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Remdesivir for the Treatment of Covid-19 - Final Report

Beigel, John H; Tomashek, Kay M; Dodd, Lori E; Mehta, Aneesh K; Zingman, Barry S; Kalil, Andre C; Hohmann, Elizabeth; Chu, Helen Y; Luetkemeyer, Annie; Kline, Susan; Lopez de Castilla, Diego; Finberg, Robert W; Dierberg, Kerry; Tapson, Victor; Hsieh, Lanny; Patterson, Thomas F; Paredes, Roger; Sweeney, Daniel A; Short, William R; Touloumi, Giota; Lye, David Chien; Ohmagari, Norio; Oh, Myoung-Don; Ruiz-Palacios, Guillermo M; Benfield, Thomas; Fätkenheuer, Gerd; Kortepeter, Mark G; Atmar, Robert L; Creech, C Buddy; Lundgren, Jens; Babiker, Abdel G; Pett, Sarah; Neaton, James D; Burgess, Timothy H; Bonnett, Tyler; Green, Michelle; Makowski, Mat; Osinusi, Anu; Nayak, Seema; Lane, H Clifford; Ahn, Jenny; Ahuja, Neera; Alaaeddine, Ghina; Ali, Farhana; Amin, Alpesh N; Angus, Brian; Antoniadou, Anastasia; Arguinchona, Christa; Arguinchona, Henry; Atmar, Robert L; Babiker, Abdel G; Barmparessou, Zafeiria; Beigel, John H; Bell, Taison D; Benfield, Thomas; Benson, Constance A; Billings, Joanne; Boesecke, Christoph; Bonnett, Tyler; Branche, Angela R; Burgess, Timothy H; Cantos, Valeria D; Cao, Huyen; Chambers, Susan E; Chary, Aarthi; Chrysanthidis, Theofilos; Chu, Helen Y; Chung, Kevin K; Cohen, Stuart H; Colombo, Christopher J; Colombo, Rhonda E; Creech, C Buddy; Crouch, Pierre-Cedric B; Davey, Richard T; Dempsey, Walla; Dierberg, Kerry; Dodd, Lori E; Duncan, Christopher J A; Eckhardt, Benjamin; El Sahly, Hana M; Elsafy, Mohamed; Engel, Theresa; Erdmann, Nathaniel; Falsey, Ann R; Fatkenheuer, Gerd; Ferreira, Jennifer L; Finberg, Robert W; Follmann, Dean; Frank, Maria; Ganesan, Anuradha; George, Sarah L; Germain Seymour, Jack David; Gerstoft, Jan; Gettinger, Nikki; Gioukari, Vicky; Goepfert, Paul; Goodman, Anna; Green, Margaret; Green, Michelle; Grein, Jonathan; Grossberg, Robert; Helleberg, Marie; Hewlett, Angela; Hohmann, Elizabeth; Holodniy, Mark; Hsieh, Lanny; Huprikar, Nikhil; Hynes, Noreen A; Jackson, Patrick E H; Jang, Hannah; Javeri, Heta; Jensen, Tomas; Jilg, Nikolaus; Johansen, Isik; Jung, Jongtak; Jurao, Robert; Kalil, Andre C; Kalomenidis, Ioannis; Kim, Eu Suk; Kline, Susan; Knudsen, Lene; Koehler, Philipp; Koo, Hyung; Kortepeter, Mark G; Kotloff, Karen L; Koulouris, Nikolaos; Krueger, Karen; Lalani, Tahaniyat; Lane, H Clifford; Larson, LuAnn; Lee, Marina; Lee, Tida; Lindegaard, Birgitte; Lindholm, David A; Llewelyn, Martin; Lopez de Castilla, Diego; Luetkemeyer, Annie; Lundgren, Jens; Lye, David Chien; Madsen, Lone W; Makowski, Mat; Malin, Jakob J; Marks, G Lynn; Martinez-Orozco, Jose Arturo; Mateu, Lourdes; Maves, Ryan C; McGill, Fiona; McLellan, Susan L F; Mehta, Aneesh