A randomized, controlled trial of ZMapp for ebola virus infection

Richard T. Davey, Lori Dodd, Michael A. Proschan, Jim Neaton, Jacqueline A Nordwall, Joe Koopmeiners, John Beigel, John Tierney, H. Clifford Lane, Anthony S. Fauci, Moses B.F. Massaquoi, Foday Sahr, Denis Malvy

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Abstract

BACKGROUND Data from studies in nonhuman primates suggest that the triple monoclonal antibody cocktail ZMapp is a promising immune-based treatment for Ebola virus disease (EVD). METHODS Beginning in March 2015, we conducted a randomized, controlled trial of ZMapp plus the current standard of care as compared with the current standard of care alone in patients with EVD that was diagnosed in West Africa by polymerasechain-reaction (PCR) assay. Eligible patients of any age were randomly assigned in a 1:1 ratio to receive either the current standard of care or the current standard of care plus three intravenous infusions of ZMapp (50 mg per kilogram of body weight, administered every third day). Patients were stratified according to baseline PCR cycle-threshold value for the virus (≤22 vs. >22) and country of enrollment. Oral favipiravir was part of the current standard of care in Guinea. The primary end point was mortality at 28 days. RESULTS A total of 72 patients were enrolled at sites in Liberia, Sierra Leone, Guinea, and the United States. Of the 71 patients who could be evaluated, 21 died, representing an overall case fatality rate of 30%. Death occurred in 13 of 35 patients (37%) who received the current standard of care alone and in 8 of 36 patients (22%) who received the current standard of care plus ZMapp. The observed posterior probability that ZMapp plus the current standard of care was superior to the current standard of care alone was 91.2%, falling short of the prespecified threshold of 97.5%. Frequentist analyses yielded similar results (absolute difference in mortality with ZMapp, -15 percentage points; 95% confidence interval, -36 to 7). Baseline viral load was strongly predictive of both mortality and duration of hospitalization in all age groups. CONCLUSIONS In this randomized, controlled trial of a putative therapeutic agent for EVD, although the estimated effect of ZMapp appeared to be beneficial, the result did not meet the prespecified statistical threshold for efficacy.

Original languageEnglish (US)
Pages (from-to)1448-1456
Number of pages9
JournalNew England Journal of Medicine
Volume375
Issue number15
DOIs
StatePublished - Oct 13 2016

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Ebola Hemorrhagic Fever
Standard of Care
Randomized Controlled Trials
Guinea
Mortality
Liberia
Sierra Leone
ZMapp
Western Africa
Viral Load
Intravenous Infusions
Primates
Hospitalization
Age Groups

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A randomized, controlled trial of ZMapp for ebola virus infection. / Davey, Richard T.; Dodd, Lori; Proschan, Michael A.; Neaton, Jim; Nordwall, Jacqueline A; Koopmeiners, Joe; Beigel, John; Tierney, John; Lane, H. Clifford; Fauci, Anthony S.; Massaquoi, Moses B.F.; Sahr, Foday; Malvy, Denis.

In: New England Journal of Medicine, Vol. 375, No. 15, 13.10.2016, p. 1448-1456.

Research output: Contribution to journalArticle

Davey, RT, Dodd, L, Proschan, MA, Neaton, J, Nordwall, JA, Koopmeiners, J, Beigel, J, Tierney, J, Lane, HC, Fauci, AS, Massaquoi, MBF, Sahr, F & Malvy, D 2016, 'A randomized, controlled trial of ZMapp for ebola virus infection', New England Journal of Medicine, vol. 375, no. 15, pp. 1448-1456. https://doi.org/10.1056/NEJMoa1604330
Davey, Richard T. ; Dodd, Lori ; Proschan, Michael A. ; Neaton, Jim ; Nordwall, Jacqueline A ; Koopmeiners, Joe ; Beigel, John ; Tierney, John ; Lane, H. Clifford ; Fauci, Anthony S. ; Massaquoi, Moses B.F. ; Sahr, Foday ; Malvy, Denis. / A randomized, controlled trial of ZMapp for ebola virus infection. In: New England Journal of Medicine. 2016 ; Vol. 375, No. 15. pp. 1448-1456.
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abstract = "BACKGROUND Data from studies in nonhuman primates suggest that the triple monoclonal antibody cocktail ZMapp is a promising immune-based treatment for Ebola virus disease (EVD). METHODS Beginning in March 2015, we conducted a randomized, controlled trial of ZMapp plus the current standard of care as compared with the current standard of care alone in patients with EVD that was diagnosed in West Africa by polymerasechain-reaction (PCR) assay. Eligible patients of any age were randomly assigned in a 1:1 ratio to receive either the current standard of care or the current standard of care plus three intravenous infusions of ZMapp (50 mg per kilogram of body weight, administered every third day). Patients were stratified according to baseline PCR cycle-threshold value for the virus (≤22 vs. >22) and country of enrollment. Oral favipiravir was part of the current standard of care in Guinea. The primary end point was mortality at 28 days. RESULTS A total of 72 patients were enrolled at sites in Liberia, Sierra Leone, Guinea, and the United States. Of the 71 patients who could be evaluated, 21 died, representing an overall case fatality rate of 30{\%}. Death occurred in 13 of 35 patients (37{\%}) who received the current standard of care alone and in 8 of 36 patients (22{\%}) who received the current standard of care plus ZMapp. The observed posterior probability that ZMapp plus the current standard of care was superior to the current standard of care alone was 91.2{\%}, falling short of the prespecified threshold of 97.5{\%}. Frequentist analyses yielded similar results (absolute difference in mortality with ZMapp, -15 percentage points; 95{\%} confidence interval, -36 to 7). Baseline viral load was strongly predictive of both mortality and duration of hospitalization in all age groups. CONCLUSIONS In this randomized, controlled trial of a putative therapeutic agent for EVD, although the estimated effect of ZMapp appeared to be beneficial, the result did not meet the prespecified statistical threshold for efficacy.",
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AU - Dodd, Lori

