Foremost among the pathogens under study in this new project is the influenza virus, including the agents of conventional seasonal influenza, novel new strains of influenza A such as the A(H1N1)pdm09 strain that emerged in April 2009, as well as the ongoing threat of avian subtypes such as the H5N1 and H7N9 viruses. Novel means first to better characterize and then to treat infection with these respiratory pathogens using existing or newly developed strategies are a primary focus of this important project within the Clinical Research Section. Beginning with the emergence of the pandemic strain of A(H1N1)pdm09 influenza in April 2009, our section undertook clinical research efforts to help better characterize and treat infection with both novel and seasonal subtypes of influenza. A protocol was developed to allow serial collection of high-titer anti-influenza plasma either from patients recovering from naturally-acquired infection or from recipients of the trivalent vaccine. The purpose was to allow harvesting of a pool of high-titer antisera (in the form of either plasma or a manufactured IVIG product) that could then be tested as a potential therapeutic adjunct in the management of patients with severe or life-threatening influenza infection. A treatment trial involving open-label administration of two units of hyperimmune plasma to hospitalized patients with severe influenza was launched domestically with the goal of enrolling and studying up to 100 patients on a multicenter basis. This trial was completed in summer 2015 and preliminary analysis shows that the use of adjunctive hyperimmune plasma plus conventional antiviral appears to confer a statistically significant benefit in improving the oxygenation status of recipients compared to antiviral therapy alone. Most recently we have also designed an international multi-center randomized, double-blind study of hyperimmune IVIG plus standard-of-care versus standard-of-care alone in hospitalized patients with severe influenza. This clinical outcome trial was preceded by successful completion of a multi-center pilot trial in 31 patients through domestic US sites within the INSIGHT network that primarily addressed the safety, pharmacokinetics, and logistics of administering hyperimmune IVIG to patents with acute influenza. The pilot trial showed that administration of IVIG to hospitalized patients or outpatients was both feasible and safe, resulted in a significant boost in HAI titers against the infecting influenza A subtypes, and could be done while maintaining the blind. We have also been conducting two randomized multicenter trials internationally evaluating 1) the virologic and clinical correlation of triple combination anti-influenza treatment versus monotherapy in at-risk populations, and 2) the use of virologic assessments in measuring the effects of oseltamivir versus placebo in mild outpatient disease. The section has also initiated a safety and pharmacokinetic study in normal volunteers of a single dose-escalating phase followed by a multiple daily dosing phase of a novel antisense compound, AVI-7100, that has strong in vitro activity against influenza. Recruitment into the single dose phase has been completed and has shown that the administration is both safe and well tolerated; completion of the multi-dose phase (at the highest dose of 8 mg/kg) is expected to be completed by early September 2015. We continue to provide scientific and logistical support to the Mexico infectious diseases network La Red, a multi-site collaboration with the Mexico Ministry of Health. Active sites in Mexico City include two pediatric sites. The most recent initiative through La Red has been an ongoing study of the licensed antiparasitic drug nitazoxanide as a potential antiviral medication in patients presenting with influenza-like illness. In addition to the ongoing international IVIG trial mentioned above, we have also continued to contribute to the management and oversight of three large international observational protocols for outpatients or hospitalized patients with seasonal influenza infection administered under the auspices of the INSIGHT clinical trials network. These protocols have also been modified to also permit enrollment of patients diagnosed with other respiratory diseases of major public health importance, such as those due to novel coronavirus infections such as the MERS-CoV agent. In addition to the clinical trials described above, we continue to 1) monitor yearly the clinical and psychological status of a subset of patients previously exposed to anthrax as a result of the October 2001 anthrax attacks, including maintaining an open clinical protocol for the study of additional anthrax exposures that may occur through accidental or occupational exposures, and 2) continue to enroll patients on a protocol designed to permit diagnosis and characterization of patients presenting with unusual medical conditions that may be due to underlying (and often previously undiagnosed) infectious diseases. With the deployment of American health care workers (HCWs) in large numbers to provide care during the outbreak of Ebola infection in West Africa in 2014, the Special Clinical Studies Unit (SCSU) was one of three special high containment patient care units within the US called upon to hospitalize and provide care to medically-evacuated HCWs exposed to or infected with Ebola virus. Care in the SCSU was rendered by a multidisciplinary team of infectious diseases and critical care medicine physicians, medical-surgical and ICU-experienced nursing colleagues, and numerous ancillary support staff. The CRS has been instrumental in the development of several critical protocols intended to broaden our understanding and approach to prevention and management of filovirus infections. One example is a protocol allowing for the harvesting of hyper-immune plasma collected either from recipients of investigational anti-Ebola vaccines as a potential therapeutic adjunct in treating patients with Ebola infection. In concert with the Walter Reed Army Institute of Research, we also launched and successfully completed a phase 1 randomized, double-blind dose-escalating safety and immunogenicity trial of (VSVΔG-ZEBOV) vaccine in a prime-boost strategy in late 2014 and early 2015. This study established the safety parameters of the experimental vaccine as well as provided comparative immunogenicity data on the three different dosing levels tested. Finally, beginning in Fall 2014 the section conducted a series of face-to-face meetings between U.S. clinical investigators, statisticians, the FDA, and various other federal agencies participating in the oversight of medically-evacuated HCWs with Ebola infection that were designed to provide some scientific order and rationale to the study of various investigational medical countermeasures (MCMs) employed in the treatment of these patients. As a result of these meetings, the section authored and implemented the only multicenter randomized controlled safety and efficacy study of putative MCMs in the treatment of patients with confirmed Ebola infection during the current crisis. Initially introduced in the U.S. in March 2015 and then implemented in Liberia, Sierra Leone, and most recently Guinea in active collaboration with local investigators and their respective Ministries of Health, the protocol employs a unique adaptive trial design intended to allow for the pairwise comparison of various putative MCMs against a backbone of optimized standard of care. The first investigational countermeasure to be studied in this ongoing is a triple monoclonal antibody product called ZMappTM. The study is ongoing as of late summer 2015 and is being closed monitored by a Data Safety and Monitoring Board (DSMB) composed of international clinical trial experts.
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