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Stroke Preclinical Assessment Network (SPAN) to Support Translational Studies for Acute Cerebroprotection- Interventions from Small Businesses (U44 Clinical Trial Not Allowed)

Description:

Purpose The purpose of this funding opportunity announcement (FOA) is to solicit applications for cerebroprotective intervention research projects from eligible U.S. small businesses to be tested in the NINDS Stroke Preclinical Assessment Network (SPAN).SPAN will support late-stage preclinical studies of putative cerebroprotectants to be given prior to or at the time of reperfusion in rodent models of transient middle cerebral artery occlusion (tMCAo), with clinically relevant long-term outcomes and in models of comorbidities. SPAN testing laboratories (RFA-NS-22-003) will be responsible for the parallel testing of up to 8 selected cerebroprotective interventions that will be chosen from among well-scoring applications submitted under the companion SPAN intervention FOAs (RFA-NS-22-032, RFA-NS-22-033). The overall goal is to determine whether such interventions can significantly improve outcome compared to reperfusion alone and/or extend the therapeutic window for reperfusion, in the hopes of guiding the selection of the best agent(s) to transition to future Phase II clinical trials (to be conducted through StrokeNet). SPAN will consist of one Coordinating Center (CC, RFA-NS-22-004) and up to 8 testing laboratories (RFA-NS-22-003), which will assess up to 8 interventions. The SPAN program will not support any human subjects research. Background Until 2015, intravenous recombinant tissue-type plasminogen activator (rt-PA) was the only FDA-approved therapy for acute ischemic stroke. Despite its overall efficacy and safety, rt-PA presents some limitations, such as an increased risk of hemorrhagic transformation, a narrow time window of a few hours from stroke onset, and a low success rate in lysing large clots. Over the past few years, acute endovascular therapy (EVT) with stent-retriever devices and access to advanced imaging modalities have transformed the standard of care for ischemic stroke, offering the opportunity to significantly improve clinical outcomes in selected patients that have salvageable tissue treated as late as 24 hours after their stroke. Unfortunately, despite the success of EVT in clinical trials, many patients still experience neurological deficits following therapy. Thus, there is a critical need to develop adjunctive approaches to improve long-term outcomes after ischemic stroke. These recent advances in stroke treatment such as EVT now offer a new and timely opportunity to further evaluate the potential benefit of cerebrovascular protective agents in the context of mechanical revascularization. Indeed, a cerebroprotectant that can stabilize the stroke penumbra or reduce the rate of infarct core expansion may offer significant benefits if administered as early as possible in a stroke’s evolution. In 2018, the NINDS launched the Stroke Preclinical Assessment Network (SPAN), the first iteration of which consisted of one coordinating center (CC) and six study sites, each of which proposed a promising neuroprotective modality, all selected following rigorous NIH peer review. The network was designed to perform highly rigorous and reliable preclinical testing with a timeline and resources that would not be possible for a single laboratory, while at the same time allowing a blinded head-to-head comparison of each putative neuroprotective therapy. It also developed a rigorous data analysis pipeline that involves deposition of all raw experimental data from each site into a centralized, secure database followed by randomized assignment of the de-identified data to blinded reviewers at each of the six sites for analysis. During the first funding cycle, the SPAN network successfully demonstrated its ability to test interventions in a time and cost-effective manner. As a result, the NINDS now wishes to build on this momentum by further expanding the network to include more testing sites and promising cerebroprotective interventions. Research Objectives The overall goal of this program is to support a preclinical stroke network to conduct late-stage preclinical studies of potential cerebrovascular protective strategies to be given prior to or at the time of reperfusion. SPAN will test in parallel up to 8 compounds/interventions in animal models of tMCAo following the same rigor and methodology characteristic of clinical trials. The parallel testing of multiple interventions, including an adaptive study design that will eliminate compounds that do not demonstrate significant efficacy compared to the others, will allow the identification of the most promising candidates to advance to clinical testing. Only drugs/interventions that are supported by robust and rigorous preliminary data and are likely to be ready for clinical testing by the end of the award will be eligible to be tested through the SPAN network. Selected SBIR intervention research projects will contribute to these objectives by collaborating with the SPAN Coordinating Center (RFA-NS-22-004) and testing laboratories (RFA-NS-22-003) to provide scientific and organizational leadership for the assessment of their intervention within the network. Small business applications will be expected to propose a detailed research project involving their cerebroprotective agent, with intervention preclinical testing itself then subcontracted to the SPAN testing laboratories via the Coordinating Center. As such, applicants to this FOA will be required to incorporate the SPAN infrastructure into their proposed study. SPAN Organization The Coordinating Center (CC) provides scientific and organizational leadership to SPAN to achieve both efficiency and excellence in the implementation and performance of cerebroprotective