ASA - A Novel Immune Modulator For Patients With Necrotizing Soft Tissue Infections (NSTI): Results Of A Multicenter, Phase 3 Randomized Controlled Trial

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A Novel Immune Modulator For Patients With Necrotizing Soft Tissue Infections (NSTI): Results Of A Multicenter, Phase 3 Randomized Controlled Trial
Eileen M Bulger¹, Addison K May², *Bryce R.H. Robinson¹, *David C Evans³, *Sharon Henry⁴, *John M Green⁵, *Eric Toschlog⁶, Jason L Sperry⁷, *Peter Fagenholz⁸, *Niels D. Martin⁹, *Wayne M Dankner¹⁰, *Greg Maislin¹¹, *David Wilfret¹⁰, *Andrew C Bernard¹², *NA on behalf of the ACCUTE Study Investigators¹³
¹University of Washington, Seattle, WA;²Atrium Health, Charlotte, NC;³Ohio Health Grant & Mansfield Hospitals, Columbus, OH;⁴University of Maryland, Baltimore, MD;⁵Carolinas Medical Center, Charlotte, NC;⁶East Carolina University, Greenville, NC;⁷University of Pittsburgh, Pittsburgh, PA;⁸Massachusetts General Hospital, Boston, MA;⁹University of Pennsylvania, Philadelphia, PA;¹⁰Atox Bio Ltd, Durham, NC;¹¹Biomedical Statistical Consulting, Wynnewood, PA;¹²University of Kentucky, Louisville, KY;¹³⁶⁵ clinical sites US and France, Seattle, WA

OBJECTIVE(S): Reltecimod (aka AB103), a CD 28 T-lymphocyte receptor mimetic, inhibits T-cell stimulation by an array of bacterial pathogens. A Phase 2 trial demonstrated safety and improved resolution of organ dysfunction in patients with NSTI. We hypothesized that early administration of Reltecimod would improve outcome in severe NSTI. METHODS: Randomized, double-blind, placebo-controlled trial of single dose Reltecimod (0.5mg/kg) administered within 6 hours of NSTI diagnosis at 65 sites (US/Europe). Inclusion: surgical confirmation of NSTI and organ dysfunction based on an mSOFA score ≥3. Primary analysis was a modified intent to treat (mITT), responder analysis using a previously validated composite endpoint, NICCE, defined as: alive at Day 28, ≤3 debridements, no amputation beyond first operation, and Day 14 mSOFA ≤1 with ≥3 point reduction mSOFA (organ dysfunction resolution). A pre-specified, per-protocol (PP) analysis excluded 19 patients with major protocol violations before unblinding. RESULTS: 290 patients were enrolled in mITT (Reltecimod 142, Placebo 148): mean age 55 ± 15 years, 60% male, 42.4% diabetic, 28.6% perineal infection, screening mSOFA mean 5.5 ± 2.4. Baseline characteristics were well matched between groups. 28 day mortality was 15% in both groups. CONCLUSIONS: Early administration of Reltecimod in severe NSTI resulted in a significant difference in the primary composite endpoint in the PP population but not in the primary mITT population. Reltecimod was associated with improved resolution of organ dysfunction.
*mSOFA=modified Sequential Organ Failure Assessment Score w/o bilirubin, **d14 survivors
Analysis population Reltecimod (%) Placebo (%) p value
NICCE success mITT (N=290) 67/142 (47.2% 59/148 (39.9%) 0.209
NICCE success PP (N=271) 68/127 (53.5%) 58/144 (40.3%) 0.029
Day 14 mSOFA* <=1 and reduction >=3 mITT (N=261)** 82/126 (65.1%) 71/135 (52.6%) 0.041
Day 14 mSOFA* <=1 and reduction >=3 PP (N=246)** 81/115 (70.4%) 70/131 (53.4%) 0.006

*mSOFA=modified Sequential Organ Failure Assessment Score w/o bilirubin, **d14 survivors
	Analysis population	Reltecimod (%)	Placebo (%)	p value
NICCE success	mITT (N=290)	67/142 (47.2%	59/148 (39.9%)	0.209
NICCE success	PP (N=271)	68/127 (53.5%)	58/144 (40.3%)	0.029
Day 14 mSOFA* <=1 and reduction >=3	mITT (N=261)**	82/126 (65.1%)	71/135 (52.6%)	0.041
Day 14 mSOFA* <=1 and reduction >=3	PP (N=246)**	81/115 (70.4%)	70/131 (53.4%)	0.006

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