Journal Article

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

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

2016

Overview

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. 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. 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. Pan African Clinical Trials Registry PACTR201501000997429.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adult / Aged / Aged, 80 and over / Antiviral agents / Antiviral Agents - therapeutic use / Biology and Life Sciences / Body fluids / Clinical trials / Drug dosages / Drug therapy / Ebola hemorrhagic fever / Ebola virus / Ebolavirus - genetics / Ebolavirus - pathogenicity / Enrollments / Female / Health aspects / Hemorrhagic Fever, Ebola - diagnosis / Hemorrhagic Fever, Ebola - drug therapy / Hemorrhagic Fever, Ebola - genetics / Hemorrhagic Fever, Ebola - mortality / Hemorrhagic Fever, Ebola - virology / Host-Pathogen Interactions / Humans / Infusions, Intravenous / Laboratories / Male / Medicine and Health Sciences / Middle Aged / Nanoparticles / Patients / Research and analysis methods / Researchers / RNA, Small Interfering - administration & dosage / RNA, Small Interfering - therapeutic use / RNA, Viral - blood / RNA, Viral - genetics / RNAi Therapeutics - adverse effects / RNAi Therapeutics - methods / Sierra Leone / Studies / Survival Analysis / Time Factors / Treatment Outcome / Viral Load - drug effects / Viral Load - genetics / Young Adult