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

1. World Health Organization. Ethical considerations for use of unregistered interventions for Ebola viral disease. WHO/HIS/KER/GHE/14.1. Geneva: World Health Organization; 2014.

2. Schieffelin JS, Shaffer JG, Goba A, Gbakie M, Gire SK, Colubri A, et al. Clinical illness and outcomes in patients with Ebola in Sierra Leone. N Engl J Med. 2014;371:2092–2100. doi: 10.1056/NEJMoa1411680 25353969

3. Towner JS, Rollin PE, Bausch DG, Sanchez A, Crary SM, Vincent M, et al. Rapid diagnosis of Ebola hemorrhagic fever by reverse transcription-PCR in an outbreak setting and assessment of patient viral load as a predictor of outcome. J Virol. 2004;78:4330–4341. 15047846

4. Fitzpatrick G, Vogt F, Gbabai OB, Decroo T, Keane M, De Clerck H, et al. The contribution of Ebola viral load at admission and other patient characteristics to mortality in a Medecins Sans Frontieres (MSF) Ebola Case Management Centre (CMC), Kailahun, Sierra Leone, June–October, 2014. J Infect Dis. 2015;12:1752–1758. doi: 10.1093/infdis/jiv304

5. Wolf T, Kann G, Becker S, Stephan C, Brodt HR, de Leuw P, et al. Severe Ebola virus disease with vascular leakage and multiorgan failure: treatment of a patient in intensive care. Lancet. 2015;385:1428–1435. doi: 10.1016/S0140-6736(14)62384-9 25534190

6. Takada A, Kawaoka Y. The pathogenesis of Ebola hemorrhagic fever. Trends Microbiol. 2001;9:506–511. 11597453

7. Mahanty S, Bray M. Pathogenesis of filoviral haemorrhagic fevers. Lancet Infect Dis. 2004;4:487–498. doi: 10.1016/S1473-3099(04)01103-X 15288821

8. World Health Organization. Potential Ebola therapies and vaccines. WHO/EVD/HIS/EMP/14.1. Geneva: World Health Organization; 2014.

9. Geisbert TW, Lee AC, Robbins M, Geisbert JB, Honko AN, Sood V, et al. Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study. Lancet. 2010;375:1896–1905. doi: 10.1016/s0140-6736(10)60357-1 20511019

10. Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124:188–195. doi: 10.1182/blood-2014-05-552729 24876563

11. Liddell AM, Davey RT Jr, Mehta AK, Varkey JB, Kraft CS, Tseggay GK, et al. Characteristics and clinical management of a cluster of 3 patients with Ebola virus disease, including the first domestically acquired cases in the United States. Ann Intern Med. 2015;163:81–90. doi: 10.7326/M15-0530 25961438

12. Kraft CS, Hewlett AL, Koepsell S, Winkler AM, Kratochvil CJ, Larson L, et al. The use of TKM-100802 and convalescent plasma in 2 patients with Ebola virus disease in the United States. Clin Infect Dis. 2015;61:496–502. doi: 10.1093/cid/civ334 25904375

13. Thi EP, Mire CE, Lee AC, Geisbert JB, Zhou JZ, Agans KN, et al. Lipid nanoparticle siRNA treatment of Ebola-virus-Makona-infected nonhuman primates. Nature. 2015;521:362–365. doi: 10.1038/nature14442 25901685

14. Cooper BS, Boni MF, Pan-Ngum W, Day NP, Horby PW, Olliaro P, et al. Evaluating clinical trial designs for investigational treatments of Ebola virus disease. PLoS Med. 2015;12:e1001815. doi: 10.1371/journal.pmed.1001815 25874579

15. Adebamowo C, Bah-Sow O, Binka F, Bruzzone R, Caplan A, Delfraissy JF, et al. Randomised controlled trials for Ebola: practical and ethical issues. Lancet. 2014;384:1423–1424. doi: 10.1016/S0140-6736(14)61734-7 25390318

16. Whitehead J, Matsushita T. Stopping clinical trials because of treatment ineffectiveness: a comparison of a futility design with a method of stochastic curtailment. Stat Med. 2003;22:677–687. doi: 10.1002/sim.1429 12587099

