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1. Experimental Treatment of Ebola Virus Disease with TKM-130803: A Single-Arm Phase 2 Clinical Trial

Author

Dunning, Jake, Sahr, Foday, Rojek, Amanda, Gannon, Fiona, Carson, Gail, Idriss, Baimba, Massaquoi, Thomas, Gandi, Regina, Joseph, Sebatu, Osman, Hassan K., Brooks, Timothy J. G., Simpson, Andrew J. H., Goodfellow, Ian, Thorne, Lucy, Arias, Armando, Merson, Laura, Castle, Lyndsey, Howell-Jones, Rebecca, Pardinaz-Solis, Raul, Hope-Gill, Benjamin, Ferri, Mauricio, Grove, Jennifer, Kowalski, Mark, Stepniewska, Kasia, Lang, Trudie, Whitehead, John, Olliaro, Piero, Samai, Mohammed, and Horby, Peter W.

Subjects
Ebola hemorrhagic fever -- Drug therapy -- Research, Antiviral agents -- Health aspects -- Research, Biological sciences
Abstract

Background TKM-130803, a small interfering RNA lipid nanoparticle product, has been developed for the treatment of Ebola virus disease (EVD), but its efficacy and safety in humans has not been evaluated. Methods and Findings In this single-arm phase 2 trial, adults with laboratory-confirmed EVD received 0.3 mg/kg of TKM-130803 by intravenous infusion once daily for up to 7 d. On days when trial enrolment capacity was reached, patients were enrolled into a concurrent observational cohort. The primary outcome was survival to day 14 after admission, excluding patients who died within 48 h of admission. After 14 adults with EVD had received TKM-130803, the pre-specified futility boundary was reached, indicating a probability of survival to day 14 of [less than or equal to]0.55, and enrolment was stopped. Pre-treatment geometric mean Ebola virus load in the 14 TKM-130803 recipients was 2.24 x 10.sup.9 RNA copies/ml plasma (95% CI 7.52 x 10.sup.8, 6.66 x 10.sup.9). Two of the TKM-130803 recipients died within 48 h of admission and were therefore excluded from the primary outcome analysis. Of the remaining 12 TKM-130803 recipients, nine died and three survived. The probability that a TKM-130803 recipient who survived for 48 h will subsequently survive to day 14 was estimated to be 0.27 (95% CI 0.06, 0.58). TKM-130803 infusions were well tolerated, with 56 doses administered and only one possible infusion-related reaction observed. Three patients were enrolled in the observational cohort, of whom two died. Conclusions Administration of TKM-130803 at a dose of 0.3 mg/kg/d by intravenous infusion to adult patients with severe EVD was not shown to improve survival when compared to historic controls. Trial registration Pan African Clinical Trials Registry PACTR201501000997429, Author(s): Jake Dunning 1, Foday Sahr 2,3, Amanda Rojek 1, Fiona Gannon 4, Gail Carson 1,5, Baimba Idriss 2, Thomas Massaquoi 2, Regina Gandi 2, Sebatu Joseph 2, Hassan K. [...]

Published
2016
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2. Using research to prepare for outbreaks of severe acute respiratory infection

