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Principal Investigator: Richard Davey
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2022
Award: $3,483,874
Funding agency: National Institute of Allergy and Infectious Diseases
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. In this regard, our Section has undertaken clinical research efforts to help better characterize and treat infection with both novel and seasonal subtypes of influenza. A prior treatment trial (FLU005) with hyperimmune intravenous immunoglobulin (IVIG) showed a significant treatment benefit in patients hospitalized with influenza B infection despite the lower antibody titers present in IVIG against influenza B virus. This outcome lead to the design of a new IVIG trial (FLU006) aimed at targeting a larger number of patients hospitalized with influenza B. However, the exigencies of the COVID-19 pandemic and anticipation of a mild influenza season as a result of public health measures against the former has placed launching of this new trial on temporary hold.
The Special Clinical Studies Unit (SCSU) with the NIH Clinical Center remains one of a small number of special high containment patient care units within the US called upon to hospitalize patients or staff suffering high-risk exposures to highly-infectious agents who require observation and/or care under conditions of high containment. The section continues to provide direct medical oversight to the SCSU. During the current pandemic this has included hospitalizing and providing care for seriously ill patients with COVID-19 from the surrounding community who have been transferred to the NIH for access to investigational therapies. Through engagement with a large domestic and international network enterprise as coordinated through NIAIDs Division of Microbiology and Infectious Diseases (DMID), the Section enrolled patients on three of the four separate phases of the Adaptive COVID-19 Treatment Trial (ACTT) studying investigational therapeutics in COVID-19 inpatients presenting with respiratory compromise:
ACTT-1: Remdesivir for the treatment of COVID-19
This was a double-blind, randomized, placebo-controlled trial of intravenous
remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract infection. Patients were randomly assigned to receive either intravenous remdesivir or placebo for up to 10 days. A total of 1062 patients underwent 1:1 randomization, with those receiving remdesivir having a median recovery time of 10 days as compared with 15 days among placebo recipients. Using an eight-category ordinal scale to measure outcomes, patients who received remdesivir were found to be more likely than placebo recipients to have clinical improvement at day 15. While the trial wasnt powered to show an effect on mortality, overall these data suggested that remdesivir was superior to placebo in shortening the time to recovery in hospitalized adults.
ACTT-2: Baracitinib plus remdesivir for hospitalized adults with COVID-19
This was a double-blind, randomized, placebo-controlled trial evaluating the JAK inhibitor baricitinib plus remdesivir in hospitalized adults with Covid-19. Patients received remdesivir (10 days) and either baricitinib (14 days) or placebo (control). A total of 1033 patients underwent 1:1 randomization, with those receiving baricitinib having a median time
to recovery of 7 days as compared with 8 days in control patients and having a 30% higher odds of improvement in clinical status at day 15. Patients receiving high-flow oxygen or noninvasive
ventilation at enrollment appeared to have the greatest benefit. From these data it was concluded that baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery
time and accelerating improvement in clinical status among COVID-19 patients.
ACTT-4: Baricitinib/remdesivir vs. dexamethasone/remdesivir.
As the fourth of the ACTT trials, this was a 1:1 randomized, double-blind comparison of the efficacy of baricitinib + remdesivir versus dexamethasone + remdesivir in patients receiving supplemental oxygen, with the primary outcome being their mechanical ventilation free survival by Day 29. Overall 1010 out of a desired 1500 patients were enrolled. However, Data Safety Monitoring Board (DSMB) review of the futility analysis plan in April, 2021 determined that the study met pre-defined futility criteria, meaning that it would be unlikely for the study to show a significant difference in outcomes between the two arms if it were to continue to the full enrollment. From these results it was concluded that baracitinib should be considered an acceptable alternative to dexamethasone in treating hospitalized patients with COVID-19.
In addition to the ACTT trials, the section also participated in two other COVID-19-related clinical trials: ITAC (INSIGHT 013) An International Multicenter, Adaptive, Randomized Double-Blind, Placebo-Controlled Trial of the Safety, Tolerability and Efficacy of Anti-Coronavirus Hyperimmune Intravenous Immunoglobulin for the Treatment of Adult Hospitalized Patients at Onset of Clinical Progression of COVID-19, and a phase II double-blind, randomized, placebo-controlled trial study of the spleen tyrosine kinase inhibitor fostamatinib in hospitalized adults with Covid-19 where patients receiving remdesivir and corticosteroids were randomized to receive either fostamatinib (up to 14 days) or placebo. The results of both studies have been published.
In collaboration with the Institut National pour la Recherche Biomedicale (INRB), the WHO, and several international partners, the Section was instrumental in helping design an investigational RCT of 4 different MCMs employed during the 10th outbreak of Ebola virus infection in the Democratic Republic of the Congo (DRC) that began in August 2018. 693 patients were accrued in this landmark trial that ultimately established both the safety and efficacy of two different monoclonal antibody products (REGN-EB3 and Mab-114) in treating both adult and pediatric patients with Ebola virus disease (EVD), not only proving for the first time that effective treatment of EVD was possible but also establishing that important clinical research could be safely conducted in the midst of a public health crisis. Currently we are engaged in an effort to develop a means of independently validating which study participants did or did not receive prior vaccination with the Merck vaccine in order to analyze the effect of prior vaccination on disease outcome.
Launched in 2016, the Section is also continuing an ongoing pre-exposure vaccination protocol called PREPARE that is using VSVG-ZEBOV vaccine to immunize HCWs, BSL-4 Laboratory staff, and other at-risk personnel against Ebola virus infection. The protocol features 1:1 randomization to a homologous booster immunization at month 18 to determine whether the booster further augments antibody levels induced by the primary immunization as assessed at month 36. 233 patients have been enrolled and will provide the basis for the primary endpoint determination that should be completed within the next 6 months.
As of summer 2022 the Section is also advising on the development and implementation of a placebo-controlled RCT studying the role of the antiviral drug tecovirimat (TPoxx) in treating cases of clade 1 Monkeypox infection at three centers in the DRC. With the recent outbreak of an increasing number of cases of clade 3 Monkeypox infections in the developed world, which was recently designated as a Public Health Emergency in the United States, domestically we are also collaborating with DMID and others in the design and implementation of a dose-sparing trial of the licensed JYNNEOS Monkeypox vaccine that is presently in limited supply in the Strategic National Stockpile.
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