Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19: A Randomized Controlled Trial

Christina Barkauskas; Eleftherios Mylonakis; Garyfallia Poulakou; Barnaby E Young; David M Vock; Lianne Siegel; Nicole Engen; Greg Grandits; Nilima R Mosaly; Andrew M Vekstein; Ralph Rogers; Fadi Shehadeh; Matthew Kaczynski; Evangelia K Mylona; Konstantinos N Syrigos; Vasiliki Rapti; David C Lye; Diong Shiau Hui; Lindsay Leither; Kirk U Knowlton; Mamta K Jain; Rubria Marines-Price; Alice Osuji; J Scott Overcash; Ioannis Kalomenidis; Zafeiria Barmparessou; Michael Waters; Karla Zepeda; Peter Chen; Sam Torbati; Francis Kiweewa; Nicholus Sebudde; Eyad Almasri; Alyssa Hughes; Sanjay R Bhagani; Alison Rodger; Uriel Sandkovsky; Robert L Gottlieb; Eriobu Nnakelu; Barbara Trautner; Vidya Menon; Joseph Lutaakome; Michael Matthay; Philip Robinson; Konstantinos Protopapas; Nikolaos Koulouris; Ivan Kimuli; Amiran Baduashvili; Daniel D Murray; Tomas Østergaard Jensen; Jens D Lundgren; ACTIV-3/TICO Study Group; Birgitte  Lindegaard Madsen; Thomas Ingemann Pedersen; ZItta Barrella Harboe

doi:10.7326/M22-1503

Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19: A Randomized Controlled Trial

Christina Barkauskas^*, Eleftherios Mylonakis, Garyfallia Poulakou, Barnaby E Young, David M Vock, Lianne Siegel, Nicole Engen, Greg Grandits, Nilima R Mosaly, Andrew M Vekstein, Ralph Rogers, Fadi Shehadeh, Matthew Kaczynski, Evangelia K Mylona, Konstantinos N Syrigos, Vasiliki Rapti, David C Lye, Diong Shiau Hui, Lindsay Leither, Kirk U KnowltonMamta K Jain, Rubria Marines-Price, Alice Osuji, J Scott Overcash, Ioannis Kalomenidis, Zafeiria Barmparessou, Michael Waters, Karla Zepeda, Peter Chen, Sam Torbati, Francis Kiweewa, Nicholus Sebudde, Eyad Almasri, Alyssa Hughes, Sanjay R Bhagani, Alison Rodger, Uriel Sandkovsky, Robert L Gottlieb, Eriobu Nnakelu, Barbara Trautner, Vidya Menon, Joseph Lutaakome, Michael Matthay, Philip Robinson, Konstantinos Protopapas, Nikolaos Koulouris, Ivan Kimuli, Amiran Baduashvili, Daniel D Murray, Tomas Østergaard Jensen, Jens D Lundgren, ACTIV-3/TICO Study Group, Birgitte Lindegaard Madsen (Medlem af forfattergruppering), Thomas Ingemann Pedersen (Medlem af forfattergruppering), ZItta Barrella Harboe (Medlem af forfattergruppering)

^*Corresponding author af dette arbejde

Abstrakt

BACKGROUND: Ensovibep (MP0420) is a designed ankyrin repeat protein, a novel class of engineered proteins, under investigation as a treatment of SARS-CoV-2 infection.

OBJECTIVE: To investigate if ensovibep, in addition to remdesivir and other standard care, improves clinical outcomes among patients hospitalized with COVID-19 compared with standard care alone.

DESIGN: Double-blind, randomized, placebo-controlled, clinical trial. (ClinicalTrials.gov: NCT04501978).

SETTING: Multinational, multicenter trial.

PARTICIPANTS: Adults hospitalized with COVID-19.

INTERVENTION: Intravenous ensovibep, 600 mg, or placebo.

MEASUREMENTS: Ensovibep was assessed for early futility on the basis of pulmonary ordinal scores at day 5. The primary outcome was time to sustained recovery through day 90, defined as 14 consecutive days at home or place of usual residence after hospital discharge. A composite safety outcome that included death, serious adverse events, end-organ disease, and serious infections was assessed through day 90.

RESULTS: An independent data and safety monitoring board recommended that enrollment be halted for early futility after 485 patients were randomly assigned and received an infusion of ensovibep (n = 247) or placebo (n = 238). The odds ratio (OR) for a more favorable pulmonary outcome in the ensovibep (vs. placebo) group at day 5 was 0.93 (95% CI, 0.67 to 1.30; P = 0.68; OR > 1 would favor ensovibep). The 90-day cumulative incidence of sustained recovery was 82% for ensovibep and 80% for placebo (subhazard ratio [sHR], 1.06 [CI, 0.88 to 1.28]; sHR > 1 would favor ensovibep). The primary composite safety outcome at day 90 occurred in 78 ensovibep participants (32%) and 70 placebo participants (29%) (HR, 1.07 [CI, 0.77 to 1.47]; HR < 1 would favor ensovibep).

LIMITATION: The trial was prematurely stopped because of futility, limiting power for the primary outcome.

CONCLUSION: Compared with placebo, ensovibep did not improve clinical outcomes for hospitalized participants with COVID-19 receiving standard care, including remdesivir; no safety concerns were identified.

PRIMARY FUNDING SOURCE: National Institutes of Health.

Originalsprog	Engelsk
Tidsskrift	Annals of Internal Medicine
Vol/bind	175
Udgave nummer	9
Sider (fra-til)	1266-1274
Antal sider	9
ISSN	0003-4819
DOI	https://doi.org/10.7326/M22-1503
Status	Udgivet - sep. 2022

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10.7326/M22-1503

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Barkauskas, C., Mylonakis, E., Poulakou, G., Young, B. E., Vock, D. M., Siegel, L., Engen, N., Grandits, G., Mosaly, N. R., Vekstein, A. M., Rogers, R., Shehadeh, F., Kaczynski, M., Mylona, E. K., Syrigos, K. N., Rapti, V., Lye, D. C., Hui, D. S., Leither, L., ... Harboe, ZI. B. (2022). Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19: A Randomized Controlled Trial. Annals of Internal Medicine, 175(9), 1266-1274. https://doi.org/10.7326/M22-1503

Barkauskas, C, Mylonakis, E, Poulakou, G, Young, BE, Vock, DM, Siegel, L, Engen, N, Grandits, G, Mosaly, NR, Vekstein, AM, Rogers, R, Shehadeh, F, Kaczynski, M, Mylona, EK, Syrigos, KN, Rapti, V, Lye, DC, Hui, DS, Leither, L, Knowlton, KU, Jain, MK, Marines-Price, R, Osuji, A, Overcash, JS, Kalomenidis, I, Barmparessou, Z, Waters, M, Zepeda, K, Chen, P, Torbati, S, Kiweewa, F, Sebudde, N, Almasri, E, Hughes, A, Bhagani, SR, Rodger, A, Sandkovsky, U, Gottlieb, RL, Nnakelu, E, Trautner, B, Menon, V, Lutaakome, J, Matthay, M, Robinson, P, Protopapas, K, Koulouris, N, Kimuli, I, Baduashvili, A, Murray, DD , Østergaard Jensen, T , Lundgren, JD, ACTIV-3/TICO Study Group, Lindegaard Madsen, B , Pedersen, TI & Harboe, ZIB 2022, 'Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19: A Randomized Controlled Trial', Annals of Internal Medicine, bind 175, nr. 9, s. 1266-1274. https://doi.org/10.7326/M22-1503

@article{bab8721c56624d93b0b66026cef7d8dc,

title = "Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19: A Randomized Controlled Trial",

abstract = "BACKGROUND: Ensovibep (MP0420) is a designed ankyrin repeat protein, a novel class of engineered proteins, under investigation as a treatment of SARS-CoV-2 infection.OBJECTIVE: To investigate if ensovibep, in addition to remdesivir and other standard care, improves clinical outcomes among patients hospitalized with COVID-19 compared with standard care alone.DESIGN: Double-blind, randomized, placebo-controlled, clinical trial. (ClinicalTrials.gov: NCT04501978).SETTING: Multinational, multicenter trial.PARTICIPANTS: Adults hospitalized with COVID-19.INTERVENTION: Intravenous ensovibep, 600 mg, or placebo.MEASUREMENTS: Ensovibep was assessed for early futility on the basis of pulmonary ordinal scores at day 5. The primary outcome was time to sustained recovery through day 90, defined as 14 consecutive days at home or place of usual residence after hospital discharge. A composite safety outcome that included death, serious adverse events, end-organ disease, and serious infections was assessed through day 90.RESULTS: An independent data and safety monitoring board recommended that enrollment be halted for early futility after 485 patients were randomly assigned and received an infusion of ensovibep (n = 247) or placebo (n = 238). The odds ratio (OR) for a more favorable pulmonary outcome in the ensovibep (vs. placebo) group at day 5 was 0.93 (95% CI, 0.67 to 1.30; P = 0.68; OR > 1 would favor ensovibep). The 90-day cumulative incidence of sustained recovery was 82% for ensovibep and 80% for placebo (subhazard ratio [sHR], 1.06 [CI, 0.88 to 1.28]; sHR > 1 would favor ensovibep). The primary composite safety outcome at day 90 occurred in 78 ensovibep participants (32%) and 70 placebo participants (29%) (HR, 1.07 [CI, 0.77 to 1.47]; HR < 1 would favor ensovibep).LIMITATION: The trial was prematurely stopped because of futility, limiting power for the primary outcome.CONCLUSION: Compared with placebo, ensovibep did not improve clinical outcomes for hospitalized participants with COVID-19 receiving standard care, including remdesivir; no safety concerns were identified.PRIMARY FUNDING SOURCE: National Institutes of Health.",

