Dunning Jake, Sahr Foday, Rojek Amanda, Gannon Fiona, Carson Gail, Idriss Baimba, Massaquoi Thomas, Gandi Regina, Joseph Sebatu, Osman Hassan K, Brooks Timothy J G, Simpson Andrew J H, Goodfellow Ian, Thorne Lucy, Arias Armando, Merson Laura, Castle Lyndsey, Howell-Jones Rebecca, Pardinaz-Solis Raul, Hope-Gill Benjamin, Ferri Mauricio, Grove Jennifer, Kowalski Mark, Stepniewska Kasia, Lang Trudie, Whitehead John, Olliaro Piero, Samai Mohammed, Horby Peter W
Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.
Military 34 Hospital, Republic of Sierra Leone Armed Forces, Freetown, Sierra Leone.
PLoS Med. 2016 Apr 19;13(4):e1001997. doi: 10.1371/journal.pmed.1001997. eCollection 2016 Apr.
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.
TKM - 130803是一种小干扰RNA脂质纳米颗粒产品，已被开发用于治疗埃博拉病毒病（EVD），但其在人体中的疗效和安全性尚未得到评估。
在这项单臂2期试验中，实验室确诊为EVD的成年患者每天静脉输注0.3 mg/kg的TKM - 130803，持续7天。在达到试验入组能力的日子里，患者被纳入一个同期观察队列。主要结局是入院后第14天存活，排除入院后48小时内死亡的患者。14名EVD成年患者接受TKM - 130803治疗后，达到了预先设定的无效界限，表明存活至第14天的概率≤0.55，于是停止入组。14名接受TKM - 130803治疗的患者治疗前埃博拉病毒载量几何平均值为2.24×10⁹RNA拷贝/ml血浆（95%CI 7.52×10⁸，6.66×10⁹）。两名接受TKM - 130803治疗的患者在入院后48小时内死亡，因此被排除在主要结局分析之外。其余12名接受TKM - 130803治疗的患者中，9人死亡，3人存活。估计存活48小时的TKM - 130803治疗患者随后存活至第14天的概率为0.27（95%CI 0.06，0.58）。TKM - 130803输注耐受性良好，共输注56剂，仅观察到1例可能与输注相关的反应。3名患者被纳入观察队列，其中2人死亡。
与历史对照相比，对严重EVD成年患者静脉输注剂量为0.3 mg/kg/d的TKM - 130803未显示能提高生存率。
泛非临床试验注册中心PACTR201501000997429。