Author

Mich, Vann, Pho, Yaty, Bory, Sotharith, Vann, Mich, Teav, Bunlor, Som, Leakhann, Jarrvisalo, Mikko J, Pulkkinen, Anni, Kuitunen, Anne, Ala-kokko, Tero, Melto, Sari, Daix, Thomas, Philippart, Francois, Antoine, Marchalot, Tiercelet, Kelly, Bruel, Cedric, Nicholas, Sedillot, Siami, Shidasp, Fabienne, Taimon, Bruyere, Raomi, Forceville, Xavier, Erickson, Simon, Campbell, Lewis, Sonawane, Ravikiran, Santamaria, John, Kol, Mark, Awasthi, Shally, Powis, Jeff, Hall, Richard, McCarthy, Anne E, Jouvet, Philippe, Opaysky, Mary Anne, Gilfoyle, Elaine, Farshait, Nataly, Martin, Dori-Ann, Griesdale, Donald, Katz, Kevin, Ruberto, Aaron J, Carrier, Francois Martin, Lamontagne, Francois, Muscedere, John, Rishu, Asgar, Sin, Wai Ching, Ngai, Wallace Chun Wai, Young, Paul, Forrest, Annette, Kazemi, Alex, Henderson, Seton, Browne, Troy, Ganeshalingham, Anusha, McConnochie, Rachael, Cho, Jae Hwa, Park, Tai Sun, Sim, Yun Su, Chang, Youjin, Lee, Heung Bum, Park, Seung Yong, Chan, Wai Ming, Lee, Won-Yeon, Wallace, David J, Angus, Derek C, Charles, Anthony G, van Doom, H Rogier, Kinh, Nguyen Van, Trung, Nguyen Vu, Prin, Meghan, Twagirumugabe, Theogene, Umuhire, Olivier Felix, Sylvain, Habarurema, Al Qasim, Eman, Heraud, Jean-Michel, Raberahona, Mihaja, Rabarison, Joelinotahiana Hasina, Patrigeon, Santiago Perez, Ramirez-Venegas, Alejandra, Melendez, Javier Araujo, Guerrero, M Lourdes, Mambule, Ivan, Ochieng, Otieno George, Nadjm, Behzad, Li, Iris Wai Sum, Choi, Won-Il, Florence, Komurian-Pradel, Arabi, Yaseen M, West, T Eoin, Riviello, Elisabeth D, Parke, Rachael, Djillali, Annane E, Fowler, Robert, Murthy, Srinivas, Nichol, Alistair, Cheng, Allen C, Semple, Calum, George, Maya, Valkonen, Miia, McArthur, Colin, Carson, Gail, O'Neill, Genevieve, Cobb, J Perren, Dunning, Jake, Chiche, Jean-Daniel, Huh, Jin-Won, Marshall, John, Rello, Jordi, Guillebaud, Julia, Razanazatovo, Norosoa, Otieno, Juilett Wambura, Green, Karen, Rowan, Kathy, Baillie, John Kenneth, Merson, Laura, Hsu, Li Yang, Christian, Michael D, Egi, Moritoki, Shindo, Nahoko, Horby, Peter, Pardinaz-Solis, Raul, Ubiergo, Sebastian Ugarte, Webb, Steve AR, Uyeki, Timothy M, Gordon, Anthony C, Paterson, David L, Everett, Dean, Giamarellos-Bourboulis, Evangelos J, Longuere, Kajsa-Stina, Maslove, David, Ohuma, Eric, Growl, Gloria, PedutemHumber, Theresa, EllazarHumber, Edward, Bahinskaya, Ilona, Osbourne-Townsend, Joan, Bentley, Andrew, Goodson, Jennifer, Welters, Ingeborg, Malik, Nadia, Browne, TS, Mahesh, Vinaya, Investigators, SPRINT-SARI, HUS Perioperative, Intensive Care and Pain Medicine, University of Helsinki, Anestesiologian yksikkö, University College Dublin [Dublin] (UCD), Monash University [Melbourne], We acknowledge support from the National Health and Medical Research Council in Australia, the Australia New Zealand Intensive Care Society Clinical Trials Group and the Seventh Framework Program in Europe, which have facilitated the progress that has been made for central project infrastructure. Data collection was funded locally by local research coordinators and investigators, including the International Respiratory and Severe Illness Center, University of Washington., Collaborators Vann Mich, Khmer Soviet Friend Hospital. Yaty Pho, Khmer Soviet Friend Hospital. Sotharith Bory, Calmette Hospital and University of Health Sciences. Mich Vann, Khmer-Soviet Friendship Hospital and University of Health Sciences. Bunlor Teav, Takeo Provincial Hospital. Leakhann Som, National Pediatric Hospital. Mikko J Jarrvisalo, Turku university hospital, ICU. Anni Pulkkinen, Central Hospital of Central Finland. Anne Kuitunen, Tampere University Hospital. Tero Ala-kokko, Oulu University Hospital, Research Group of Anesthesiology, Surgery and Intensive Care Medicine. Sari. Melto, South Karelia Central Hospital. Thomas DAIX, Reanimation polyvalente, CHU Dupuytren, Limoges, France and Inserm CIC 1435, CHU Dupuytren, Limoges, France. Francois Philippart, Intensive Care Unit. Marchalot Antoine, Dieppe General Hospital. Kelly Tiercelet, Groupe hospitalier Paris Saint Joseph. Cedric Bruel, Groupe hospitalier Paris Saint Joseph. BRUYERE Remi, Centre Hospitalier Fleyriat. Sedillot Nicholas, Centre Hospitalier Fleyriat. Shidasp SIAMI, General Intensive Care Medicine, Sud Essonne Hospital Etampes. Marchalot Antoine, Centre Hospitalier Dieppe. Taimon Fabienne, Service de Medecine Intensive et Reanimation, Rouen University Hospital (G.B.), and Normandie University, Universite de Rouen, U1096, Rouen University Hospital. Philippart, Groupe hospitalier Paris Saint joseph. Raomi Bruyere, Service de reanimation. Centre Hospitalier Fleyriat. Xavier Forceville, Grand Hopital de l'Est Francilien. Simon Erickson, Perth Children's Hospital. Lewis Campbell, Royal Darwin Hospital. Ravikiran Sonawane, Rockingham General Hospital. John Santamaria, St Vincent's Hospital (Melbourne). Mark Kol, Concord Hospital. Shally Awasthi, King George's Medical University. Jeff Powis, Michael Garron Hospital. Richard Hall, Dalhousie University. Anne E McCarthy, University of Ottawa and the Ottawa Hospital. Philippe Jouvet, Ste-Justine Hospital and Research Center. Mary Anne Opavsky, Joseph Brant Hospital. Elaine Gilfoyle, University of Calgary. Nataly Farshait, Humber River Hospital. Dori-Ann Martin, University of Calgary. Donald Griesdale, Department of Anesthesiology, Pharmacology & Therapeutics Department of Medicine, Divisions of Critical Care Medicine & Neurology University of British Columbia. Kevin Katz, North York General Hospital. Aaron J. Ruberto, Queen's University & Kingston Health Sciences Centre. Francois Martin Carrier, Centre Hospitalier de l'Universite de Montreal. Francois Lamontagne, Universite de Sherbrooke. John Muscedere, Queens University. Asgar Rishu, Sunnybrook Health Sciences Centre. Wai Ching Sin, Department of Adult Intensive Care Unit, Queen Mary Hospital. Wallace Chun Wai Ngai, Department of Adult Intensive Care Unit, Queen Mary Hospital. Paul