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

Dunning J, Sahr F, Rojek A, Gannon F, Carson G, Idriss B, Massaquoi T, Gandi R, Joseph S, Osman HK, Brooks TJ, Simpson AJ, Goodfellow I, Thorne L, Arias A, Merson L, Castle L, Howell-Jones R, Pardinaz-Solis R, Hope-Gill B, Ferri M, Grove J, Kowalski M, Stepniewska K, Lang T, Whitehead J, Olliaro P, Samai M, Horby PW, RAPIDE-TKM trial te - PLoS Med. (2016)

Bottom Line: 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.TKM-130803 infusions were well tolerated, with 56 doses administered and only one possible infusion-related reaction observed.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.

View Article: PubMed Central - PubMed

Affiliation: Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.

ABSTRACT

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.

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Related in: MedlinePlus

Ebola virus RT-PCR cycle threshold values and RNA copies/ml over time.Top row: TKM-130803 recipients. Bottom row: Observational patients. RT-PCR Ct upper limit of quantitation (LOQ) = 40. RT-qPCR lower limit of quantitation = 1,000 genome copies. The Ebola virus RT-qPCR quantification is expressed as the number of genome copies/millilitre of plasma. Black diamonds denote results for survivors. Grey circles denote results for non-survivors.
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pmed.1001997.g003: Ebola virus RT-PCR cycle threshold values and RNA copies/ml over time.Top row: TKM-130803 recipients. Bottom row: Observational patients. RT-PCR Ct upper limit of quantitation (LOQ) = 40. RT-qPCR lower limit of quantitation = 1,000 genome copies. The Ebola virus RT-qPCR quantification is expressed as the number of genome copies/millilitre of plasma. Black diamonds denote results for survivors. Grey circles denote results for non-survivors.

Mentions: The 14 patients enrolled into the TKM-130803 cohort received between one and seven infusions of TKM-130803 (Table 2). Of these 14 patients, three survived to day 14 and were discharged from the ETC, and 11 died. Two patients died within 48 h of admission and were excluded from the primary outcome analysis (and the ongoing futility plot). Two patients died on 15 June 2015, at which point enrolment to the trial was stopped since the futility boundary had been reached, with only three of the twelve patients eligible for inclusion in the primary outcome analysis surviving to day 14 (Fig 2). All deaths were considered to be consistent with severe EVD. In participants who died, viral loads were high at admission and remained high over time (Fig 3); correspondingly, EBOV PCR Ct values were low at admission and remained low over time (Ct values are inversely proportional to viral load). Serial viral load and Ct data were available for two patients in the observational cohort; viral load steadily decreased in the survivor, whereas viral load increased in the patient who died. The final point estimate of the probability that a patient receiving TKM-130803 who survives for 48 h will subsequently survive to day 14 was 0.27 (95% CI 0.06, 0.58). Two of the three patients in the observational cohort died.


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

Dunning J, Sahr F, Rojek A, Gannon F, Carson G, Idriss B, Massaquoi T, Gandi R, Joseph S, Osman HK, Brooks TJ, Simpson AJ, Goodfellow I, Thorne L, Arias A, Merson L, Castle L, Howell-Jones R, Pardinaz-Solis R, Hope-Gill B, Ferri M, Grove J, Kowalski M, Stepniewska K, Lang T, Whitehead J, Olliaro P, Samai M, Horby PW, RAPIDE-TKM trial te - PLoS Med. (2016)

Ebola virus RT-PCR cycle threshold values and RNA copies/ml over time.Top row: TKM-130803 recipients. Bottom row: Observational patients. RT-PCR Ct upper limit of quantitation (LOQ) = 40. RT-qPCR lower limit of quantitation = 1,000 genome copies. The Ebola virus RT-qPCR quantification is expressed as the number of genome copies/millilitre of plasma. Black diamonds denote results for survivors. Grey circles denote results for non-survivors.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4836798&req=5

pmed.1001997.g003: Ebola virus RT-PCR cycle threshold values and RNA copies/ml over time.Top row: TKM-130803 recipients. Bottom row: Observational patients. RT-PCR Ct upper limit of quantitation (LOQ) = 40. RT-qPCR lower limit of quantitation = 1,000 genome copies. The Ebola virus RT-qPCR quantification is expressed as the number of genome copies/millilitre of plasma. Black diamonds denote results for survivors. Grey circles denote results for non-survivors.
Mentions: The 14 patients enrolled into the TKM-130803 cohort received between one and seven infusions of TKM-130803 (Table 2). Of these 14 patients, three survived to day 14 and were discharged from the ETC, and 11 died. Two patients died within 48 h of admission and were excluded from the primary outcome analysis (and the ongoing futility plot). Two patients died on 15 June 2015, at which point enrolment to the trial was stopped since the futility boundary had been reached, with only three of the twelve patients eligible for inclusion in the primary outcome analysis surviving to day 14 (Fig 2). All deaths were considered to be consistent with severe EVD. In participants who died, viral loads were high at admission and remained high over time (Fig 3); correspondingly, EBOV PCR Ct values were low at admission and remained low over time (Ct values are inversely proportional to viral load). Serial viral load and Ct data were available for two patients in the observational cohort; viral load steadily decreased in the survivor, whereas viral load increased in the patient who died. The final point estimate of the probability that a patient receiving TKM-130803 who survives for 48 h will subsequently survive to day 14 was 0.27 (95% CI 0.06, 0.58). Two of the three patients in the observational cohort died.

Bottom Line: 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.TKM-130803 infusions were well tolerated, with 56 doses administered and only one possible infusion-related reaction observed.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.

View Article: PubMed Central - PubMed

Affiliation: Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus