Novel means first to better characterize and then to treat infection with major 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 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. In this trial, 98 patients were randomized to receive either hyperimmune plasma plus standard-of-care treatments (investigational arm) or standard-of-care therapy alone (control arm). 28 (67%) of 42 in the plasma plus standard care group normalized their respiratory status by day 28 compared with 24 (53%) of 45 participants on standard care alone (p=0069). Overall, while falling short of statistical significance, investigational arm participants had fewer days in the hospital, in the ICU, on mechanical ventilation, and had improved disposition at Day 7. Based upon these highly suggestive trends, the CRS then designed and helped launch a follow-up multicenter trial enrolling patients with severe influenza A infection who are being randomized in a double-blind manner to receive either high-titer (hyperimmune) plasma or a low-titer (control) plasma in addition to standard-of-care treatments. To date 82 subjects have been randomized, including 45 subjects that were enrolled at 36 active study sites during this most recent Northern Hemisphere influenza season. As a separate trial launched through the INSIGHT clinical trials network, we have also helped design and conduct an international multi-center randomized, double-blind, placebo-controlled study of hyperimmune intravenous immunoglobulin (IVIG) versus standard-of-care in hospitalized patients with severe influenza. This ongoing 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 showed that administration of IVIG to hospitalized patients or outpatients was safe, significantly boosted HAI titers against the infecting influenza A subtypes, and could be conducted at clinical sites while maintaining the blind. As of early August 2017 the trial has enrolled 189 patients of the desired 320 patients needed to power the endpoint of clinical improvement at Day 7 of illness. We have also been completing two randomized international multicenter trials evaluating 1) the virologic and clinical correlation of triple combination anti-influenza treatment versus monotherapy in at-risk populations (IRC003), and 2) the use of virologic assessments in measuring the effects of oseltamivir versus placebo in mild outpatient disease (IRC004). In IRC003, 80 of 200 (40.0%) participants in the combination arm had detectable viral shedding at Day 3 compared to 97 of 194 (50.0%) (95%C.I. 0.2-19.8%, p=0.046) in the control arm. Despite this effect on viral shedding, however, there was no observed benefit in multiple clinical endpoints. Further investigations are needed to understand the lack of clinical benefit when a difference in virologic outcome is identified. In addition to the ongoing interventional trials mentioned above, we continue 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 network. The section has also recently completed a safety and pharmacokinetic study in normal volunteers of a novel antisense compound, AVI-7100, that has strong in vitro activity against influenza. We also 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. One of the most recent initiative through La Red has been a recently completed study of the licensed antiparasitic drug nitazoxanide as a potential antiviral medication in patients presenting with influenza-like illness.Ongoing observational trials of the Zika virus and its sequellae in affected populations in Mexico are another recent facet of the LA Red network. In the realm of biodefense-related initiatives, 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, and 2) continue to enroll patients on a protocol designed to permit diagnosis and characterization of patients presenting with unusual, previously undiagnosed infectious or inflammatory conditions. The Special Clinical Studies Unit (SCSU) with the Nih Clinical Center was one of three special high containment patient care units within the US originally called upon to hospitalize and provide care to medically-evacuated HCWs exposed to or infected with Ebola virus in 2014-15. The section continues to provide the medical oversight to the SCSU in the event that patients or staff suffering high-risk exposures to select agents require observation and/or care under conditions of high containment. The section helped design and orchestrate the only multicenter randomized controlled safety and efficacy study of putative MCMs in the treatment of patients with confirmed Ebola infection during the recent West African crisis. The first investigational countermeasure studied was a triple monoclonal antibody product ZMapp. Although the goal was to enroll a total of 200 patients, the trial was terminated in early January 2016 due to the extinction of new cases of Ebola in the affected countries. By that time a total of 71 evaluable patients had been enrolled at sites in Liberia, Sierra Leone, Guinea, and the United States. Within this cohort there were a total of 21 deaths, for an overall case fatality rate of 29.6%: 13/35 (37.1%) in the oSOC alone arm versus 8/36 (22.2%) in the ZMappTM-containing arm. While the observed posterior probability that ZMappTM plus oSOC was superior to oSOC alone reached 91.2%, this fell short of the predefined threshold of 97.5% required to establish efficacy. However, these data suggest at least the possibility of a potential beneficial effect of ZMapp had it been possible to complete full accrual. In concert with WRAIR, we successfully completed a phase 1 randomized, double-blind dose-escalating safety and immunogenicity trial of (VSVG-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. In Fall 2016 NIAID also launched a pre-exposure vaccination protocol called PREPARE utilizing VSVG-ZEBOV vaccine to immunize HCWs, BSL-4 Laboratory staff, and other at-risk personnel against Ebola virus infection. The protocol features randomization to a homologous booster immunization at month 18 to determine whether the booster further augments antibody levels induced by the primary immunization. Finally, in order to develop a potential MCM against Middle East Respiratory Syndrome (MERS) virus, in summer 2016 we launched a phase 1, randomized double-blind, placebo-controlled, single ascending dose safety, tolerability, and pharmacokinetics study of a novel product called SAB-301 consisting of human polyclonal IgG raised in transchromosomic cattle immunized with the causative agent of MERS. The study confirmed the favorable pharmacokinetic profile and safety of this novel immunotherapeutic agent.
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