Young, Medical Research Institute of New Zealand. Dr Annette Forrest, Waikato Hospital. Alex Kazemi, Middlemore Hospital. Seton Henderson, Christchurch Hospital. Troy Browne, Tauranga Hospital. Anusha Ganeshalingham, Starship Hospital. Rachael McConnochie, Department of Critical Care Medicine, Auckland City Hospital. Jae Hwa Cho, Yonsei University. Tai Sun Park, Hanyang University Guri Hospital. Yun Su Sim, Hallym University Kangnam Sacred Hospital. Youjin Chang, Inje University, College of Medicine, Sanggye Paik Hospital. Heung Bum Lee, Chonbuk National University Hospital. Seung Yong Park, Chonbuk National University Hospital. Wai Ming Chan, Department of Adult Intensive Care Unit, Queen Mary Hospital, Hong Kong. Won-Yeon Lee, Yonsei University Wonju College of Medicine. David J. Wallace, University of Pittsburgh School of Medicine. Derek C. Angus, University of Pittsburgh School of Medicine. Anthony G Charles, University of North Carolina at Chapel Hill. H Rogier van Doorn, Oxford University Clinical Research Unit. Nguyen Van Kinh, National Hospital for Tropical Diseases. Nguyen Vu Trung, National Hospital for Tropical Diseases. Meghan Prin, Columbia University College of Physicians & Surgeons. Theogene Twagirumugabe, University of Rwanda /College of Medicine and Health Sciences. Olivier Felix Umuhire, Department of Anesthesia, Emergency Medicine and Critical Care. University of Rwanda. Habarurema Sylvain, Centre hospitalier Universitaire de Butare(CHUB). Eman Al Qasim, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center. Jean-Michel Heraud, Institut Pasteur de Madagascar. Mihaja Raberahona, University Hospital Joseph Raseta Befelatanana. Joelinotahiana Hasina Rabarison, Insttut Pasteur de Madagascar. Santiago Perez Patrigeon, Instituto Nacional de Ciencias Medicas y Nutrición Salvador Subirán. Alejandra Ramirez-Venegas, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas. Javier Araujo Meléndez, Hospital Central 'Dr. Ignacio Morones Prieto'. M. Lourdes Guerrero, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiren. Ivan Mambule, Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health University of Liverpool and Malawi-Liverpool-Wellcome Trust, Clinical Research Programme. Otieno George Ochieng, Kijabe Mission Hospital. Behzad Nadjm, Imperial College Healthcare NHS Trust, GBR. Iris Wai Sum Li, Queen Mary Hospital, School of Public Health, the University of Hong Kong. Won-Il Choi, Department of Medicine, Keimyung University, Dongsan Hospital. Komurian-Pradel Florence, Fondation Merieux. Yaseen M Arabi, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Intensive Care Department, King Abdulaziz Medical City. T. Eoin West, University of Washington. Elisabeth D Riviello, Harvard Medical School and Beth Israel Deaconess Medical Center. Rachael Parke, Cardiothoracic and Vascular ICU, Auckland City Hospital. AnnaneE Djillali, Raymond Poincare Hospital (APHP) Unievrsity of Versailles SQY/University Paris Saclay. Robert Fowler, Interdepartmental Division of Critical Care Medicine, University of Toronto. Srinivas Murthy, Department of Pediatrics. Alistair Nichol, University College Dublin / Monash University. Allen C Cheng, School of Public Health and Preventive Medicine, Monash University. Calum Semple, University of Liverpool. Maya George, Australian and New Zealand Intensive Care Research Centre, Monash University. Miia Valkonen, University of Helsinki and Helsinki University Hospital. Colin McArthur, Auckland City Hospital (DCCM 82). Gail Carson, University of Oxford. Genevieve O'Neill, Australian and New Zealand Intensive Care Research Centre, Monash University. J. Perren Cobb, University of Southern California. Jake Dunning, University of Oxford, Imperial College London. Jean-Daniel Chiche, Hopitaux Universitaire Paris Centre, site Cochin. Jin-Won Huh, ASAN Medical Center. John Marshall, St. Michael's Hospital. Jordi Rello, Ciberes & Vall d'Hebron University Hospital, Barcelona, Spain. Julia Guillebaud, Institut Pasteur de Madagascar. Norosoa Razanazatovo, Institut Pasteur de Madagascar. Juilett Wambura Otieno, KEMRI-Wellcome Trust Research Programme. Karen Green, Toronto Invasive Bacterial Diseases Network. Kathy Rowan, Intensive Care National Audit and Research Centre. John Kenneth Baillie, Roslin Institute, University of Edinburgh. Laura Merson, Infectious Diseases Data Observatory, Oxford, UK, Centre for Tropical Medicine & Global Health, Nuffield Department of Medicine, Oxford University, Oxford UK. Li Yang Hsu, National University of Singapore. Michael D. Christian, Essex & Herts Air Ambulance Trust. Miia Valkonen, Helsinki University Central Hospital. Moritoki Egi, Kobe University Hospital. Nahoko Shindo, World Health Organization. Peter Horby, University of Oxford. Raul Pardinaz-Solis, Nuffield Department of Medicine, University of Oxford. Sebastián Ugarte Ubiergo, Universidad Andrés Bello. Steve AR Webb, Monash University. Timothy M. Uyeki, Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia USA. Anthony C Gordon, Imperial College London. David L Paterson, University of Queensland Centre. Dean Everett, University of Edinburgh, The Queens Medical Research Institute and Malawi-Liverpool-Wellcome Trust, Clinical Research Programme. Evangelos J. Giamarellos-Bourboulis, National and Kapodistrian University of Athens, Medical School. Kajsa-Stina Longuere, University of Oxford. David Maslove, Queens University. Eric Ohuma, Oxford University. Gloria Crowl, Michael Garron Hospital. Theresa PedutemHumber, River Hospital. Edward EllazarHumber, River Hospital. Ilona Bahinskaya, University Health Network TGH MOT. Joan Osbourne-Townsend, Humber River Hospital. Andrew Bentley, University of Manchester. Ingeborg Welters, University of Liverpool. Nadia Malik, MountSinai Hospital/ William Osler Health Centre. Dr T S Browne, Tauranga Hospital. Jennifer Goodson, Tauranga Hospital. Vinaya Mahesh, North York General Hospital., and Carson, G