17. Jovic G, Whitehead J. An exact method for analysis following a two-stage phase II cancer clinical trial. Stat Med. 2010;29:3118–3125. doi: 10.1002/sim.3837 21170906

18. Trombley AR, Wachter L, Garrison J, Buckley-Beason VA, Jahrling J, Hensley LE, et al. Comprehensive panel of real-time TaqMan polymerase chain reaction assays for detection and absolute quantification of filoviruses, arenaviruses, and New World hantaviruses. Am J Trop Med Hyg. 2010;82:954–960. doi: 10.4269/ajtmh.2010.09–0636 20439981

19. Nakayama E, Saijo M. Animal models for Ebola and Marburg virus infections. Front Microbiol. 2013;4:267. doi: 10.3389/fmicb.2013.00267 24046765

20. Martins K, Cooper C, Warren T, Wells J, Bell T, Raymond J, et al. Characterization of clinical and immunological parameters during Ebola virus infection of rhesus macaques. Viral Immunol. 2015;28:32–41. doi: 10.1089/vim.2014.0085 25514385

21. Arbutus Biopharma. Tekmira announces new preclinical data from anti-viral programs. 2013 Nov 12 [cited 16 Oct 2015]. Burnaby (Canada); Arbutus Biopharma. Available: http://investor.arbutusbio.com/releasedetail.cfm?ReleaseID=806769.

22. Qin E, Bi J, Zhao M, Wang Y, Guo T, Yan T, et al. Clinical features of patients with Ebola Virus disease in Sierra Leone. Clin Infect Dis. 2015;61:491–495. doi: 10.1093/cid/civ319 25995207

23. Qureshi AI, Chughtai M, Bah EI, Barry M, Beavogui K, Loua TO, et al. High survival rates and associated factors among Ebola virus disease patients hospitalized at Donka National Hospital, Conakry, Guinea. J Vasc Interv Neurol. 2015;8:S4–S11. 25992182

24. Bah EI, Lamah MC, Fletcher T, Jacob ST, Brett-Major DM, Sall AA, et al. Clinical presentation of patients with Ebola virus disease in Conakry, Guinea. N Engl J Med. 2015;372:40–47. doi: 10.1056/NEJMoa1411249 25372658

25. WHO Ebola Response Team. Ebola virus disease in West Africa—the first 9 months of the epidemic and forward projections. N Engl J Med. 2014;371:1481–1495. doi: 10.1056/NEJMoa1411100 25244186

26. WHO Ebola Response Team, Agua-Agum J, Ariyarajah A, Blake IM, Cori A, Donnelly CA, et al. Ebola virus disease among children in West Africa. N Engl J Med. 2015;372:1274–1277. doi: 10.1056/NEJMc1415318

27. Barry M, Toure A, Traore FA, Sako FB, Sylla D, Kpamy DO, et al. Clinical predictors of mortality in patients with Ebola virus disease. Clin Infect Dis. 2015;60:1821–1824. doi: 10.1093/cid/civ202 25770172

28. Kortepeter MG, Bausch DG, Bray M. Basic clinical and laboratory features of filoviral hemorrhagic fever. J Infect Dis. 2011;204 (Suppl 3):S810–S816. doi: 10.1093/infdis/jir299 21987756

29. Julien B, Ludovic K, Marie CJ, Nicolas G, Magali B, Claire R, et al. Dyspnea and risk of death in Ebola infected patients. Is lung really involved? Clin Infect Dis. 2015; 61:852. doi: 10.1093/cid/civ441

30. Florescu DF, Kalil AC, Hewlett AL, Schuh AJ, Stroher U, Uyeki TM, et al. Administration of brincidofovir and convalescent plasma in a patient with Ebola virus disease. Clin Infect Dis. 2015;61:969–973. doi: 10.1093/cid/civ395 25991468

31. Chertow DS, Kleine C, Edwards JK, Scaini R, Giuliani R, Sprecher A. Ebola virus disease in West Africa—clinical manifestations and management. N Engl J Med. 2014;371:2054–2057. doi: 10.1056/NEJMp1413084 25372854