keywords = "Adult, COVID-19/drug therapy, Designed Ankyrin Repeat Proteins, Double-Blind Method, Humans, Recombinant Fusion Proteins, SARS-CoV-2, Treatment Outcome",

author = "Christina Barkauskas and Eleftherios Mylonakis and Garyfallia Poulakou and Young, {Barnaby E} and Vock, {David M} and Lianne Siegel and Nicole Engen and Greg Grandits and Mosaly, {Nilima R} and Vekstein, {Andrew M} and Ralph Rogers and Fadi Shehadeh and Matthew Kaczynski and Mylona, {Evangelia K} and Syrigos, {Konstantinos N} and Vasiliki Rapti and Lye, {David C} and Hui, {Diong Shiau} and Lindsay Leither and Knowlton, {Kirk U} and Jain, {Mamta K} and Rubria Marines-Price and Alice Osuji and Overcash, {J Scott} and Ioannis Kalomenidis and Zafeiria Barmparessou and Michael Waters and Karla Zepeda and Peter Chen and Sam Torbati and Francis Kiweewa and Nicholus Sebudde and Eyad Almasri and Alyssa Hughes and Bhagani, {Sanjay R} and Alison Rodger and Uriel Sandkovsky and Gottlieb, {Robert L} and Eriobu Nnakelu and Barbara Trautner and Vidya Menon and Joseph Lutaakome and Michael Matthay and Philip Robinson and Konstantinos Protopapas and Nikolaos Koulouris and Ivan Kimuli and Amiran Baduashvili and Murray, {Daniel D} and {{\O}stergaard Jensen}, Tomas and Lundgren, {Jens D} and {ACTIV-3/TICO Study Group} and {Lindegaard Madsen}, Birgitte and Pedersen, {Thomas Ingemann} and Harboe, {ZItta Barrella}",

