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 H1N1v strain that emerged in April 2009, as well as the emerging threat of avian (H5N1) virus. 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 new project within the Clinical Research Section of the LIR. The first major initiative undertaken in this project has been a collaborative protocol undertaken with the Department of Veterans Affairs (DVA) as well as the Department of Defense. The goal of this multi-center protocol was to determine if novel pharmacokinetic means could be used to extend the useful half-life of oseltamivir, the major licensed oral antiviral drug used to treat seasonal influenza in the United states and elsewhere and also a drug in comparatively short supply on a global scale. Specifically, the protocol examined the effect of two different doses of oral probenecid, a licensed uricosuric agent known to affect the renal secretion of certain drugs, on the relative pharmacokinetics of conventional prophylactic doses of oral oseltamivir administered every other day compared to daily oral oseltamivir alone. This protocol was conducted in 53 normal volunteers above and below 65 years of age at 4 centers in the United States: two DVA sites (including the Palo Alto Health Care system as lead center), one DOD site, and the NIH Clinical Center. The pharmacokinetics of oseltamvir plus probenecid were analyzed and showed a dose-dependent favorable effect of the latter upon both the trough and area-under-the-curve concentrations of the former. At the schedule of four times daily dosing with probenecid, these parameters were not statistically different from daily dosing of oseltamivir alone, suggesting that probenecid might be useful in extending the supply of oseltamivir in a situation of limited drug supply. The ability of oseltamivir to treat effectively severe cases of seasonal influenza may be limited, and knowledge of its utility in treating human cases of avian influenza is largely anecdotal. For these reasons NIAID undertook three clinical trials focused on the therapeutics of human influenza. One is a phase II double-blinded, randomized clinical trial conducted within a network of research collaborators in Southeast Asia that is comparing the relative efficacy of high dose versus standard-dose oseltamivir for the treatment of severe influenza and avian influenza. This trial is presently still accruing in the affected countries. The second was a phase I double-blind, placebo-controlled, dose-escalating study to evaluate the relative safety and tolerability of a novel intravenous anti-influenza agent, peramivir, in healthy volunteer subjects. This trial was initiated at the Clinical Center but then largely completed by the sponsor through a Clinical Research Organization. Data from that trial should help guide the future clinical development of peramivir as a parenteral neuraminidase inhibitor. The third trial is a phase II vaccine dose-finding pilot study for the development of an anti-influenza A (H5N1) intravenous hyper-immune globulin preparation of potential utility in the treatment of human cases of avian influenza. H5N1 avian influenza represents an episodic zoonotic disease with the potential to cause a pandemic, and antiviral resistance is of considerable concern. We sought to generate high-titer H5N1 antibodies in healthy volunteers for the purpose of developing hyperimmune intravenous immunoglobulin. We conducted a dose-escalating, unblinded clinical trial involving 75 subjects aged 18-59 years. Three cohorts of twenty-five subjects were enrolled sequentially and received 90, 120, or 180 microg of H5N1 A/Vietnam/1203/04 vaccine in 4 doses administered approximately 28 days apart. No statistically significant dose-related increases in the geometric mean titers (GMTs) of serum hemagglutination inhibition antibody were observed when the 90-microg, 120-microg, and 180-microg cohorts were compared. When the cohorts were analyzed together to determine the effect of additional vaccinations, the GMTs of hemagglutination inhibition antibody after the first, second, third, and fourth vaccinations were 1:15.7, 1:22.2, 1:36.0, and 1:32.0, respectively (first vaccination vs. baseline, P<.001;second vs. first vaccination, P=.02;and third vs. second vaccination, P<.001). The microneutralization GMTs after the first, second, third, and fourth vaccinations were 1:17.5, 1:33.1, 1:55.7, and 1:68.4, respectively (P<.001 for all comparisons). The results of this study suggest that a third and fourth dose of the H5N1 A/Vietnam/1203/04 vaccine may result in higher hemagglutination inhibition and microneutralization GMTs, compared with the GMTs resulting from fewer doses. However, there was no benefit to increasing the dose of the vaccine. In addition to these trials, we have also undertaken a study of a novel nasally-administered agent with potential antiviral activity against a variety of respiratory viruses, including influenza. In this phase I double-blind, placebo-controlled, dose-escalating study to evaluate the safety and tolerability of topical nasal Poly-ICLC (synthetic dsRNA strands of poly-inosinic and poly-cytidylic acids), normal volunteers received escalating doses of this biologic response modifier to determine its safety when nasally administered as well as to measure both local and systemic immunologic effects of its administration. This trial is currently in the final stages of unblinding and data analysis. In response to the emergence of a pandemic strain of novel H1N1 influenza A called H1N1v (or """"""""swine"""""""" flu) in April 2009, our section undertook additional clinical research efforts to help better characterize and treat infection with this novel new strain. To begin with, protocol 07-I-0229 Influenza in the Immunocompromised Host was revised to allow enrollment and study of normal volunteers in addition to patients with immunodeficiency disorders. A new protocol was also developed to allow serial collection of high-titer anti-H1N1v plasma either from patients recovering from H1N1v naturally-acquired infection or from recipients of H1N1v vaccine when the latter becomes available in Fall 2009. The goal of this protocol is to allow harvesting of a pool of high-titer antisera (in the form of either plasma or an IVIG product) that could then be tested as a potential therapeutic adjunct in the management of patients with severe or life-threatening H1N1v infection. Finally, we have also contributed to the development of one domestic and two large international observational protocols for outpatients or hospitalized patients with H1N1v infection that will be administered under the auspices of DMID or on an international basis under the auspices of the INSIGHT clinical trials network, respectively. The goal of the latter two large trials is to better characterize the clinical aspects of H1N1v infection on a global basis, to define predictors of severe disease and/or death, and to develop a repository of clinical research specimens potentially of great value in helping map viral antigenic drift, emerging patterns of drug resistance, and other aspects of the evolving pandemic. Lastly, in addition to the clinical trials described above, we continue to monitor on a yearly basis the clinical and psychologic status and well-being of a subset of patients previously exposed to anthrax as a result of the October 2001 anthrax attack, as well as maintaining an open clinical protocol for the study of additional anthrax exposures that may occur through accidental or occupational exposure
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