A novel drug for treatment of necrotizing soft-tissue infections

A randomized clinical trial

Eileen M. Bulger, Ronald V. Maier, Jason Sperry, Manjari Joshi, Sharon Henry, Frederick A. Moore, Lyle L. Moldawer, Demetrios Demetriades, Peep Talving, Martin Schreiber, Lyle (Bruce) Ham, Mitchell Cohen, Steven Opal, Irit Segalovich, Greg Maislin, Raymond Kaempfer, Anat Shirvan

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

IMPORTANCE: Necrotizing soft-tissue infections (NSTI) have high morbidity and mortality rates despite aggressive surgical debridement and antibiotic therapy. AB103 is a peptide mimetic of the T-lymphocyte receptor, CD28. We hypothesized that AB103 will limit inflammatory responses to bacterial toxins and decrease the incidence of organ failure. OBJECTIVES: To establish the safety of AB103 in patients with NSTI and evaluate the potential effects on clinically meaningful parameters related to the disease. DESIGN, SETTING, AND PARTICIPANTS: A prospective, randomized, placebo-controlled, double-blinded study was performed in 6 academic medical centers in the United States. Participants included adults with NSTI. Of 345 patients screened, 43 were enrolled for the intent-to-treat analysis, and 40 met criteria for the modified intent-to-treat analysis; 15 patients each were included in the high-dose and low-dose treatment arms, and 10 in the placebo arm. INTERVENTION: Single intravenous dose of AB103 (0.5 or 0.25mg/kg) within 6 hours after diagnosis of NSTI. MAIN OUTCOMES AND MEASURES: Change in the Sequential Organ Failure Assessment score within 28 days, intensive care unit-free and ventilator-free days, number and timing of debridements, plasma and tissue cytokine levels at 0 to 72 hours, and adverse events. RESULTS: Baseline characteristics were comparable in the treatment groups. The Sequential Organ Failure Assessment score improved from baseline in both treatment groups compared with the placebo group at 14 days (change from baseline score, -2.8 in the high-dose, -2 in the low-dose, and +1.3 in the placebo groups; P = .04). AB103-treated patients had a similar number of debridements (mean [SD], 2.2 [1.1] for the high-dose, 2.3 [1.2] for the low-dose, and 2.8 [2.1] for the placebo groups; P = .56). There were no statistically significant differences in intensive care unit-free and ventilator-free days or in plasma and tissue cytokine levels. No drug-related adverse events were detected. CONCLUSIONS AND RELEVANCE: AB103 is a safe, promising new agent for modulation of inflammation after NSTI. Further study is warranted to establish efficacy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01417780

Original languageEnglish (US)
Pages (from-to)528-536
Number of pages9
JournalJAMA Surgery
Volume149
Issue number6
DOIs
StatePublished - 2014

Fingerprint

Soft Tissue Infections
Randomized Controlled Trials
Placebos
Debridement
Pharmaceutical Preparations
Organ Dysfunction Scores
Mechanical Ventilators
Intensive Care Units
Therapeutics
Cytokines
Peptide T
Bacterial Toxins
Drug-Related Side Effects and Adverse Reactions
AB103
Outcome Assessment (Health Care)
Anti-Bacterial Agents
Inflammation
Morbidity
T-Lymphocytes
Safety

ASJC Scopus subject areas

  • Surgery

Cite this

Bulger, E. M., Maier, R. V., Sperry, J., Joshi, M., Henry, S., Moore, F. A., ... Shirvan, A. (2014). A novel drug for treatment of necrotizing soft-tissue infections: A randomized clinical trial. JAMA Surgery, 149(6), 528-536. https://doi.org/10.1001/jamasurg.2013.4841

A novel drug for treatment of necrotizing soft-tissue infections : A randomized clinical trial. / Bulger, Eileen M.; Maier, Ronald V.; Sperry, Jason; Joshi, Manjari; Henry, Sharon; Moore, Frederick A.; Moldawer, Lyle L.; Demetriades, Demetrios; Talving, Peep; Schreiber, Martin; Ham, Lyle (Bruce); Cohen, Mitchell; Opal, Steven; Segalovich, Irit; Maislin, Greg; Kaempfer, Raymond; Shirvan, Anat.

In: JAMA Surgery, Vol. 149, No. 6, 2014, p. 528-536.