K; Mende, Katrin; Merrick, Blair; Metallidis, Simeon; Mikami, Ayako; Minton, Jane; Munoz, Jose; Nadeau, Kari; Nayak, Seema; Neaton, James D; Neumann, Henry J; Nielsen, Henrik; Nomicos, Effie; Noren, Brooke; Novak, Richard M; Oh, Myoung-Don; Ohmagari, Norio; Ong, Sean W X; Ortiz, Justin R; Osinusi, Anu; Ostergaard, Lars; Paredes, Roger; Park, Wan Beom; Patterson, Thomas F; Paules, Catharine I; Pett, Sarah; Philips, Barbara; Pikaart-Tautges, Rhonda; Ponce de Leon, Alfredo; Price, D Ashley; Proschan, Michael; Protopapas, Konstantinos; Rajme, Sandra; Regalado Pineda, Justino; Rice, Todd W; Riedo, Francis X; Riska, Paul F; Roldan, Montserrat; Rouphael, Nadine G; Ruiz-Palacios, Guillermo M; Sauer, Lauren M; Short, William R; Staerke, Nina; Stephan, Christoph; Stephens, David S; Sutterwala, Fayyaz; Sweeney, Daniel A; Swiatlo, Edwin; Taiwo, Babafemi; Tapson, Victor; Tebas, Pablo; Tennant, Janice; Thompson, George R 3rd; Thomsen, Isaac; Tomashek, Kay M; Torgersen, Jessie; Torres-Soto, Mariam; Touloumi, Giota; Traenkner, Jessica J; Utz, Gregory C; Uyeki, Timothy M; Van Winkle, Jason W; Voell, Jocelyn D; Vu, Trung; Wald, Anna; Walker, Robert; Walter, Emmanuel B; Wang, Jennifer P; Wang, Jing; Wasmuth, Jan-Christian; Weise, Lothar; Wendrow, Andrea; Wessolossky, Mireya; Whitaker, Jennifer; Widmer, Kyle; Wierzbicki, Michael R; Wolf, Timo; Wolfe, Cameron; Wolff, Peter; Yang, Otto O; Young, Heather; Zakynthinos, Spyros G; Zingman, Barry S
BACKGROUND:Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), no antiviral agents have yet been shown to be efficacious. METHODS:We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only. RESULTS:A total of 1062 patients underwent randomization (with 541 assigned to remdesivir and 521 to placebo). Those who received remdesivir had a median recovery time of 10 days (95% confidence interval [CI], 9 to 11), as compared with 15 days (95% CI, 13 to 18) among those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; P<0.001, by a log-rank test). In an analysis that used a proportional-odds model with an eight-category ordinal scale, the patients who received remdesivir were found to be more likely than those who received placebo to have clinical improvement at day 15 (odds ratio, 1.5; 95% CI, 1.2 to 1.9, after adjustment for actual disease severity). The Kaplan-Meier estimates of mortality were 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% with remdesivir and 15.2% with placebo by day 29 (hazard ratio, 0.73; 95% CI, 0.52 to 1.03). Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients who received placebo (31.6%). CONCLUSIONS:Our data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTT-1 number, NCT04280705.).
PMID: 32445440
ISSN: 1533-4406
CID: 4637302

