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


RESULTS
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.


BACKGROUND
Pan African Clinical Trials Registry PACTR201501000997429.
Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.
Jake
J
Dunning
Military 34 Hospital, Republic of Sierra Leone Armed Forces, Freetown, Sierra Leone.|College of Medicine and Allied Health Sciences, Freetown, Sierra Leone.
Foday
F
Sahr
Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.
Amanda
A
Rojek
GOAL Global, Dun Laoghaire, Ireland.
Fiona
F
Gannon
Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.|International Severe Acute Respiratory and Emerging Infection Consortium Coordinating Centre, University of Oxford, Oxford, United Kingdom.
Gail
G
Carson
Military 34 Hospital, Republic of Sierra Leone Armed Forces, Freetown, Sierra Leone.
Baimba
B
Idriss
Military 34 Hospital, Republic of Sierra Leone Armed Forces, Freetown, Sierra Leone.
Thomas
T
Massaquoi
Military 34 Hospital, Republic of Sierra Leone Armed Forces, Freetown, Sierra Leone.
Regina
R
Gandi
Military 34 Hospital, Republic of Sierra Leone Armed Forces, Freetown, Sierra Leone.
Sebatu
S
Joseph
Military 34 Hospital, Republic of Sierra Leone Armed Forces, Freetown, Sierra Leone.
Hassan K
HK
Osman
Rare and Imported Pathogens Laboratory, Public Health England, Porton Down, United Kingdom.
Timothy J G
TJ
Brooks
Rare and Imported Pathogens Laboratory, Public Health England, Porton Down, United Kingdom.
Andrew J H
AJ
Simpson
Division of Virology, Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
Ian
I
Goodfellow
Division of Virology, Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
Lucy
L
Thorne
Division of Virology, Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
Armando
A
Arias
Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.
Laura
L
Merson
Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.
Lyndsey
L
Castle
Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.
Rebecca
R
Howell-Jones
Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.
Raul
R
Pardinaz-Solis
Cardiff and Vale University Health Board, Cardiff, Wales, United Kingdom.
Benjamin
B
Hope-Gill
Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.
Mauricio
M
Ferri
Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.
Jennifer
J
Grove
Tekmira Pharmaceuticals, Burnaby, British Columbia, Canada.
Mark
M
Kowalski
Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.
Kasia
K
Stepniewska
Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.
Trudie
T
Lang
Department of Mathematics and Statistics, Lancaster University, Lancaster, United Kingdom.
John
J
Whitehead
Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.|UNICEF-UNDP-World Bank-WHO Special Programme for Research and Training in Tropical Diseases, Geneva, Switzerland.
Piero
P
Olliaro
College of Medicine and Allied Health Sciences, Freetown, Sierra Leone.
Mohammed
M
Samai
Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.
Peter W
PW
Horby
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult; D000998:Antiviral Agents / Q000627:therapeutic use; D029043:Ebolavirus / Q000235:genetics / Q000472:pathogenicity; D019142:Hemorrhagic Fever, Ebola / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000821:virology; D054884:Host-Pathogen Interactions; D007262:Infusions, Intravenous; D053758:Nanoparticles; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000627:therapeutic use; D012367:RNA, Viral / Q000097:blood / Q000235:genetics; D000067492:RNAi Therapeutics / Q000009:adverse effects / Q000379:methods; D012807:Sierra Leone; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load / Q000187:drug effects / Q000235:genetics
D000998:Antiviral Agents; D034741:RNA, Small Interfering; D012367:RNA, Viral; C000609910:TKM-130803