Research output: Contribution to journalArticle

Bulger, EM, Maier, RV, Sperry, J, Joshi, M, Henry, S, Moore, FA, Moldawer, LL, Demetriades, D, Talving, P, Schreiber, M, Ham, LB, Cohen, M, Opal, S, Segalovich, I, Maislin, G, Kaempfer, R & Shirvan, A 2014, 'A novel drug for treatment of necrotizing soft-tissue infections: A randomized clinical trial', JAMA Surgery, vol. 149, no. 6, pp. 528-536. https://doi.org/10.1001/jamasurg.2013.4841
Bulger, Eileen M. ; Maier, Ronald V. ; Sperry, Jason ; Joshi, Manjari ; Henry, Sharon ; Moore, Frederick A. ; Moldawer, Lyle L. ; Demetriades, Demetrios ; Talving, Peep ; Schreiber, Martin ; Ham, Lyle (Bruce) ; Cohen, Mitchell ; Opal, Steven ; Segalovich, Irit ; Maislin, Greg ; Kaempfer, Raymond ; Shirvan, Anat. / A novel drug for treatment of necrotizing soft-tissue infections : A randomized clinical trial. In: JAMA Surgery. 2014 ; Vol. 149, No. 6. pp. 528-536.
@article{87d18ed8f6974b2f9b5e63d2a84b4c00,
title = "A novel drug for treatment of necrotizing soft-tissue infections: A randomized clinical trial",
abstract = "IMPORTANCE: Necrotizing soft-tissue infections (NSTI) have high morbidity and mortality rates despite aggressive surgical debridement and antibiotic therapy. AB103 is a peptide mimetic of the T-lymphocyte receptor, CD28. We hypothesized that AB103 will limit inflammatory responses to bacterial toxins and decrease the incidence of organ failure. OBJECTIVES: To establish the safety of AB103 in patients with NSTI and evaluate the potential effects on clinically meaningful parameters related to the disease. DESIGN, SETTING, AND PARTICIPANTS: A prospective, randomized, placebo-controlled, double-blinded study was performed in 6 academic medical centers in the United States. Participants included adults with NSTI. Of 345 patients screened, 43 were enrolled for the intent-to-treat analysis, and 40 met criteria for the modified intent-to-treat analysis; 15 patients each were included in the high-dose and low-dose treatment arms, and 10 in the placebo arm. INTERVENTION: Single intravenous dose of AB103 (0.5 or 0.25mg/kg) within 6 hours after diagnosis of NSTI. MAIN OUTCOMES AND MEASURES: Change in the Sequential Organ Failure Assessment score within 28 days, intensive care unit-free and ventilator-free days, number and timing of debridements, plasma and tissue cytokine levels at 0 to 72 hours, and adverse events. RESULTS: Baseline characteristics were comparable in the treatment groups. The Sequential Organ Failure Assessment score improved from baseline in both treatment groups compared with the placebo group at 14 days (change from baseline score, -2.8 in the high-dose, -2 in the low-dose, and +1.3 in the placebo groups; P = .04). AB103-treated patients had a similar number of debridements (mean [SD], 2.2 [1.1] for the high-dose, 2.3 [1.2] for the low-dose, and 2.8 [2.1] for the placebo groups; P = .56). There were no statistically significant differences in intensive care unit-free and ventilator-free days or in plasma and tissue cytokine levels. No drug-related adverse events were detected. CONCLUSIONS AND RELEVANCE: AB103 is a safe, promising new agent for modulation of inflammation after NSTI. Further study is warranted to establish efficacy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01417780",
author = "Bulger, {Eileen M.} and Maier, {Ronald V.} and Jason Sperry and Manjari Joshi and Sharon Henry and Moore, {Frederick A.} and Moldawer, {Lyle L.} and Demetrios Demetriades and Peep Talving and Martin Schreiber and Ham, {Lyle (Bruce)} and Mitchell Cohen and Steven Opal and Irit Segalovich and Greg Maislin and Raymond Kaempfer and Anat Shirvan",
year = "2014",
doi = "10.1001/jamasurg.2013.4841",
language = "English (US)",
volume = "149",
pages = "528--536",
journal = "JAMA Surgery",
issn = "2168-6254",
publisher = "American Medical Association",
number = "6",

}

TY - JOUR

T1 - A novel drug for treatment of necrotizing soft-tissue infections

T2 - A randomized clinical trial

AU - Bulger, Eileen M.

AU - Maier, Ronald V.

AU - Sperry, Jason

AU - Joshi, Manjari

AU - Henry, Sharon

AU - Moore, Frederick A.

AU - Moldawer, Lyle L.