Subjects
medicine.medical_specialty, INTENSIVE-CARE-UNIT, global health, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Intensive care, Case fatality rate, Epidemiology, Global health, medicine, pneumonia, 030212 general & internal medicine, Public, Environmental & Occupational Health, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Practice, OUTCOMES, Science & Technology, business.industry, Health Policy, Public Health, Environmental and Occupational Health, Outbreak, 030208 emergency & critical care medicine, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, 3126 Surgery, anesthesiology, intensive care, radiology, Intensive care unit, 3. Good health, critical care, REAL-TIME SURVEILLANCE, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Observational study, SOFA score, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, SPRINT-SARI investigators, business, influenza, Life Sciences & Biomedicine, Demography, outbreak preparedness
Abstract

International audience; Severe acute respiratory infections (SARI) remain one of the leading causes of mortality around the world in all age groups. There is large global variation in epidemiology, clinical management and outcomes, including mortality. We performed a short period observational data collection in critical care units distributed globally during regional peak SARI seasons from 1 January 2016 until 31 August 2017, using standardised data collection tools. Data were collected for 1 week on all admitted patients who met the inclusion criteria for SARI, with follow-up to hospital discharge. Proportions of patients across regions were compared for microbiology, management strategies and outcomes. Regions were divided geographically and economically according to World Bank definitions. Data were collected for 682 patients from 95 hospitals and 23 countries. The overall mortality was 9.5%. Of the patients, 21.7% were children, with case fatality proportions of 1% for those less than 5 years. The highest mortality was in those above 60 years, at 18.6%. Case fatality varied by region: East Asia and Pacific 10.2% (21 of 206), Sub-Saharan Africa 4.3% (8 of 188), South Asia 0% (0 of 35), North America 13.6% (25 of 184), and Europe and Central Asia 14.3% (9 of 63). Mortality in low-income and low-middle-income countries combined was 4% as compared with 14% in high-income countries. Organ dysfunction scores calculated on presentation in 560 patients where full data were available revealed Sequential Organ Failure Assessment (SOFA) scores on presentation were significantly associated with mortality and hospital length of stay. Patients in East Asia and Pacific (48%) and North America (24%) had the highest SOFA scores of >12. Multivariable analysis demonstrated that initial SOFA score and age were independent predictors of hospital survival. There was variability across regions and income groupings for the critical care management and outcomes of SARI. Intensive care unit-specific factors, geography and management features were less reliable than baseline severity for predicting ultimate outcome. These findings may help in planning future outbreak severity assessments, but more globally representative data are required.

