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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

Box and whisker plot of vital signs in TKM-130803 recipients, before, during, and after TKM-130803 infusions.Heart rate, respiratory rate, mean arterial blood pressure, and tympanic temperature in patients administered TKM-130803 at the following time points: immediately prior to TKM-130803 infusion (PRE), during the infusion, immediately at the end of the infusion (END), and at 1, 2, 4, and 8 h after the end of the infusion. The middle line shows the median value, the box shows the interquartile range, and the whiskers spread from the lower to the upper adjacent values. Outside values, that is, observations that are larger/smaller than the upper/lower adjacent values, are shown as circles.
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pmed.1001997.g004: Box and whisker plot of vital signs in TKM-130803 recipients, before, during, and after TKM-130803 infusions.Heart rate, respiratory rate, mean arterial blood pressure, and tympanic temperature in patients administered TKM-130803 at the following time points: immediately prior to TKM-130803 infusion (PRE), during the infusion, immediately at the end of the infusion (END), and at 1, 2, 4, and 8 h after the end of the infusion. The middle line shows the median value, the box shows the interquartile range, and the whiskers spread from the lower to the upper adjacent values. Outside values, that is, observations that are larger/smaller than the upper/lower adjacent values, are shown as circles.

Mentions: A total of 56 infusions of TKM-130803 were administered. Adverse reactions consistent with acute cytokine release syndrome were not seen during or following any of the infusions, and none of the infusions required termination or slowing of the infusion rate (Fig 4) [10]. As such, the infusions of TKM-130803 were well tolerated. One patient (203–025) was observed to have worsening tachypnoea in the 48 h following the second TKM-130803 infusion, but new onset or worsening of additional symptoms or signs that might indicate infusion-related cytokine release syndrome (tachycardia, flushing, headache, hypotension, chills, nausea, and vomiting) were not observed in this patient. The event was reported to the IDMC as a SAR because of the temporal relationship with the administration of the study drug, but it was also felt the event was compatible with progression of EVD.


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)

Box and whisker plot of vital signs in TKM-130803 recipients, before, during, and after TKM-130803 infusions.Heart rate, respiratory rate, mean arterial blood pressure, and tympanic temperature in patients administered TKM-130803 at the following time points: immediately prior to TKM-130803 infusion (PRE), during the infusion, immediately at the end of the infusion (END), and at 1, 2, 4, and 8 h after the end of the infusion. The middle line shows the median value, the box shows the interquartile range, and the whiskers spread from the lower to the upper adjacent values. Outside values, that is, observations that are larger/smaller than the upper/lower adjacent values, are shown as circles.
© Copyright Policy
Related In: Results  -  Collection

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

pmed.1001997.g004: Box and whisker plot of vital signs in TKM-130803 recipients, before, during, and after TKM-130803 infusions.Heart rate, respiratory rate, mean arterial blood pressure, and tympanic temperature in patients administered TKM-130803 at the following time points: immediately prior to TKM-130803 infusion (PRE), during the infusion, immediately at the end of the infusion (END), and at 1, 2, 4, and 8 h after the end of the infusion. The middle line shows the median value, the box shows the interquartile range, and the whiskers spread from the lower to the upper adjacent values. Outside values, that is, observations that are larger/smaller than the upper/lower adjacent values, are shown as circles.
Mentions: A total of 56 infusions of TKM-130803 were administered. Adverse reactions consistent with acute cytokine release syndrome were not seen during or following any of the infusions, and none of the infusions required termination or slowing of the infusion rate (Fig 4) [10]. As such, the infusions of TKM-130803 were well tolerated. One patient (203–025) was observed to have worsening tachypnoea in the 48 h following the second TKM-130803 infusion, but new onset or worsening of additional symptoms or signs that might indicate infusion-related cytokine release syndrome (tachycardia, flushing, headache, hypotension, chills, nausea, and vomiting) were not observed in this patient. The event was reported to the IDMC as a SAR because of the temporal relationship with the administration of the study drug, but it was also felt the event was compatible with progression of EVD.

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