Marburg Virus Disease: a Summary for Clinicians

Kortepeter, Mark G; Dierberg, Kerry; Shenoy, Erica S; Cieslak, Theodore J
OBJECTIVES/OBJECTIVE:This article is a summary of countermeasures for Marburg virus disease focusing on pathogenesis, clinical features, and diagnostics, with an emphasis on therapies and vaccines that have demonstrated potential for use in an emergency situation, through their evaluation in nonhuman primates (NHPs) and/or in humans. METHODS:A standardized literature review was conducted on vaccines and treatments for each pathogen, with a focus on human and nonhuman primate data published in the last five years. More detail on the methods used are summarized in a companion methods paper. RESULTS:We identified six treatments and four vaccine platforms that have demonstrated potential benefit for treating or preventing infection in humans, through their efficacy in NHPs. CONCLUSION/CONCLUSIONS:We provide succinct summaries of Marburg countermeasures to give the busy clinician a head start in reviewing the literature if faced with a patient with Marburg virus disease. We also provide links to other authoritative sources of information.
PMID: 32758690
ISSN: 1878-3511
CID: 4560122

Challenges and opportunities utilizing an existing research network for new protocols during the COVID-19 pandemic: The special pathogens research network experience [Meeting Abstract]

Kortepeter, M; Larson, L A; Hicks, L J; Gordon, B; Lowe, A; Arguinchona, C; Arguinchona, H; Bhadelia, N; Cieslak, T J; Davey, R; Dierberg, K; Evans, J D; Frank, M G; Grein, J; Kalil, A C; Kline, S; Kraft, C S; Kratochvil, C J; McLellan, S; Mehta, A K; Noren, B; Raabe, V; Schwedhelm, S; Shenoy, E S; Uyeki, T; Vasistha, S; Sauer, L
During the 2014-16 W. Africa outbreak of Ebola virus disease, the US had no mechanism to study investigational treatments rapidly, and individual institutions provided investigational products as emergency investigational new drugs (eINDs). Consequently, determining the optimum care for the disease was not achieved. The Special Pathogens Research Network (SPRN) was established to create the infrastructure to conduct multi-center clinical research to improve outcomes for emerging special pathogens. This included establishing a central IRB at the University of Nebraska Medical Center and 10 collaborative sites across the US. As the COVID-19 outbreak began, the SPRN quickly executed three protocols. We share efficiencies and ideas for future improvements. At the onset of the COVID-19 outbreak, the network established three clinical protocols: 1) a "natural history" protocol for collecting discarded specimens and patient data; 2) a NIAID-sponsored randomized placebo controlled trial with the antiviral drug Remdesivir; and 3) a prospective data and sample collection protocol. We evaluated the IRB approval timeline centrally and at partner sites and the rapidity of first subject enrollment. We assessed aspects that facilitated or hindered the adoption of the different protocols across the network. Central and other site IRB approvals occurred expeditiously. Subjects were enrolled within one day of site approval in all three studies. UNMC enrolled the first US patient in the Remdesivir RCT. IRB approval occurred at all 10 sites within 32 days of central IRB approval; however, contracts for data use and material transfer agreements (DUAs and MTAs) lagged. Consequently, some sites developed their own natural history protocols, rather than adopt a network protocol. In conclusion, the SPRN pre-existing network of 10 sites was able to enroll subjects rapidly at the start of the outbreak, functioning as one unit in many respects. Contracting for specimen collection protocols has proved challenging and thus has impacted the ability to organize and deliver. This continues to be addressed
ISSN: 0002-9637
CID: 5184302

Building an accessible evidence base for medical countermeasure use in bioemergencies-the special pathogen research network initiative [Meeting Abstract]

Sauer, L M; Kortepeter, M J; Bhadelia, N; Cieslak, T; Davey, R; Dierberg, K; Evans, J D; Frank, M G; Grein, J; Kraft, C S; Kratochvil, C J; McLellan, S; Measer, G T; Mehta, A K; Raabe, V; Risi, G; Shenoy, E; Uyeki, T M
During the 2014-2016 Ebola virus disease (EVD) outbreak, clinicians lacked a readily available resource cataloguing available medical countermeasures (MCMs) to treat EVD patients in West Africa and other regions. Some patients received investigational interventions under uncontrolled compassionate use protocols. Therefore, the Special Pathogens Research Network (SPRN) of the National Ebola Training and Education Center (NETEC) formed the MCMs Working Group (WG) with members from 10 Regional Ebola and other Special Pathogen Treatment Centers (RESPTC) and NETEC partners. The goal of the MCMs WG is to develop an evidence-informed, easily accessible, practical assessment of potential countermeasures for clinicians managing patients with selected highly hazardous communicable diseases. Pathogens were selected based on 1) ability to cause severe disease; 2) potential to cause large outbreaks; 3) paucity of currently available cleared MCMs; 4) occurrence of nosocomial spread to health care providers; and 5) transmissibility requiring specialized care in a biocontainment unit. After a standardized literature review is conducted, an assessment of potentially available countermeasures is performed by 2-4 subject matter experts, followed by peer review. Pathogens selected to date incluDe Marburg, Lassa, Middle East Respiratory Syndrome Coronavirus (MERS-CoV), Crimean Congo Hemorrhagic Fever (CCHF), Nipah, Variola (and Monkeypox) and South American Hemorrhagic Fever (Junin, Machupo, etc.) viruses. The list overlaps with the World Health Organization's list of ?Blueprint? priority diseases. Reviews on seven pathogens are in progress. In conclusion, the NETEC SPRN MCM WG was created to proviDe a preemptive compendium of systematic and clinically relevant summaries of available MCMs for selected pathogens based on pre-specified criteria. Challenges will incluDe updating current documents as new scientific evidence becomes available. Plans are in place for regular review and updates, with the most up-todate materials available on the NETEC website for open-source access
ISSN: 0002-9637
CID: 4285332