Published
2019

3. Using research to prepare for outbreaks of severe acute respiratory infection

Author

Mich, Vann Pho, Yaty Bory, Sotharith Vann, Mich Teav, Bunlor Som, Leakhann Jarrvisalo, Mikko J. Pulkkinen, Anni and Kuitunen, Anne Ala-kokko, Tero Melto, Sari Daix, Thomas and Philippart, Francois Antoine, Marchalot Tiercelet, Kelly and Bruel, Cedric Nicholas, Sedillot Siami, Shidasp Fabienne, Taimon Bruyere, Raomi Forceville, Xavier Erickson, Simon and Campbell, Lewis Sonawane, Ravikiran Santamaria, John Kol, Mark Awasthi, Shally Powis, Jeff Hall, Richard McCarthy, Anne E. Jouvet, Philippe Opaysky, Mary Anne Gilfoyle, Elaine and Farshait, Nataly Martin, Dori-Ann Griesdale, Donald and Katz, Kevin Ruberto, Aaron J. Carrier, Francois Martin and Lamontagne, Francois Muscedere, John Rishu, Asgar Sin, Wai Ching Ngai, Wallace Chun Wai Young, Paul Forrest, Annette and Kazemi, Alex Henderson, Seton Browne, Troy and Ganeshalingham, Anusha McConnochie, Rachael Cho, Jae Hwa and Park, Tai Sun Sim, Yun Su Chang, Youjin Lee, Heung Bum and Park, Seung Yong Chan, Wai Ming Lee, Won-Yeon Wallace, David J. Angus, Derek C. Charles, Anthony G. van Doom, H. Rogier and Nguyen Van Kinh Nguyen Vu Trung Prin, Meghan and Twagirumugabe, Theogene Umuhire, Olivier Felix Sylvain, Habarurema Al Qasim, Eman Heraud, Jean-Michel Raberahona, Mihaja Rabarison, Joelinotahiana Hasina Patrigeon, Santiago Perez Ramirez-Venegas, Alejandra Melendez, Javier Araujo and Guerrero, M. Lourdes Mambule, Ivan Ochieng, Otieno George and Nadjm, Behzad Li, Iris Wai Sum Choi, Won-Il Florence, Komurian-Pradel Arabi, Yaseen M. West, T. Eoin Riviello, Elisabeth D. Parke, Rachael Djillali, Annane E. Fowler, Robert Murthy, Srinivas Nichol, Alistair Cheng, Allen C. and Semple, Calum George, Maya Valkonen, Miia McArthur, Colin and Carson, Gail O'Neill, Genevieve Cobb, J. Perren Dunning, Jake Chiche, Jean-Daniel Huh, Jin-Won Marshall, John and Rello, Jordi Guillebaud, Julia Razanazatovo, Norosoa Otieno, Juilett Wambura Green, Karen Rowan, Kathy Baillie, John Kenneth Merson, Laura Hsu, Li Yang Christian, Michael D. and Egi, Moritoki Shindo, Nahoko Horby, Peter Pardinaz-Solis, Raul Ubiergo, Sebastian Ugarte Webb, Steve A. R. Uyeki, Timothy M. Gordon, Anthony C. Paterson, David L. Everett, Dean Giamarellos-Bourboulis, Evangelos J. Longuere, Kajsa-Stina and Maslove, David Ohuma, Eric Growl, Gloria PedutemHumber, Theresa EllazarHumber, Edward Bahinskaya, Ilona and Osbourne-Townsend, Joan Bentley, Andrew Goodson, Jennifer and Welters, Ingeborg Malik, Nadia Browne, T. S. Mahesh, Vinaya and SPRINT-SARI Investigators

Abstract

Severe acute respiratory infections (SARI) remain one of the leading causes of mortality around the world in all age groups. There is large global variation in epidemiology, clinical management and outcomes, including mortality. We performed a short period observational data collection in critical care units distributed globally during regional peak SARI seasons from 1 January 2016 until 31 August 2017, using standardised data collection tools. Data were collected for 1 week on all admitted patients who met the inclusion criteria for SARI, with follow-up to hospital discharge. Proportions of patients across regions were compared for microbiology, management strategies and outcomes. Regions were divided geographically and economically according to World Bank definitions. Data were collected for 682 patients from 95 hospitals and 23 countries. The overall mortality was 9.5%. Of the patients, 21.7% were children, with case fatality proportions of 1% for those less than 5 years. The highest mortality was in those above 60 years, at 18.6%. Case fatality varied by region: East Asia and Pacific 10.2% (21 of 206), Sub-Saharan Africa 4.3% (8 of 188), South Asia 0% (0 of 35), North America 13.6% (25 of 184), and Europe and Central Asia 14.3% (9 of 63). Mortality in low-income and low-middle-income countries combined was 4% as compared with 14% in high-income countries. Organ dysfunction scores calculated on presentation in 560 patients where full data were available revealed Sequential Organ Failure Assessment (SOFA) scores on presentation were significantly associated with mortality and hospital length of stay. Patients in East Asia and Pacific (48%) and North America (24%) had the highest SOFA scores of >12. Multivariable analysis demonstrated that initial SOFA score and age were independent predictors of hospital survival. There was variability across regions and income groupings for the critical care management and outcomes of SARI. Intensive care unit-specific factors, geography and management features were less reliable than baseline severity for predicting ultimate outcome. These findings may help in planning future outbreak severity assessments, but more globally representative data are required.

Published
2019

4. Experimental treatment of Ebola virus disease with brincidofovir

Author

Dunning, Jake, Kennedy, Stephen B., Antierens, Annick, Whitehead, John, Ciglenecki, Iza, Carson, Gail, Kanapathipillai, Rupa, Castle, Lyndsey, Howell-Jones, Rebecca, Pardinaz-Solis, Raul, Grove, Jennifer, Scott, Janet, Lang, Trudie, Olliaro, Piero, and Horby, Peter W.

Subjects
Diarrhea, RNA viruses, Adult, Male, Viral Diseases, dsDNA viruses, Organophosphonates, Gastroenterology and Hepatology, Drug research and development, Pathology and Laboratory Medicine, Ebola Hemorrhagic Fever, Microbiology, Antiviral Agents, Cytosine, Young Adult, Signs and Symptoms, Clinical trials, Adverse Reactions, Drug Therapy, Diagnostic Medicine, Medicine and Health Sciences, Humans, Microbial Pathogens, Pharmacology, Viral Hemorrhagic Fevers, Biology and life sciences, Hemorrhagic Fever Viruses, Pharmaceutics, Organisms, Hemorrhagic Fever, Ebola, Middle Aged, Tropical Diseases, Ebolavirus, Liberia, Research and analysis methods, Infectious Diseases, Treatment Outcome, Medical Microbiology, Filoviruses, Viral Pathogens, Clinical medicine, Viruses, Female, Pathogens, Ebola Virus, DNA viruses, Phase II clinical investigation, Research Article, Neglected Tropical Diseases
Abstract

Background The nucleotide analogue brincidofovir was developed to prevent and treat infections caused by double-stranded DNA viruses. Based on in vitro data suggesting an antiviral effect against Ebola virus, brincidofovir was included in the World Health Organisation list of agents that should be prioritised for clinical evaluation in patients with Ebola virus disease (EVD) during the West African epidemic. Methods and Findings In this single-arm phase 2 trial conducted in Liberia, patients with laboratory-confirmed EVD (two months of age or older, enrolment bodyweight ≥50 kg) received oral brincidofovir 200 mg as a loading dose on day 0, followed by 100 mg brincidofovir on days 3, 7, 10, and 14. Bodyweight-adjusted dosing was used for patients weighing

Published
2016

5. Experimental Treatment of Ebola Virus Disease with Brincidofovir

Author

Glod, John W, Dunning, Jake, Kennedy, Stephen B., Antierens, Annick, Whitehead, John, Ciglenecki, Iza, Carson, Gail, Kanapathipillai, Rupa, Castle, Lyndsey, Howell-Jones, Rebecca, Pardinaz-Solis, Raul, Grove, Jennifer, Scott, Janet, Lang, Trudie, Olliaro, Piero, and Horby, Peter W.

Subjects
Adult, Male, RAPIDE-BCV trial team, General Science & Technology, Science, Organophosphonates, Hemorrhagic Fever, Ebola, Middle Aged, Ebolavirus, Liberia, Antiviral Agents, Cytosine, Young Adult, Treatment Outcome, MD Multidisciplinary, Humans, Medicine, Female
Abstract

Background: \ud The nucleotide analogue brincidofovir was developed to prevent and treat infections caused by double-stranded DNA viruses. Based on in vitro data suggesting an antiviral effect against Ebola virus, brincidofovir was included in the World Health Organisation list of agents that should be prioritised for clinical evaluation in patients with Ebola virus disease (EVD) during the West African epidemic.\ud \ud Methods and Findings: \ud In this single-arm phase 2 trial conducted in Liberia, patients with laboratory-confirmed EVD (two months of age or older, enrolment bodyweight ≥50 kg) received oral brincidofovir 200 mg as a loading dose on day 0, followed by 100 mg brincidofovir on days 3, 7, 10, and 14. Bodyweight-adjusted dosing was used for patients weighing

Published
2016

6. Experimental Treatment of Ebola Virus Disease with TKM-130803: A Single-Arm Phase 2 Clinical Trial

Author

Dunning, Jake, Sahr, Foday, Rojek, Amanda, Gannon, Fiona, Carson, Gail, Idriss, Baimba, Massaquoi, Thomas, Gandi, Regina, Joseph, Sebatu, Osman, Hassan K, Brooks, Timothy JG, Simpson, Andrew JH, Goodfellow, Ian, Thorne, Lucy, Arias, Armando, Merson, Laura, Castle, Lyndsey, Howell-Jones, Rebecca, Pardinaz-Solis, Raul, Hope-Gill, Benjamin, Ferri, Mauricio, Grove, Jennifer, Kowalski, Mark, Stepniewska, Kasia, Lang, Trudie, Whitehead, John, Olliaro, Piero, Samai, Mohammed, Horby, Peter W, RAPIDE-TKM Trial Team, Von Seidlein, L, Goodfellow, Ian [0000-0002-9483-510X], Apollo - University of Cambridge Repository, and von Seidlein, Lorenz

Subjects
Male, RNA viruses, Viral Diseases, Time Factors, Artificial Gene Amplification and Extension, Drug research and development, Pathology and Laboratory Medicine, Biochemistry, Polymerase Chain Reaction, Clinical trials, Medicine and Health Sciences, Small interfering RNAs, RNA, Small Interfering, Infusions, Intravenous, Aged, 80 and over, Pharmaceutics, 11 Medical And Health Sciences, Middle Aged, Viral Load, Ebolavirus, Nucleic acids, Treatment Outcome, Infectious Diseases, Medical Microbiology, Filoviruses, Viral Pathogens, Host-Pathogen Interactions, Viruses, Medicine, RNA, Viral, Female, Pathogens, Ebola Virus, Phase II clinical investigation, Research Article, Neglected Tropical Diseases, Adult, Drug Administration, Antiviral Agents, Microbiology, Ebola Hemorrhagic Fever, Sierra Leone, Young Adult, Extraction techniques, SDG 3 - Good Health and Well-being, Drug Therapy, General & Internal Medicine, Virology, Genetics, Humans, Non-coding RNA, Molecular Biology Techniques, Microbial Pathogens, Molecular Biology, Aged, Pharmacology, Viral Hemorrhagic Fevers, Hemorrhagic Fever Viruses, Organisms, Biology and Life Sciences, Reverse Transcriptase-Polymerase Chain Reaction, Hemorrhagic Fever, Ebola, Tropical Diseases, Survival Analysis, RNA extraction, Gene regulation, Research and analysis methods, RNAi Therapeutics, Clinical medicine, Nanoparticles, RNA, Gene expression, Viral Transmission and Infection
Abstract

