Supplementary document5 (TIF 567 KB) 134_2021_6537_MOESM5_ESM.tif (567K) GUID:?E147E970-536F-40B9-9F4E-5E4388EB5079 Supplement Shape Raltitrexed (Tomudex) 5: Kaplan-Meier storyline for 28-day time mortality PP inhabitants (n=294). PP. For every ideal period stage the utmost amount of individuals with available SOFA rating data was used. *P 0.05 for 24h change. Supplementary document4 (TIF 651 KB) 134_2021_6537_MOESM4_ESM.tif (651K) GUID:?2A72D0FB-C061-4091-8BE3-7BA0A215DBF0 Supplement Figure 4: Effectiveness endpoints in the PP population – Hazard Ratios (HR). HR with 95%-CI for 28-day time mortality (n=294). Mixed=both dosages of Adrecizumab + the placebo group as control; 2 mg/kg=treatment arm with 2 mg/kg Adrecizumab + the placebo group as control; 4 mg/kg=treatment arm with 4 mg/kg Adrecizumab + the placebo group as control. The entire HRs for the various groups are shown unadjusted (unadj.). Treatment results were modified for initial intensity: baseline bio-ADM (bio-ADM adj.); pre-IMP SOFA score previous Adrecizumab administration (score; Couch adj.) C to be able to eliminate baseline differences influencing the noticed mortality reduction. Supplementary file5 (TIF 567 KB) 134_2021_6537_MOESM5_ESM.tif (567K) GUID:?E147E970-536F-40B9-9F4E-5E4388EB5079 Supplement Figure 5: Kaplan-Meier plot for 28-day mortality PP population (n=294). A) Adrecizumab combined and placebo and B) for each treatment arm separately. 0.857 HR and 0.699 HR, log-rank p=0.152 and Raltitrexed (Tomudex) 0.195 comparing placebo to 2mg and 4mg, respectively. Supplementary file6 (TIF 573 KB) 134_2021_6537_MOESM6_ESM.tif (573K) GUID:?EEA60FC1-6D57-4655-ACD3-911B0DF7CA74 Supplement Figure 6: Post-hoc sensitivity analysis for SOFA score change. SOFA score change (points) starting prior Adrecizumab administration (pre-IMP) (mean with 95% CI) for ITT (n=254 with pre-IMP SOFA score available). For each time point the maximum number of patients with available SOFA score data was used. All time points show the same directionality. As the number SCNN1A of missing patients differed between time-points, two kinds of sensitivity analysis were performed post hoc: A) the data set was limited to patients with valid SOFA score data up to 96h (n=196 for change up to 96h); B) the last observed value was used for all time points with missing data (n=254 for all time points). Both sensitivity analysis showed greater or equal benefits for Adrecizumab than the result based on all available data points. Supplementary file7 (DOCX 156 KB) 134_2021_6537_MOESM7_ESM.docx (156K) GUID:?1416F479-D4BE-4D02-96C8-592CDF64C255 Supplement Figure 7: Histograms of SOFA score change for each timepoint and by treatment arm. Supplementary file8 (DOCX 168 KB) 134_2021_6537_MOESM8_ESM.docx (168K) GUID:?6E01ABAF-88A3-4D3D-A525-644BCEC7B745 Supplementary file9 (DOCX 17 KB) 134_2021_6537_MOESM9_ESM.docx (17K) GUID:?A0D4ADBA-4DB8-42C7-9209-855D213D4737 Supplementary file10 (DOCX 14 KB) 134_2021_6537_MOESM10_ESM.docx (14K) GUID:?19C36EB4-BBB1-41B5-A39C-5DD41DC32965 Supplementary file11 (DOCX 19 KB) 134_2021_6537_MOESM11_ESM.docx (19K) GUID:?87AD1E71-C85A-43C8-9394-B8DEE2C27495 Supplementary file12 (DOCX 28 KB) 134_2021_6537_MOESM12_ESM.docx (27K) GUID:?AF5F81EE-5983-4A5E-B21B-4D99031DC04D Supplementary file13 (DOCX 27 KB) 134_2021_6537_MOESM13_ESM.docx (26K) GUID:?D7135BBC-2F8E-4069-87BC-C61604EDA626 Supplementary file14 (DOCX 14 KB) 134_2021_6537_MOESM14_ESM.docx (14K) GUID:?D3DD889C-2472-4846-B1DA-042408B96A7A Supplementary file15 (DOCX 146 KB) 134_2021_6537_MOESM15_ESM.docx (146K) GUID:?F69C7319-581C-4A4E-84FF-0B2CE59A8EE9 Supplementary file16 (DOCX 142 KB) 134_2021_6537_MOESM16_ESM.docx (142K) GUID:?09595057-5E39-4519-8D8C-5FB96468E938 Abstract Purpose Investigate safety and tolerability of Raltitrexed (Tomudex) 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 ?1.93C0.49, values are 2-sided. values below 0.05 were considered significant. This phase 2 trial was not powered to prove clinical efficacy. No confirmative testing was considered, and as secondary outcome parameters were in part correlated, especially for variables evaluated at multiple time points, reported values were not corrected for multiple testing. The sample size calculation was based on simulation of real patient data, described in the method paper [17] and in the electronic supplementary material..