Strengthening provision of essential medicines to women and children in post-Ebola Sierra Leone

Kahn, Rebecca; Bangura, Sheriff; Hann, Katrina; Salvi, Ameet; Gassimu, Joseph; Kabba, Alpha; Mesman, Annelies W; Dierberg, Kerry L; Marsh, Regan H
PMID: 31217949
ISSN: 2047-2986
CID: 3939242

A comprehensive district-level laboratory intervention after the Ebola epidemic in Sierra Leone

Mesman, Annelies W; Bangura, Musa; Kanawa, Sahr M; Gassimu, Joseph S; Dierberg, Kerry L; Sheku, Mohamed M; Orozco, J Daniel; Marsh, Regan H
Background/UNASSIGNED:The 2014-2016 Ebola outbreak exposed the poor laboratory systems in Sierra Leone. Immense needs were recognised across all areas, from facilities, diagnostic capacity, supplies, trained personnel to quality assurance mechanisms. Objective/UNASSIGNED:We aimed to describe the first year of a comprehensive intervention, which started in 2015, in a public hospital's general laboratory serving a population of over 500 000 in a rural district. Methods/UNASSIGNED:The intervention focused on (1) supporting local authorities and healthcare workers in policy implementation and developing procedures to enhance access to services, (2) addressing gaps by investing in infrastructure, supplies, and equipment, (3) development of quality assurance mechanisms via mentorship, bench-side training, and the introduction of quality control and information systems. All work was performed alongside counterparts from the Ministry of Health and Sanitation. Results/UNASSIGNED:We observed a strong increase in patient visits and inpatient and outpatient testing volumes. Novel techniques and procedures were taken up well by staff, leading to improved and expanded service and safety, laying foundations for further improvements. Conclusion/UNASSIGNED:This comprehensive approach was successful and the results suggest an increase in trust from patients and healthcare workers.
PMID: 31745458
ISSN: 2225-2002
CID: 4208962

Strengthening the Free Healthcare Initiative through a pharmacy and supply chain intervention: Partners in Health's experience in rural Sierra Leone [Meeting Abstract]

Bangura, Sheriff L; Hann, Katrina; Salvi, Ameet; Kahn, Rebecca; Dierberg, Kerry L; Gassimu, Joseph; Kabbah, Alpha; Marsh, Regan H
ISSN: 2214-109x
CID: 2674142

Minimally Symptomatic Infection in an Ebola 'Hotspot': A Cross-Sectional Serosurvey

Richardson, Eugene T; Kelly, J Daniel; Barrie, Mohamed Bailor; Mesman, Annelies W; Karku, Sahr; Quiwa, Komba; Marsh, Regan H; Koedoyoma, Songor; Daboh, Fodei; Barron, Kathryn P; Grady, Michael; Tucker, Elizabeth; Dierberg, Kerry L; Rutherford, George W; Barry, Michele; Jones, James Holland; Murray, Megan B; Farmer, Paul E
INTRODUCTION: Evidence for minimally symptomatic Ebola virus (EBOV) infection is limited. During the 2013-16 outbreak in West Africa, it was not considered epidemiologically relevant to published models or projections of intervention effects. In order to improve our understanding of the transmission dynamics of EBOV in humans, we investigated the occurrence of minimally symptomatic EBOV infection in quarantined contacts of reported Ebola virus disease cases in a recognized 'hotspot.' METHODOLOGY/PRINCIPAL FINDINGS: We conducted a cross-sectional serosurvey in Sukudu, Kono District, Sierra Leone, from October 2015 to January 2016. A blood sample was collected from 187 study participants, 132 negative controls (individuals with a low likelihood of previous exposure to Ebola virus), and 30 positive controls (Ebola virus disease survivors). IgG responses to Ebola glycoprotein and nucleoprotein were measured using Alpha Diagnostic International ELISA kits with plasma diluted at 1:200. Optical density was read at 450 nm (subtracting OD at 630nm to normalize well background) on a ChroMate 4300 microplate reader. A cutoff of 4.7 U/mL for the anti-GP ELISA yielded 96.7% sensitivity and 97.7% specificity in distinguishing positive and negative controls. We identified 14 seropositive individuals not known to have had Ebola virus disease. Two of the 14 seropositive individuals reported only fever during quarantine while the remaining 12 denied any signs or symptoms during quarantine. CONCLUSIONS/SIGNIFICANCE: By using ELISA to measure Zaire Ebola virus antibody concentrations, we identified a significant number of individuals with previously undetected EBOV infection in a 'hotspot' village in Sierra Leone, approximately one year after the village outbreak. The findings provide further evidence that Ebola, like many other viral infections, presents with a spectrum of clinical manifestations, including minimally symptomatic infection. These data also suggest that a significant portion of Ebola transmission events may have gone undetected during the outbreak. Further studies are needed to understand the potential risk of transmission and clinical sequelae in individuals with previously undetected EBOV infection.
PMID: 27846221
ISSN: 1935-2735
CID: 2673922

