Search

Your search keyword '"Pardinaz-Solis, R"' showing total 9 results
Start Over Author "Pardinaz-Solis, R"
9 results on '"Pardinaz-Solis, R"'

2. Understanding the neuroprotective effect of tranexamic acid: an exploratory analysis of the CRASH-3 randomised trial

Author

Brenner, A., Belli, A., Chaudhri, R., Coats, T., Frimley, L., Jamaluddin, S. F., Jooma, R., Mansukhani, R., Sandercock, P., Shakur-Still, H., Shokunbi, T., Roberts, I., Aeron-Thomas, A., Chaudary, M. A., Jamaluddin, S. F. B., Javaid, K., Kayani, A., Leech, C., Mahmood, K., Noor, J. M., Mejia-Mantilla, J., Moss, P., Pott, J., Vallecilla, L., Hartzenberg, H. B., Joshipura, M., Perel, P., Clarke, M. J., Ohaegbulam, S. C., Rodgers, A., Brady, T., Dewan, Y., Edwards, P., Komolafe, E. O., Arribas, M., Austin, E., Balogun, E., Barneston, L., Barrow, C., Beaumont, D., Benyahia, M., Brooks, I., Cargill, M., Carrington, L., Cook, L., Cornu-Hewitt, B., Geer, A., Gilbert, D., Gilliam, C., Gil-Onandia, J., Hetherington, D., Howe, C., Hughes, C., I'Anson, D., Jackson, R., Joshi, M., Kansagra, S., Kawahara, T., Ker, K., Kostrov, S., Mahmood, A., Miah, H., Ndungu, B., Needham, K., Okusi, C., Outtandy, A., Pardinaz-Solis, R., Pearson, D., Pepple, T., Pisani, C., Prieto-Merino, D., Prowse, D., Quashi, N., Quinn, A., Ramos, M., Reid, M., Roukas, C., Scrapa, G., Squires, C., Tanner, J., Thayne, A., Vidaurre, L., Woods, E., Fawole, B., Adetayo, O., Okunade, O., Gogichaishvili, T., de los Angeles Munoz-Sanchez, M., Olldashi, F., Krishnan, S., Djientcheu, V., Castellanos, J. L., Rasulo, F., Hama, Q., Mulla, Y., Florian, I. S., Tobar, J., Khamis, H., Deasy, C., Wellsh, B., Williams-Johnson, J., Chandra, S., Mutiso, V., Butt, R., Nasir, M. H., Ahmad, S., Aslam, F., Ishaque, K., Usmani, F., Rizvi, S., Ali, F., Sajjad, O., Zunair, A., Rehman, L., Rizvi, R., Javeed, F., Ahmed, S., Abbas, A., Afzal, A., Mikdad, A., Bashir, A., Chaudary, A., Salahuddin, T., Ahemed, B., Aziz, A., Ashraf, N., Hussain, S., Ahmad, U., Asif, M., Adil, M., Rauf, A., Khan, R., Ahmad, B., Afzal, U., Raza, H., Ain, Q., Yaqoob, S., Waseem, Q., Nishat, M., Semvel, S., Iqbal, J., Majeed, S., Zulfiqar, S., Iqbal, M., Majeed, N., Ahmed, M., Akhtar, N., Malik, M., Shehzad, Y., Yousaf, M., Wahid, A., Samad, A., Shah, S., Ali, M., Zeb, J., Khan, A. S., Irfan, A., Sharif, S., Memon, R., Bloom, B., Harris, T., Skene, I., Bellhouse, G., Boulton, O., Ward, G., Jarvis, C., Swann, C., Ratnam, S., Carrera, R., Yakoub, K., Davies, D., Fellows, E., Jarman, H., Rounding, S., Johnson, E., Loughran, C., Lecky, F., Clayton, K., Michael, A., Coumbarides, A., Kendall, J., Faulkner, B., Worner, R., Gendall, E., Hopkins, P., Riozzi, P., Cotton, H., Astin-Chamberlain, R., Wilson, M., Bodnar, J., Williams, R., Rigoni, A., Sattout, A., Fletcher, J., Edge, C., Maryanji, N., Boyle, A., Hardwick, S., Nichols, E., Hayhurst, C., Coffey, F., Gough, C., Miller, P., Ryan, L., Darwent, M., Espinosa, A., Beer, S., Norton, J., Maguire, H., Finney, K., Kehoe, A., Squire, R., Jeffery, A., Vorwerk, C., Foord, D., Wilkinson, E., Kuhrt, A., Ramlakhan, S., Reid, S., Curran, A., Mcmullan, S., Hassan, T., Nuttall, S., Haig, S., Al-Nahhas, S., Bulters, D., Zolnourian, A., Ribbons, T., Mew, I., de