016/j.annemergmed.2019.07.029

DO - 10.1016/j.annemergmed.2019.07.029

M3 - Review article

C2 - 31668572

AN - SCOPUS:85074340522

SN - 0196-0644

VL - 75

SP - 400

EP - 407

JO - Annals of Emergency Medicine

JF - Annals of Emergency Medicine

IS - 3

ER -