year = "2022",

month = sep,

doi = "10.7326/M22-1503",

language = "English",

volume = "175",

pages = "1266--1274",

journal = "Annals of Internal Medicine",

issn = "0003-4819",

publisher = "American College of Physicians",

number = "9",

}

TY - JOUR

T1 - Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19

T2 - A Randomized Controlled Trial

AU - Barkauskas, Christina

AU - Mylonakis, Eleftherios

AU - Poulakou, Garyfallia

AU - Young, Barnaby E

AU - Vock, David M

AU - Siegel, Lianne

AU - Engen, Nicole

AU - Grandits, Greg

AU - Mosaly, Nilima R

AU - Vekstein, Andrew M

AU - Rogers, Ralph

AU - Shehadeh, Fadi

AU - Kaczynski, Matthew

AU - Mylona, Evangelia K

AU - Syrigos, Konstantinos N

AU - Rapti, Vasiliki

AU - Lye, David C

AU - Hui, Diong Shiau

AU - Leither, Lindsay

AU - Knowlton, Kirk U

AU - Jain, Mamta K

AU - Marines-Price, Rubria

AU - Osuji, Alice

AU - Overcash, J Scott

AU - Kalomenidis, Ioannis

AU - Barmparessou, Zafeiria

AU - Waters, Michael

AU - Zepeda, Karla

AU - Chen, Peter

AU - Torbati, Sam

AU - Kiweewa, Francis

AU - Sebudde, Nicholus

AU - Almasri, Eyad

AU - Hughes, Alyssa

AU - Bhagani, Sanjay R

AU - Rodger, Alison

AU - Sandkovsky, Uriel

AU - Gottlieb, Robert L

AU - Nnakelu, Eriobu

AU - Trautner, Barbara

AU - Menon, Vidya

AU - Lutaakome, Joseph

AU - Matthay, Michael

AU - Robinson, Philip

AU - Protopapas, Konstantinos

AU - Koulouris, Nikolaos

AU - Kimuli, Ivan

AU - Baduashvili, Amiran

AU - Murray, Daniel D

AU - Østergaard Jensen, Tomas

AU - Lundgren, Jens D

AU - ACTIV-3/TICO Study Group

A2 - Lindegaard Madsen, Birgitte

A2 - Pedersen, Thomas Ingemann

A2 - Harboe, ZItta Barrella

PY - 2022/9

Y1 - 2022/9

N2 - BACKGROUND: Ensovibep (MP0420) is a designed ankyrin repeat protein, a novel class of engineered proteins, under investigation as a treatment of SARS-CoV-2 infection.OBJECTIVE: To investigate if ensovibep, in addition to remdesivir and other standard care, improves clinical outcomes among patients hospitalized with COVID-19 compared with standard care alone.DESIGN: Double-blind, randomized, placebo-controlled, clinical trial. (ClinicalTrials.gov: NCT04501978).SETTING: Multinational, multicenter trial.PARTICIPANTS: Adults hospitalized with COVID-19.INTERVENTION: Intravenous ensovibep, 600 mg, or placebo.MEASUREMENTS: Ensovibep was assessed for early futility on the basis of pulmonary ordinal scores at day 5. The primary outcome was time to sustained recovery through day 90, defined as 14 consecutive days at home or place of usual residence after hospital discharge. A composite safety outcome that included death, serious adverse events, end-organ disease, and serious infections was assessed through day 90.RESULTS: An independent data and safety monitoring board recommended that enrollment be halted for early futility after 485 patients were randomly assigned and received an infusion of ensovibep (n = 247) or placebo (n = 238). The odds ratio (OR) for a more favorable pulmonary outcome in the ensovibep (vs. placebo) group at day 5 was 0.93 (95% CI, 0.67 to 1.30; P = 0.68; OR > 1 would favor ensovibep). The 90-day cumulative incidence of sustained recovery was 82% for ensovibep and 80% for placebo (subhazard ratio [sHR], 1.06 [CI, 0.88 to 1.28]; sHR > 1 would favor ensovibep). The primary composite safety outcome at day 90 occurred in 78 ensovibep participants (32%) and 70 placebo participants (29%) (HR, 1.07 [CI, 0.77 to 1.47]; HR < 1 would favor ensovibep).LIMITATION: The trial was prematurely stopped because of futility, limiting power for the primary outcome.CONCLUSION: Compared with placebo, ensovibep did not improve clinical outcomes for hospitalized participants with COVID-19 receiving standard care, including remdesivir; no safety concerns were identified.PRIMARY FUNDING SOURCE: National Institutes of Health.

AB - BACKGROUND: Ensovibep (MP0420) is a designed ankyrin repeat protein, a novel class of engineered proteins, under investigation as a treatment of SARS-CoV-2 infection.OBJECTIVE: To investigate if ensovibep, in addition to remdesivir and other standard care, improves clinical outcomes among patients hospitalized with COVID-19 compared with standard care alone.DESIGN: Double-blind, randomized, placebo-controlled, clinical trial. (ClinicalTrials.gov: NCT04501978).SETTING: Multinational, multicenter trial.PARTICIPANTS: Adults hospitalized with COVID-19.INTERVENTION: Intravenous ensovibep, 600 mg, or placebo.MEASUREMENTS: Ensovibep was assessed for early futility on the basis of pulmonary ordinal scores at day 5. The primary outcome was time to sustained recovery through day 90, defined as 14 consecutive days at home or place of usual residence after hospital discharge. A composite safety outcome that included death, serious adverse events, end-organ disease, and serious infections was assessed through day 90.RESULTS: An independent data and safety monitoring board recommended that enrollment be halted for early futility after 485 patients were randomly assigned and received an infusion of ensovibep (n = 247) or placebo (n = 238). The odds ratio (OR) for a more favorable pulmonary outcome in the ensovibep (vs. placebo) group at day 5 was 0.93 (95% CI, 0.67 to 1.30; P = 0.68; OR > 1 would favor ensovibep). The 90-day cumulative incidence of sustained recovery was 82% for ensovibep and 80% for placebo (subhazard ratio [sHR], 1.06 [CI, 0.88 to 1.28]; sHR > 1 would favor ensovibep). The primary composite safety outcome at day 90 occurred in 78 ensovibep participants (32%) and 70 placebo participants (29%) (HR, 1.07 [CI, 0.77 to 1.47]; HR < 1 would favor ensovibep).LIMITATION: The trial was prematurely stopped because of futility, limiting power for the primary outcome.CONCLUSION: Compared with placebo, ensovibep did not improve clinical outcomes for hospitalized participants with COVID-19 receiving standard care, including remdesivir; no safety concerns were identified.PRIMARY FUNDING SOURCE: National Institutes of Health.

KW - Adult

KW - COVID-19/drug therapy

KW - Designed Ankyrin Repeat Proteins

KW - Double-Blind Method

KW - Humans

KW - Recombinant Fusion Proteins

KW - SARS-CoV-2

KW - Treatment Outcome

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U2 - 10.7326/M22-1503

DO - 10.7326/M22-1503

M3 - Journal article

C2 - 35939810

VL - 175

SP - 1266

EP - 1274

JO - Annals of Internal Medicine

JF - Annals of Internal Medicine

SN - 0003-4819

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ER -

Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19: A Randomized Controlled Trial

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