Weymarn, T., Hughes, V., Mcvicar, J., Mckiernan, C., Keating, L., Reschreiter, H., Wright, J., Chan, L., Kataria, H., Ireland, A., Body, R., Corfield, A., Francis, S., Townend, W., Gagg, J., Wilson, S., Cottingham, R., Tucker, S., Sutherland, F., Mitchell, L., Parker, L., Afolabi, O., Hunter, F., Jadav, M., Adeboye, K., Grocutt, M., May, G., Watson, D., Wootten, A., Robertshaw, S., Dorrian, S., Perry, R., Choi, H., Mcgroarty, C., Shone, P., Maritz, D., Jamaluddin, S., Noor, J., Rosli, N., Xian, L. L. S., De Jun, Y., Mohamed, F., Song, C. H., Hawari, A., Chin, L. Y., Hussein, H. M., Lotfi, M., Hamid, H., Udin, N., Lian, P., Choo, S., Wong, K., Gani, F., Jusoh, M., Rajakumar, D., Yang, C. B., Dzulkiflee, N. S. B., W. C., Ky, Azman, M. A. B. M., Osman, A. B., Ahmad, A. H., Ismail, R., Lai, S. Q., Mohidin, M. A. B., Deraman, N. B., Selamat, S. B., Abidin, I., Halim, N., Bakar, Z., Ismail, Z. M., Hisham, B., Kamal, R., Effendy, Z., Ismail, M., Azleen, N., Seng, L. Y., Baharuddin, K. A., Kandasamy, R., Kamalludin, A., Asmee, S., Fadzil, M., Basitz, A., Abdullah, N., Ingorokva, G., Ingorokva, S., Agdgomelashvili, I., Mumladze, K., Maisuradze, I., Kugusheva, I., Shalamberidze, B., Tomadze, G., Fernandez-Ortega, J., Seara-Valero, R., Ibanez-Botella, G., Garcia-Martinez, V., Martul, M. G., Ramos, S. F., Preciado, G. L., Garcia-Alfaro, C., Munoz-Sanchez, A., Bellido-Alba, R., Corcobado, C., Bueno, A., Ambros, A., Jimenez, J. T., Ramirez, J. R., Martin, J., Rodriguez, L. I., Fontanals, J., Jimenez-Moragas, J. M., Berbegal, J. P., Oluwole, O., Mahmud, R., Ukwu, N., Bankole, F., Oseni, A., Adebayo, B., Malomo, A., Tiamiyu, L., Adekanmbi, A., Thanni, L., Olubodun, A., Ojeblenu, F., Uwaezuoke, M., Komolafe, E., Owagbemi, O., Ishola, F., Durodola, A., Udoffa, U., James, A., Tella, A., Dongo, A., Ekpemiro, U., Anyanwu, S., Aigoro, N., Mezue, W., Shilong, D., Azeez, A., Babalola, O., Ibrahim, M., Obande, J., Franco, A. C., Salazar, E. V., Londono, S. B., Cardona, V. M., Morales, C., Naranjo, S., Agudelo, J., Carvajal, S., Fajardo-Gaviria, Y., Roka, Y., Ghising, U., Roka, N., Shrestha, M., Devkota, U., Vaidya, B., Nepal, P., Thapa, A., Kc, B., Shrestha, A., Jha, R., Shrestha, P., Hodaj, I., Spaho, E., Selaj, A., Bendo, N., Shoko, T., Endo, H., Senda, A., Hagihara, Y., Fuse, T., Masunaga, N., Otomo, Y., Egashira, R., Ohnuki, T., Almazmi, A., Saha, S., Suvarov, A., Aung, T. L., Tun, K. M., Khaing, T. T., Maw, T., Ndome, O., Moumi, M., Mbida, A., Fondop, J., Sebastien, M., Azim, A., Adil, J., Amiry, Z., Loria-Castellanos, J., Rubio, N. G., Leon, P. O., Estrada, F., de Oca-Garcia, E. M., Sanchez, H., Soria, A., Bonucci, P., Franchi, F., Girardini, A., Hameed, H., Basim, M., Stock, S., Hourt, E., Ilunga, A., Mulenga, J., Ples, H., Danil, A., Gorgan, M., Florian, I., Vlahovic, D., French, J., East, J., Kurniawan, A., and Kiboi, J.

Subjects
medicine.medical_specialty, Tranexamic acid, Traumatic brain injury, Epidemiology, Critical Care and Intensive Care Medicine, Placebo, CRASH-3 trial, Neuroprotection, Intracranial haemorrhage, law.invention, Emergence care, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, Medicine, Humans, 030212 general & internal medicine, Randomised controlled trial, business.industry, Multiple Trauma, Research, lcsh:Medical emergencies. Critical care. Intensive care. First aid, 030208 emergency & critical care medicine, lcsh:RC86-88.9, Protective Factors, medicine.disease, Polytrauma, Antifibrinolytic Agents, 3. Good health, Neuroprotective Agents, Relative risk, Brain Injuries, business, medicine.drug
Abstract

Background The CRASH-3 trial hypothesised that timely tranexamic acid (TXA) treatment might reduce deaths from intracranial bleeding after traumatic brain injury (TBI). To explore the mechanism of action of TXA in TBI, we examined the timing of its effect on death. Methods The CRASH-3 trial randomised 9202 patients within 3 h of injury with a GCS score ≤ 12 or intracranial bleeding on CT scan and no significant extracranial bleeding to receive TXA or placebo. We conducted an exploratory analysis of the effects of TXA on all-cause mortality within 24 h of injury and within 28 days, excluding patients with a GCS score of 3 or bilateral unreactive pupils, stratified by severity and country income. We pool data from the CRASH-2 and CRASH-3 trials in a one-step fixed effects individual patient data meta-analysis. Results There were 7637 patients for analysis after excluding patients with a GCS score of 3 or bilateral unreactive pupils. Of 1112 deaths, 23.3% were within 24 h of injury (early deaths). The risk of early death was reduced with TXA (112 (2.9%) TXA group vs 147 (3.9%) placebo group; risk ratio [RR] RR 0.74, 95% CI 0.58–0.94). There was no evidence of heterogeneity by severity (p = 0.64) or country income (p = 0.68). The risk of death beyond 24 h of injury was similar in the TXA and placebo groups (432 (11.5%) TXA group vs 421 (11.7%) placebo group; RR 0.98, 95% CI 0.69–1.12). The risk of death at 28 days was 14.0% in the TXA group versus 15.1% in the placebo group (544 vs 568 events; RR 0.93, 95% CI 0.83–1.03). When the CRASH-2 and CRASH-3 trial data were pooled, TXA reduced early death (RR 0.78, 95% CI 0.70–0.87) and death within 28 days (RR 0.88, 95% CI 0.82–0.94). Conclusions Tranexamic acid reduces early deaths in non-moribund TBI patients regardless of TBI severity or country income. The effect of tranexamic acid in patients with isolated TBI is similar to that in polytrauma. Treatment is safe and even severely injured patients appear to benefit when treated soon after injury. Trial registration ISRCTN15088122, registered on 19 July 2011; NCT01402882, registered on 26 July 2011.

Published
2020
Full Text
View/download PDF

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

Author

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

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

Glod, JW, Dunning, J, Kennedy, SB, Antierens, A, Whitehead, J, Ciglenecki, I, Carson, G, Kanapathipillai, R, Castle, L, Howell-Jones, R, Pardinaz-Solis, R, Grove, J, Scott, J, Lang, T, Olliaro, P, Horby, PW, RAPIDE-BCV trial team, Glod, JW, Dunning, J, Kennedy, SB, Antierens, A, Whitehead, J, Ciglenecki, I, Carson, G, Kanapathipillai, R, Castle, L, Howell-Jones, R, Pardinaz-Solis, R, Grove, J, Scott, J, Lang, T, Olliaro, P, Horby, PW, and RAPIDE-BCV trial team

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 <50 kg at enrolment. The primary outcome was survival at Day 14 after the first dose of brincidofovir. Four patients were enrolled between 01 January 2015 and 31 January 2015. The trial was stopped following the decision by the manufacturer to terminate their program of development of brincidofovir for EVD. No Serious Adverse Reactions or Suspected Unexpected Serious Adverse Reactions were identified. All enrolled subjects died of an illness consistent with EVD. CONCLUSIONS: Due to the small sample size it was not possible to determine the efficacy of brincidofovir for the treatment of EVD. The premature termination of the trial highlights the need to establish better practices for preclinical in-vitro and animal screening of therapeutics for potentially emerging epidemic infectious diseases prior to their use in patients. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201411000939962.