Background TKM-130803, a small interfering RNA lipid nanoparticle product, has been developed for the treatment of Ebola virus disease (EVD), but its efficacy and safety in humans has not been evaluated. Methods and Findings In this single-arm phase 2 trial, adults with laboratory-confirmed EVD received 0.3 mg/kg of TKM-130803 by intravenous infusion once daily for up to 7 d. On days when trial enrolment capacity was reached, patients were enrolled into a concurrent observational cohort. The primary outcome was survival to day 14 after admission, excluding patients who died within 48 h of admission. After 14 adults with EVD had received TKM-130803, the pre-specified futility boundary was reached, indicating a probability of survival to day 14 of ≤0.55, and enrolment was stopped. Pre-treatment geometric mean Ebola virus load in the 14 TKM-130803 recipients was 2.24 × 109 RNA copies/ml plasma (95% CI 7.52 × 108, 6.66 × 109). Two of the TKM-130803 recipients died within 48 h of admission and were therefore excluded from the primary outcome analysis. Of the remaining 12 TKM-130803 recipients, nine died and three survived. The probability that a TKM-130803 recipient who survived for 48 h will subsequently survive to day 14 was estimated to be 0.27 (95% CI 0.06, 0.58). TKM-130803 infusions were well tolerated, with 56 doses administered and only one possible infusion-related reaction observed. Three patients were enrolled in the observational cohort, of whom two died. Conclusions Administration of TKM-130803 at a dose of 0.3 mg/kg/d by intravenous infusion to adult patients with severe EVD was not shown to improve survival when compared to historic controls. Trial registration Pan African Clinical Trials Registry PACTR201501000997429, In a single-arm trial, Peter Horby and colleagues probe the effectiveness of a small interfering RNA-based drug intended to treat Ebola virus disease., Editors' Summary Background Ebola virus disease (EVD) is a frequently fatal disease that first appeared in human populations in 1976 in central Africa and that recently caused thousands of deaths in West Africa. Ebola virus is transmitted to people from wild animals and spreads in human populations through contact with the bodily fluids (including blood, saliva, and urine) and organs of infected people and through contact with bedding and other materials contaminated with bodily fluids. The symptoms of EVD, which start 2–21 days after infection, include fever, headache, vomiting, diarrhea, and internal and external bleeding. Infected individuals are not infectious until they develop symptoms, but they remain infectious as long as their bodily fluids contain virus, which can be several weeks. Infectious virus can persist in the semen of male survivors and suspected male-to-female sexual transmission was reported to have occurred five months after resolution of EVD. In West Africa supportive care—given under strict isolation conditions to prevent the spread of the virus—may improve survival, but there is no proven, specific treatment for EVD. Why Was This Study Done? Several potential treatments for EVD have looked promising in animal studies, including TKM-130803, a drug that prevents the production of two essential viral proteins. In rhesus monkeys, the active component of TKM-130803 provided 100% protection against Makona Ebola virus, the virus variant responsible for the West African EVD outbreak. Here, the researchers evaluate the effectiveness of TKM-130803 in a single-arm phase 2 clinical trial. During the West African EVD outbreak, experts designed the RAPIDE (Rapid Assessment of Potential Interventions and Drugs for Ebola) clinical trial platform to speed up the development of treatments for EVD. Using this platform, prioritised drugs go straight into a single-arm phase 2 trial in which people with EVD are administered a selected drug to generate early evidence of the drug’s effectiveness or ineffectiveness. For the assessment of the TKM-130803, a modified RAPIDE approach identifies evidence of lack of effectiveness in the phase 2 trial, by assessing whether a “futility” boundary—a pre-specified survival probability threshold at 14 days after admission—is reached. What Did the Researchers Do and Find? Adults with laboratory-confirmed EVD volunteered to participate in the trial, which was undertaken in Sierra Leone. Trial participants were given TKM-130803 once daily by intravenous infusion for up to seven days, in addition to supportive care. The primary outcome was survival to 14 days after admission, excluding patients who died within 48 hours of admission. Using historical data on survival rates for 1,820 people with EVD, the researchers designed their trial so that if the survival probability of the trial participants was greater than 0.55 (that is, if the chance of a patient being alive after 14 days was greater than 55%), TKM-130803 would be regarded as promising and worthy of further evaluation; if the survival probability of the participants was less than or equal to 0.55, then the futility boundary would be reached and enrollment stopped. After 14 adults had received TKM-130803, the pre-specified futility boundary was reached, and enrollment was stopped. Two patients who received TKM-130803 died within 48 hours of admission and were excluded from the primary outcome analysis. Of the remaining patients who received TKM-130803, nine died and three survived. The researchers estimated that TKM-130803 recipients who survived for 48 hours after being admitted had a probability of surviving to 14 days of 0.27. What Do These Findings Mean? These findings show that TKM-130803 given once daily at the dose used in this trial did not improve survival in patients with EVD compared to historic controls. This result contrasts with the protective effect of TKM-130803 and related formulations in non-human primates “challenged” (infected) with Ebola virus. One reason for this difference may be that, whereas in the animal studies, experimental drugs were given soon after viral challenge, in the phase 2 trial, the drug was given when the patients had advanced disease. That is, the failure of TKM-130803 to achieve a survival probability exceeding 0.55 in this study may be because the experimental drug had an insufficient antiviral effect in the face of the high viral loads and existing organ damage in these patients. In patients with advanced disease, it could be that the target survival rate was set too high to detect a small or even moderate beneficial effect of TKM-130803. Thus, further work is needed to assess whether the lack of effectiveness seen in this trial is generalizable to other patient subgroups (for example, patients with less advanced disease and lower viral loads) in other treatment settings. Additional Information This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001997. The World Health Organization (WHO) provides information about EVD, information about potential EVD vaccines and therapies, and regular updates on the West African EVD epidemic; the WHO website also provides information about efforts to control Ebola in the field and personal stories from people who have survived EVD The UK National Health Service Choices website provides detailed information on EVD The US Centers for Disease Control and prevention also provides information about EVD The Ebola treatment center in Sierra Leone where this trial was undertaken is run by the international humanitarian organization GOAL Global, whose website provides detailed information about fighting EVD in Sierra Leone More information about this trial is available

