Safety and tolerability of non-neutralizing adrenomedullin antibody adrecizumab (HAM8101) in septic shock patients: the AdrenOSS-2 phase 2a biomarker-guided trial
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Safety and tolerability of non-neutralizing adrenomedullin antibody adrecizumab (HAM8101) in septic shock patients: the AdrenOSS-2 phase 2a biomarker-guided trial. / Laterre, Pierre-François; Pickkers, Peter; Marx, Gernot; Wittebole, Xavier; Meziani, Ferhat; Dugernier, Thierry; Huberlant, Vincent; Schuerholz, Tobias; François, Bruno; Lascarrou, Jean-Baptiste; Beishuizen, Albertus; Oueslati, Haikel; Contou, Damien; Hoiting, Oscar; Lacherade, Jean-Claude; Chousterman, Benjamin; Pottecher, Julien; Bauer, Michael; Godet, Thomas; Karakas, Mahir; Helms, Julie; Bergmann, Andreas; Zimmermann, Jens; Richter, Kathleen; Hartmann, Oliver; Pars, Melanie; Mebazaa, Alexandre; AdrenOSS-2 study participants.
In: INTENS CARE MED, Vol. 47, No. 11, 11.2021, p. 1284-1294.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Safety and tolerability of non-neutralizing adrenomedullin antibody adrecizumab (HAM8101) in septic shock patients: the AdrenOSS-2 phase 2a biomarker-guided trial
AU - Laterre, Pierre-François
AU - Pickkers, Peter
AU - Marx, Gernot
AU - Wittebole, Xavier
AU - Meziani, Ferhat
AU - Dugernier, Thierry
AU - Huberlant, Vincent
AU - Schuerholz, Tobias
AU - François, Bruno
AU - Lascarrou, Jean-Baptiste
AU - Beishuizen, Albertus
AU - Oueslati, Haikel
AU - Contou, Damien
AU - Hoiting, Oscar
AU - Lacherade, Jean-Claude
AU - Chousterman, Benjamin
AU - Pottecher, Julien
AU - Bauer, Michael
AU - Godet, Thomas
AU - Karakas, Mahir
AU - Helms, Julie
AU - Bergmann, Andreas
AU - Zimmermann, Jens
AU - Richter, Kathleen
AU - Hartmann, Oliver
AU - Pars, Melanie
AU - Mebazaa, Alexandre
AU - AdrenOSS-2 study participants
PY - 2021/11
Y1 - 2021/11
N2 - PURPOSE: Investigate safety and tolerability of adrecizumab, a humanized monoclonal adrenomedullin antibody, in septic shock patients with high adrenomedullin.METHODS: Phase-2a, double-blind, randomized, placebo-controlled biomarker-guided trial with a single infusion of adrecizumab (2 or 4 mg/kg b.w.) compared to placebo. Patients with adrenomedullin above 70 pg/mL, < 12 h of vasopressor start for septic shock were eligible. Randomization was 1:1:2. Primary safety (90-day mortality, treatment emergent adverse events (TEAE)) and tolerability (drug interruption, hemodynamics) endpoints were recorded. Efficacy endpoints included the Sepsis Support Index (SSI, reflecting ventilator- and shock-free days alive), change in Sequential-related Organ Failure Assessment (SOFA) and 28-day mortality.RESULTS: 301 patients were enrolled (median time of 8.5 h after vasopressor start). Adrecizumab was well tolerated (one interruption, no hemodynamic alteration) with no differences in frequency and severity in TEAEs between treatment arms (TEAE of grade 3 or higher: 70.5% in the adrecizumab group and 71.1% in the placebo group) nor in 90-day mortality. Difference in change in SSI between adrecizumab and placebo was 0.72 (CI -1.93-0.49, p = 0.24). Among various secondary endpoints, delta SOFA score (defined as maximum versus minimum SOFA) was more pronounced in the adrecizumab combined group compared to placebo [difference at 0.76 (95% CI 0.18-1.35); p = 0.007]. 28-day mortality in the adrecizumab group was 23.9% and 27.7% in placebo with a hazard ratio of 0.84 (95% confidence interval 0.53-1.31, log-rank p = 0.44).CONCLUSIONS: Overall, we successfully completed a randomized trial evaluating selecting patients for enrolment who had a disease-related biomarker. There were no overt signals of harm with using two doses of the adrenomedullin antibody adrecizumab; however, further randomized controlled trials are required to confirm efficacy and safety of this agent in septic shock patients.
AB - PURPOSE: Investigate safety and tolerability of adrecizumab, a humanized monoclonal adrenomedullin antibody, in septic shock patients with high adrenomedullin.METHODS: Phase-2a, double-blind, randomized, placebo-controlled biomarker-guided trial with a single infusion of adrecizumab (2 or 4 mg/kg b.w.) compared to placebo. Patients with adrenomedullin above 70 pg/mL, < 12 h of vasopressor start for septic shock were eligible. Randomization was 1:1:2. Primary safety (90-day mortality, treatment emergent adverse events (TEAE)) and tolerability (drug interruption, hemodynamics) endpoints were recorded. Efficacy endpoints included the Sepsis Support Index (SSI, reflecting ventilator- and shock-free days alive), change in Sequential-related Organ Failure Assessment (SOFA) and 28-day mortality.RESULTS: 301 patients were enrolled (median time of 8.5 h after vasopressor start). Adrecizumab was well tolerated (one interruption, no hemodynamic alteration) with no differences in frequency and severity in TEAEs between treatment arms (TEAE of grade 3 or higher: 70.5% in the adrecizumab group and 71.1% in the placebo group) nor in 90-day mortality. Difference in change in SSI between adrecizumab and placebo was 0.72 (CI -1.93-0.49, p = 0.24). Among various secondary endpoints, delta SOFA score (defined as maximum versus minimum SOFA) was more pronounced in the adrecizumab combined group compared to placebo [difference at 0.76 (95% CI 0.18-1.35); p = 0.007]. 28-day mortality in the adrecizumab group was 23.9% and 27.7% in placebo with a hazard ratio of 0.84 (95% confidence interval 0.53-1.31, log-rank p = 0.44).CONCLUSIONS: Overall, we successfully completed a randomized trial evaluating selecting patients for enrolment who had a disease-related biomarker. There were no overt signals of harm with using two doses of the adrenomedullin antibody adrecizumab; however, further randomized controlled trials are required to confirm efficacy and safety of this agent in septic shock patients.
U2 - 10.1007/s00134-021-06537-5
DO - 10.1007/s00134-021-06537-5
M3 - SCORING: Journal article
C2 - 34605947
VL - 47
SP - 1284
EP - 1294
JO - INTENS CARE MED
JF - INTENS CARE MED
SN - 0342-4642
IS - 11
ER -