Published
2016

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

Author

von Seidlein, L, Dunning, J, Sahr, F, Rojek, A, Gannon, F, Carson, G, Idriss, B, Massaquoi, T, Gandi, R, Joseph, S, Osman, HK, Brooks, TJG, Simpson, AJH, Goodfellow, I, Thorne, L, Arias, A, Merson, L, Castle, L, Howell-Jones, R, Pardinaz-Solis, R, Hope-Gill, B, Ferri, M, Grove, J, Kowalski, M, Stepniewska, K, Lang, T, Whitehead, J, Olliaro, P, Samai, M, Horby, PW, von Seidlein, L, Dunning, J, Sahr, F, Rojek, A, Gannon, F, Carson, G, Idriss, B, Massaquoi, T, Gandi, R, Joseph, S, Osman, HK, Brooks, TJG, Simpson, AJH, Goodfellow, I, Thorne, L, Arias, A, Merson, L, Castle, L, Howell-Jones, R, Pardinaz-Solis, R, Hope-Gill, B, Ferri, M, Grove, J, Kowalski, M, Stepniewska, K, Lang, T, Whitehead, J, Olliaro, P, Samai, M, and Horby, PW

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

7. Short period incidence sTudy of severe acute respiratory infection (SPRINT-SARI) initial data from a global observational study to better describe SARI epidemiology in critically ill patients

Author

Carson, G.L., primary, Castle, L., additional, George, M., additional, Horby, P., additional, Longuere, K.-S., additional, Merson, L., additional, Murthy, S., additional, O’neill, G., additional, Pardinaz-Solis, R., additional, and Webb, S., additional

Published
2016
Full Text
View/download PDF

8. Experimental Treatment of Ebola Virus Disease with Brincidofovir.

Author

Dunning J, Kennedy SB, Antierens A, Whitehead J, Ciglenecki I, Carson G, Kanapathipillai R, Castle L, Howell-Jones R, Pardinaz-Solis R, Grove J, Scott J, Lang T, Olliaro P, and Horby PW

Subjects
Adult, Antiviral Agents pharmacology, Cytosine pharmacology, Cytosine therapeutic use, Ebolavirus drug effects, Female, Hemorrhagic Fever, Ebola virology, Humans, Liberia, Male, Middle Aged, Organophosphonates pharmacology, Treatment Outcome, Young Adult, Antiviral Agents therapeutic use, Cytosine analogs & derivatives, Ebolavirus physiology, Hemorrhagic Fever, Ebola drug therapy, Organophosphonates therapeutic use
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 <50 kg at enrolment. The primary outcome was survival at Day 14 after the first dose of brincidofovir. Four patients were enrolled between 01 January 2015 and 31 January 2015. The trial was stopped following the decision by the manufacturer to terminate their program of development of brincidofovir for EVD. No Serious Adverse Reactions or Suspected Unexpected Serious Adverse Reactions were identified. All enrolled subjects died of an illness consistent with EVD., Conclusions: Due to the small sample size it was not possible to determine the efficacy of brincidofovir for the treatment of EVD. The premature termination of the trial highlights the need to establish better practices for preclinical in-vitro and animal screening of therapeutics for potentially emerging epidemic infectious diseases prior to their use in patients., Trial Registration: Pan African Clinical Trials Registry PACTR201411000939962., Competing Interests: The authors have no reported conflicts of interest. PO is a staff member of the World Health Organization (WHO); the authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions, policy or views of the WHO.

Published
2016
Full Text
View/download PDF

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

Author

Dunning J, Sahr F, Rojek A, Gannon F, Carson G, Idriss B, Massaquoi T, Gandi R, Joseph S, Osman HK, Brooks TJ, Simpson AJ, Goodfellow I, Thorne L, Arias A, Merson L, Castle L, Howell-Jones R, Pardinaz-Solis R, Hope-Gill B, Ferri M, Grove J, Kowalski M, Stepniewska K, Lang T, Whitehead J, Olliaro P, Samai M, and Horby PW

Subjects
Adult, Aged, Aged, 80 and over, Ebolavirus pathogenicity, Female, Hemorrhagic Fever, Ebola diagnosis, Hemorrhagic Fever, Ebola genetics, Hemorrhagic Fever, Ebola mortality, Hemorrhagic Fever, Ebola virology, Host-Pathogen Interactions, Humans, Infusions, Intravenous, Male, Middle Aged, Nanoparticles, RNA, Small Interfering administration & dosage, RNA, Viral blood, RNAi Therapeutics adverse effects, Sierra Leone, Survival Analysis, Time Factors, Treatment Outcome, Viral Load drug effects, Viral Load genetics, Young Adult, Antiviral Agents therapeutic use, Ebolavirus genetics, Hemorrhagic Fever, Ebola drug therapy, RNA, Small Interfering therapeutic use, RNA, Viral genetics, RNAi Therapeutics methods
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
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results