Published
2015

7. Experimental Treatment of Ebola Virus Disease with TKM-130803: A Single-Arm Phase 2 Clinical Trial

Author

von Seidlein, Lorenz, Dunning, Jake, Sahr, Foday, Rojek, Amanda, Gannon, Fiona, Carson, Gail, Idriss, Baimba, Massaquoi, Thomas, Gandi, Regina, Joseph, Sebatu, Osman, Hassan K., Brooks, Timothy J. G., Simpson, Andrew J. H., Goodfellow, Ian, Thorne, Lucy, Arias Esteban, Armando, Merson, Laura, Castle, Lyndsey, Howell-Jones, Rebecca, Pardinaz-Solis, Raul, Hope-Gill, Benjamin, Ferri, Mauricio, Grove, Jennifer, Kowalski, Mark, Stepniewska, Kasia, Lang, Trudie, Whitehead, John, Olliaro, Piero, Samai, Mohammed, Horby, Peter W., von Seidlein, Lorenz, Dunning, Jake, Sahr, Foday, Rojek, Amanda, Gannon, Fiona, Carson, Gail, Idriss, Baimba, Massaquoi, Thomas, Gandi, Regina, Joseph, Sebatu, Osman, Hassan K., Brooks, Timothy J. G., Simpson, Andrew J. H., Goodfellow, Ian, Thorne, Lucy, Arias Esteban, Armando, Merson, Laura, Castle, Lyndsey, Howell-Jones, Rebecca, Pardinaz-Solis, Raul, Hope-Gill, Benjamin, Ferri, Mauricio, Grove, Jennifer, Kowalski, Mark, Stepniewska, Kasia, Lang, Trudie, Whitehead, John, Olliaro, Piero, Samai, Mohammed, and Horby, Peter W.

Abstract

BACKGROUND: TKM-130803, a small interfering RNA lipid nanoparticle product, has been developed for the treatment of Ebola virus disease (EVD), but its efficacy and safety in humans has not been evaluated. METHODS AND FINDINGS: In this single-arm phase 2 trial, adults with laboratory-confirmed EVD received 0.3 mg/kg of TKM-130803 by intravenous infusion once daily for up to 7 d. On days when trial enrolment capacity was reached, patients were enrolled into a concurrent observational cohort. The primary outcome was survival to day 14 after admission, excluding patients who died within 48 h of admission. After 14 adults with EVD had received TKM-130803, the pre-specified futility boundary was reached, indicating a probability of survival to day 14 of ≤0.55, and enrolment was stopped. Pre-treatment geometric mean Ebola virus load in the 14 TKM-130803 recipients was 2.24 × 109 RNA copies/ml plasma (95% CI 7.52 × 108, 6.66 × 109). Two of the TKM-130803 recipients died within 48 h of admission and were therefore excluded from the primary outcome analysis. Of the remaining 12 TKM-130803 recipients, nine died and three survived. The probability that a TKM-130803 recipient who survived for 48 h will subsequently survive to day 14 was estimated to be 0.27 (95% CI 0.06, 0.58). TKM-130803 infusions were well tolerated, with 56 doses administered and only one possible infusion-related reaction observed. Three patients were enrolled in the observational cohort, of whom two died. CONCLUSIONS: Administration of TKM-130803 at a dose of 0.3 mg/kg/d by intravenous infusion to adult patients with severe EVD was not shown to improve survival when compared to historic controls. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201501000997429.

Published
2016

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