intervention testing protocols. The CC will work collaboratively with the testing sites, intervention contributors, and the NINDS to provide overall study coordination, including animal enrollment, oversight of study protocols, monitoring of the individual sites, data analysis, data management, data sharing, and reporting. Additionally, the CC will be responsible for the acquisition, formulation, and distribution of active and control compounds. Limited competition for the CC will be proposed through the companion FOA RFA-NS-22-004. Up to 8 selected cerebroprotective interventions will be tested in parallel in SPAN in a controlled, randomized, and blinded fashion. Such interventions may be proposed by academic, small business, or industry investigators. The proposed interventions should be mature to potentially rapidly advance to a clinical trial at the end of the testing phase. All selected interventions will be assessed by the testing laboratories following standard protocols and procedures, under the direction and leadership of the CC. Candidate compounds/interventions for the network will be proposed through the companion FOAs RFA-NS-22-032 and RFA-NS-22-033 (SBIR) and selected following peer review. SPAN testing laboratories will conduct tests of selected cerebroprotective interventions that will be chosen from well-scoring applications submitted under the companion intervention RFAs. It is expected that SPAN sites will be academic or other preclinical research laboratories with documented expertise in the tMCAo model of ischemic stroke and relevant comorbidities (e.g., aging, hypertension, diabetes, hyperlipidemia, obesity, etc.). In addition, laboratories must demonstrate expertise in the assessment of clinically relevant, long-term functional outcome measures, with a particular emphasis on small rodent neuroimaging and behavioral testing. It is an absolute requirement that laboratories have extensive access to animal MRI facilities. All applicants must also agree to test multiple interventions in collaboration with the other testing laboratories in a randomized and blinded fashion. Testing laboratories for the network should be proposed through the companion FOA RFA-NS-22-003. The governing body of the network is the SPAN Steering Committee, appointed by the CC in conjunction with NINDS, that will consist of the PD/PI of the CC, the PD/PI of each of the network’s testing laboratories, the PD/PI of each selected intervention, and NINDS Program staff. The CC will be responsible for managing the logistics of committee activities, such as scheduling, soliciting agenda items, finalizing and distributing agendas, arranging and leading monthly teleconferences, preparing minutes, and making logistic and financial arrangements for annual in-person SPAN meetings, including meeting space, accommodation, travel, per diem reimbursement, etc. The NINDS Director has the right to supersede any decision by the network at any time. Finally, there is also an independent External Advisory Board, appointed by and reporting to NINDS, which includes basic and clinician-scientists with expertise in cerebroprotection, representatives from pharmaceutical and biotech industry, experts in regulatory affairs, statistics, and clinical trial design, and representatives from the NINDS Stroke Clinical Trials Network (StrokeNet) Steering Committee (to facilitate a potential transition to clinical trials to be conducted in the future, if the intervention is successful in SPAN). Characteristics, Roles, and Responsibilities of SPAN Small Business Intervention Research Project PIs Up to 8 selected cerebroprotectants will be tested in parallel in SPAN in a controlled, randomized, and blinded fashion. Research projects may come from academic, small businesses or industry investigators. The proposed interventions should be mature to potentially rapidly advance to a clinical trial at the end of the testing phase. All selected interventions will be assessed by the testing laboratories following standard protocols and procedures, under the direction and leadership of the CC. Please note that the dissociation of intervention research projects from the testing laboratories themselves is a significant change from the prior SPAN funding period. In the prior cycle, the testing laboratories were also required to propose the interventions that would be tested. In contrast, for this current FOA, while the proposed research project should incorporate SPAN infrastructure in its design, the PI/PD of a successful application will not be performing the intervention testing themselves. The small business research project awardee will be responsible for the synthesis and acquisition of the drugs/interventions, reagents costs, travel to participate in steering committee meetings, etc., while preclinical testing of the proposed intervention will be subcontracted to the network (via the CC). Although all applications must include a subcontract to the CC, they must follow the small business work requirement found in section 3.2. Applicants must consider the following factors: Proposed interventions to be considered for SPAN need to be supported by extensive and rigorously obtained preliminary data (published and/or unpublished) in a relevant experimental stroke model (tMCAo) in rodents or higher species demonstrating efficacy and the lack of safety concerns. Preliminary data must include the effect of the intervention on both infarct volume and clinically relevant long-term functional outcome measures. Applications must also include information regarding the synthesis and/or acquisition of the drug/intervention, solubility and stability data, quality control, proposed route of administration, and a dose-response study. Applications must include a clear description of the proposed intervention’s mechanism of action (including supporting data). This should discuss target