AU - Demetriades, Demetrios

AU - Talving, Peep

AU - Schreiber, Martin

AU - Ham, Lyle (Bruce)

AU - Cohen, Mitchell

AU - Opal, Steven

AU - Segalovich, Irit

AU - Maislin, Greg

AU - Kaempfer, Raymond

AU - Shirvan, Anat

PY - 2014

Y1 - 2014

N2 - IMPORTANCE: Necrotizing soft-tissue infections (NSTI) have high morbidity and mortality rates despite aggressive surgical debridement and antibiotic therapy. AB103 is a peptide mimetic of the T-lymphocyte receptor, CD28. We hypothesized that AB103 will limit inflammatory responses to bacterial toxins and decrease the incidence of organ failure. OBJECTIVES: To establish the safety of AB103 in patients with NSTI and evaluate the potential effects on clinically meaningful parameters related to the disease. DESIGN, SETTING, AND PARTICIPANTS: A prospective, randomized, placebo-controlled, double-blinded study was performed in 6 academic medical centers in the United States. Participants included adults with NSTI. Of 345 patients screened, 43 were enrolled for the intent-to-treat analysis, and 40 met criteria for the modified intent-to-treat analysis; 15 patients each were included in the high-dose and low-dose treatment arms, and 10 in the placebo arm. INTERVENTION: Single intravenous dose of AB103 (0.5 or 0.25mg/kg) within 6 hours after diagnosis of NSTI. MAIN OUTCOMES AND MEASURES: Change in the Sequential Organ Failure Assessment score within 28 days, intensive care unit-free and ventilator-free days, number and timing of debridements, plasma and tissue cytokine levels at 0 to 72 hours, and adverse events. RESULTS: Baseline characteristics were comparable in the treatment groups. The Sequential Organ Failure Assessment score improved from baseline in both treatment groups compared with the placebo group at 14 days (change from baseline score, -2.8 in the high-dose, -2 in the low-dose, and +1.3 in the placebo groups; P = .04). AB103-treated patients had a similar number of debridements (mean [SD], 2.2 [1.1] for the high-dose, 2.3 [1.2] for the low-dose, and 2.8 [2.1] for the placebo groups; P = .56). There were no statistically significant differences in intensive care unit-free and ventilator-free days or in plasma and tissue cytokine levels. No drug-related adverse events were detected. CONCLUSIONS AND RELEVANCE: AB103 is a safe, promising new agent for modulation of inflammation after NSTI. Further study is warranted to establish efficacy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01417780

AB - IMPORTANCE: Necrotizing soft-tissue infections (NSTI) have high morbidity and mortality rates despite aggressive surgical debridement and antibiotic therapy. AB103 is a peptide mimetic of the T-lymphocyte receptor, CD28. We hypothesized that AB103 will limit inflammatory responses to bacterial toxins and decrease the incidence of organ failure. OBJECTIVES: To establish the safety of AB103 in patients with NSTI and evaluate the potential effects on clinically meaningful parameters related to the disease. DESIGN, SETTING, AND PARTICIPANTS: A prospective, randomized, placebo-controlled, double-blinded study was performed in 6 academic medical centers in the United States. Participants included adults with NSTI. Of 345 patients screened, 43 were enrolled for the intent-to-treat analysis, and 40 met criteria for the modified intent-to-treat analysis; 15 patients each were included in the high-dose and low-dose treatment arms, and 10 in the placebo arm. INTERVENTION: Single intravenous dose of AB103 (0.5 or 0.25mg/kg) within 6 hours after diagnosis of NSTI. MAIN OUTCOMES AND MEASURES: Change in the Sequential Organ Failure Assessment score within 28 days, intensive care unit-free and ventilator-free days, number and timing of debridements, plasma and tissue cytokine levels at 0 to 72 hours, and adverse events. RESULTS: Baseline characteristics were comparable in the treatment groups. The Sequential Organ Failure Assessment score improved from baseline in both treatment groups compared with the placebo group at 14 days (change from baseline score, -2.8 in the high-dose, -2 in the low-dose, and +1.3 in the placebo groups; P = .04). AB103-treated patients had a similar number of debridements (mean [SD], 2.2 [1.1] for the high-dose, 2.3 [1.2] for the low-dose, and 2.8 [2.1] for the placebo groups; P = .56). There were no statistically significant differences in intensive care unit-free and ventilator-free days or in plasma and tissue cytokine levels. No drug-related adverse events were detected. CONCLUSIONS AND RELEVANCE: AB103 is a safe, promising new agent for modulation of inflammation after NSTI. Further study is warranted to establish efficacy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01417780

UR - http://www.scopus.com/inward/record.url?scp=84903310649&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84903310649&partnerID=8YFLogxK

U2 - 10.1001/jamasurg.2013.4841

DO - 10.1001/jamasurg.2013.4841

M3 - Article

VL - 149

SP - 528

EP - 536

JO - JAMA Surgery

JF - JAMA Surgery

SN - 2168-6254

IS - 6

ER -