TY - JOUR

T1 - Experimental treatment of Ebola virus disease with TKM-130803

T2 - a single-arm phase 2 clinical trial

AU - Dunning, Jake

AU - Sahr, Foday

AU - Rojek, Amanda

AU - Gannon, Fiona

AU - Carson, Gail

AU - Idriss, Baimba

AU - Massaquoi, Thomas

AU - Gandi, Regina

AU - Joseph, Sebatu

AU - Osman, Hassan K.

AU - Brooks, Timothy J. G.

AU - Simpson, Andrew J. H.

AU - Goodfellow, Ian G

AU - Thorne, Lucy

AU - Arias, Armando

AU - Merson, Laura

AU - Castle, Lyndsey

AU - Howell-Jones, Rebecca

AU - Pardinaz-Solis, Raul

AU - Hope-Gill, Benjamin

AU - Ferri, Mauricio

AU - Grove, Jennifer

AU - Kowalski, Mark

AU - Stepniewska, Kasia

AU - Lang, Trudie

AU - Whitehead, John Raymond

AU - Olliaro, Piero

AU - Samai, Mohammed

AU - Horby, Peter W.

AU - RAPIDE-TKM trial team

PY - 2016/4/19

Y1 - 2016/4/19

N2 - 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 © 2016 Dunning et al.

AB - 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 © 2016 Dunning et al.

U2 - 10.1371/journal.pmed.1001997

DO - 10.1371/journal.pmed.1001997

M3 - Journal article

VL - 13

JO - PLoS Medicine

JF - PLoS Medicine

SN - 1549-1277

IS - 4

M1 - e1001997

ER -