engagement, location of the primary target (i.e., periphery or CNS), as well as penetration into the CNS (if applicable). Applicants to this FOA will be required to incorporate the SPAN network infrastructure into their proposed study, including how their intervention can be efficiently evaluated by the testing laboratories in parallel with other awarded interventions, as well as central coordination and data management through the CC. Small business intervention PIs will budget funds for personnel and the manufacture/acquisition of sufficient amounts of their proposed intervention. They will then be expected to establish a subcontract with the CC, which will be used to support the testing of small business interventions by the partially funded testing laboratories within the network. All applicants funded under this FOA must participate in and accept responsibility for driving the scientific objectives of the network and agree to become active members of the SPAN Steering Committee. Applicants must agree to synthesize and/or procure and ship their proposed compound/intervention to the CC in a sufficient amount to be tested in parallel by the SPAN network in a randomized and blinded fashion. Interventions that appear less efficacious will be removed from further testing, while those that demonstrate stronger efficacy will be prioritized, as appropriate, with the use of an adaptive design. Intervention PIs will be required to continue their commitment to SPAN (i.e., participation on the SPAN Steering Committee, attendance at all SPAN meetings) for the entire duration of the award regardless of the status of their intervention, unless directed otherwise by NINDS and the CC. In addition to the above, it is also preferable (but not strictly required) that applications also consider the following: Animal toxicity data or human safety data are strongly desirable since the proposed interventions should have the potential to rapidly advance to a clinical trial at the end of the testing phase. Responsive Applications to this FOA All applications to this FOA must at a minimum incorporate the following features: Applications are limited to research projects that propose cerebroprotective interventions for acute ischemic stroke in preclinical rodent models of tMCAo. Proposed interventions must be supported by rigorous preliminary data and be sufficiently advanced so that they can potentially move into a clinical trial upon testing completion. Required preliminary data includes the effect of the intervention on infarct volume and clinically relevant outcome measures such as long-term neuroimaging and behavioral outcomes; dose-response; CNS penetration (if applicable); and target engagement/mechanism of action. Human safety and/or preclinical toxicity data is strongly desirable, but not an absolute requirement. Although awarded interventions will not be directly tested by intervention PIs, applications must incorporate SPAN infrastructure and include a thorough description of how the intervention can be efficiently tested by the network. This must include a recommended animal sample size (supported by a power analysis), intervention dosing and treatment schedule, potential short- and long-term neuroimaging and behavioral outcome measures, and methods of rigorous data analysis that could be recommended to the CC for use within the network. All applications must include a clear statement of PI/institutional commitment to the SPAN network and their willingness to participate in SPAN scientific planning (via the SPAN Steering Committee). Applications Not Responsive to this FOA Applications that do not meet the stated scope and requirements of this FOA will be considered non-responsive and may not be reviewed for this FOA. Characteristics of non-responsive applications that are considered outside the scope of this FOA include, but are not limited to, the following: Applications that propose studies that meet the NIH definition of a clinical trial and/or involve human subjects research. Preclinical studies that focus on the investigation of the pathophysiology of stroke, target validation/identification, and/or biomarkers related to a specific cerebroprotective intervention will be considered out of scope for this FOA. Applications that propose a research project involving experimental stroke models other than transient cerebral ischemia will be considered out of scope. Out of scope experimental models would include hemorrhagic stroke, neonatal hypoxia-ischemia/pediatric stroke, cardiac arrest-induced global ischemia models, among others. Pilot studies of cerebroprotection that are in the early-phase or not supported by robust and rigorous preliminary data and/or relevant publications and have potential safety or toxicity concerns will not be supported under this FOA. Applications that propose new infrastructure to join the network as a testing laboratory are out of scope for this FOA. Such applications must be submitted under the companion FOA RFA-NS-22-003. However, while these topics are non-responsive to this FOA, they are of great interest to NINDS, and applicants are encouraged to contact NINDS program staff to determine the most appropriate funding mechanism for their study. National Institute of Neurological Disorders and Stroke The NINDS will be responsible for organizing and providing overall support for the SPAN network. NINDS Program and Grants Management staff will be responsible for the overall management of the SPAN network. In addition to regular grant stewardship, a NINDS Project Scientist will be involved substantially with the awardees as a NINDS partner, consistent with the Cooperative Agreement mechanism. Applicants are strongly encouraged to consult with NINDS Scientific/Program Staff early during the planning phase of their application (See Agency Contacts, Section VII).
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