Strengthening Health Systems While Responding to a Health Crisis: Lessons Learned by a Nongovernmental Organization During the Ebola Virus Disease Epidemic in Sierra Leone

Cancedda, Corrado; Davis, Sheila M; Dierberg, Kerry L; Lascher, Jonathan; Kelly, J Daniel; Barrie, Mohammed Bailor; Koroma, Alimamy Philip; George, Peter; Kamara, Adikali Alpha; Marsh, Ronald; Sumbuya, Manso S; Nutt, Cameron T; Scott, Kirstin W; Thomas, Edgar; Bollbach, Katherine; Sesay, Andrew; Barrie, Ahmidu; Barrera, Elizabeth; Barron, Kathryn; Welch, John; Bhadelia, Nahid; Frankfurter, Raphael G; Dahl, Ophelia M; Das, Sarthak; Rollins, Rebecca E; Eustis, Bryan; Schwartz, Amanda; Pertile, Piero; Pavlopoulos, Ilias; Mayfield, Allan; Marsh, Regan H; Dibba, Yusupha; Kloepper, Danielle; Hall, Andrew; Huster, Karin; Grady, Michael; Spray, Kimberly; Walton, David A; Daboh, Fodei; Nally, Cora; James, Sahr; Warren, Gabriel S; Chang, Joyce; Drasher, Michael; Lamin, Gina; Bangura, Sherry; Miller, Ann C; Michaelis, Annie P; McBain, Ryan; Broadhurst, M Jana; Murray, Megan; Richardson, Eugene T; Philip, Ted; Gottlieb, Gary L; Mukherjee, Joia S; Farmer, Paul E
An epidemic of Ebola virus disease (EVD) beginning in 2013 has claimed an estimated 11 310 lives in West Africa. As the EVD epidemic subsides, it is important for all who participated in the emergency Ebola response to reflect on strengths and weaknesses of the response. Such reflections should take into account perspectives not usually included in peer-reviewed publications and after-action reports, including those from the public sector, nongovernmental organizations (NGOs), survivors of Ebola, and Ebola-affected households and communities. In this article, we first describe how the international NGO Partners In Health (PIH) partnered with the Government of Sierra Leone and Wellbody Alliance (a local NGO) to respond to the EVD epidemic in 4 of the country's most Ebola-affected districts. We then describe how, in the aftermath of the epidemic, PIH is partnering with the public sector to strengthen the health system and resume delivery of regular health services. PIH's experience in Sierra Leone is one of multiple partnerships with different stakeholders. It is also one of rapid deployment of expatriate clinicians and logistics personnel in health facilities largely deprived of health professionals, medical supplies, and physical infrastructure required to deliver health services effectively and safely. Lessons learned by PIH and its partners in Sierra Leone can contribute to the ongoing discussion within the international community on how to ensure emergency preparedness and build resilient health systems in settings without either.
PMID: 27688219
ISSN: 1537-6613
CID: 2673932

Factors associated with vision impairment in Ebola virus disease uveitis in Sierra Leone [Meeting Abstract]

Mattia, John; Vandy, Matthew; Platt, Devin; Dierberg, Kerry; Pinto, Ruxandra; Mansaray, Yealie; Kamara, Amadu; Crozier, Ian; Shantha, Jessica; Yeh, Steven; Chang, Joyce
ISSN: 0146-0404
CID: 2674132