AU - Proschan, Michael A.

AU - Neaton, Jim

AU - Nordwall, Jacqueline A

AU - Koopmeiners, Joe

AU - Beigel, John

AU - Tierney, John

AU - Lane, H. Clifford

AU - Fauci, Anthony S.

AU - Massaquoi, Moses B.F.

AU - Sahr, Foday

AU - Malvy, Denis

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N2 - BACKGROUND Data from studies in nonhuman primates suggest that the triple monoclonal antibody cocktail ZMapp is a promising immune-based treatment for Ebola virus disease (EVD). METHODS Beginning in March 2015, we conducted a randomized, controlled trial of ZMapp plus the current standard of care as compared with the current standard of care alone in patients with EVD that was diagnosed in West Africa by polymerasechain-reaction (PCR) assay. Eligible patients of any age were randomly assigned in a 1:1 ratio to receive either the current standard of care or the current standard of care plus three intravenous infusions of ZMapp (50 mg per kilogram of body weight, administered every third day). Patients were stratified according to baseline PCR cycle-threshold value for the virus (≤22 vs. >22) and country of enrollment. Oral favipiravir was part of the current standard of care in Guinea. The primary end point was mortality at 28 days. RESULTS A total of 72 patients were enrolled at sites in Liberia, Sierra Leone, Guinea, and the United States. Of the 71 patients who could be evaluated, 21 died, representing an overall case fatality rate of 30%. Death occurred in 13 of 35 patients (37%) who received the current standard of care alone and in 8 of 36 patients (22%) who received the current standard of care plus ZMapp. The observed posterior probability that ZMapp plus the current standard of care was superior to the current standard of care alone was 91.2%, falling short of the prespecified threshold of 97.5%. Frequentist analyses yielded similar results (absolute difference in mortality with ZMapp, -15 percentage points; 95% confidence interval, -36 to 7). Baseline viral load was strongly predictive of both mortality and duration of hospitalization in all age groups. CONCLUSIONS In this randomized, controlled trial of a putative therapeutic agent for EVD, although the estimated effect of ZMapp appeared to be beneficial, the result did not meet the prespecified statistical threshold for efficacy.

AB - BACKGROUND Data from studies in nonhuman primates suggest that the triple monoclonal antibody cocktail ZMapp is a promising immune-based treatment for Ebola virus disease (EVD). METHODS Beginning in March 2015, we conducted a randomized, controlled trial of ZMapp plus the current standard of care as compared with the current standard of care alone in patients with EVD that was diagnosed in West Africa by polymerasechain-reaction (PCR) assay. Eligible patients of any age were randomly assigned in a 1:1 ratio to receive either the current standard of care or the current standard of care plus three intravenous infusions of ZMapp (50 mg per kilogram of body weight, administered every third day). Patients were stratified according to baseline PCR cycle-threshold value for the virus (≤22 vs. >22) and country of enrollment. Oral favipiravir was part of the current standard of care in Guinea. The primary end point was mortality at 28 days. RESULTS A total of 72 patients were enrolled at sites in Liberia, Sierra Leone, Guinea, and the United States. Of the 71 patients who could be evaluated, 21 died, representing an overall case fatality rate of 30%. Death occurred in 13 of 35 patients (37%) who received the current standard of care alone and in 8 of 36 patients (22%) who received the current standard of care plus ZMapp. The observed posterior probability that ZMapp plus the current standard of care was superior to the current standard of care alone was 91.2%, falling short of the prespecified threshold of 97.5%. Frequentist analyses yielded similar results (absolute difference in mortality with ZMapp, -15 percentage points; 95% confidence interval, -36 to 7). Baseline viral load was strongly predictive of both mortality and duration of hospitalization in all age groups. CONCLUSIONS In this randomized, controlled trial of a putative therapeutic agent for EVD, although the estimated effect of ZMapp appeared to be beneficial, the result did not meet the prespecified statistical threshold for efficacy.

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