immune enhancement to prevent infected pancreatic necrosis a double blind randomized CORD-Papers-2021-10-25 (Version 1)

Title: Immune enhancement to prevent infected pancreatic necrosis: A double-blind randomized controlled trial
Abstract: BACKGROUND&AIMS Infected pancreatic necrosis (IPN) is a highly morbid complication of acute pancreatitis(AP). Since there is evidence of immunosuppression in the early phase of AP, immune enhancement using Thymosin alpha 1 (T1), which stimulates both innate and adaptive immunity, may be a therapeutic strategy to prevent IPN. Our aim was to assess the efficacy of early T1 treatment on the development of IPN. METHODS We conducted a multicenter, randomized, double-blind, placebo-controlled trial in patients with predicted severe acute necrotizing pancreatitis (ANP). ANP patients with an APACHE II score[]8 admitted within seven days of the advent of symptoms were considered eligible. Enrolled patients were assigned to receive a subcutaneous injection of T1 1.6 mg, every 12 hours for the first 7 days and 1.6 mg once a day for the subsequent 7 days or matching placebo (normal saline). The primary outcome was the development of IPN during the index admission. RESULTS From Mar 2017 through Dec 2020, 508 patients were randomized at 16 hospitals, of whom 254 were assigned to receive T1 and 254 placebo. During the index admission, 40/254 (15.7%) patients in the T1 group developed IPN compared with 46/254 patients (18.1%) in the placebo group (difference -2.4% [95%CI -7.4% to 5.0%]; p=0.47). The results were similar in four predefined subgroups. There was no difference in other major complications, including new-onset organ failure (10.6% vs. 15.0%; p=0.15), bleeding (6.3% vs. 3.5%; p=0.15), and gastrointestinal fistula (2.0% vs. 2.4%; p=0.75) during the index admission. CONCLUSIONS The immune-enhancing T1 treatment of patients with predicted severe ANP did not reduce the incidence of IPN during the index admission.
Published: 8/10/2021
DOI: 10.1101/2021.08.09.21261580
DOI_URL: http://doi.org/10.1101/2021.08.09.21261580
Author Name: Ke, L
Author link: https://covid19-data.nist.gov/pid/rest/local/author/ke_l
Author Name: Zhou, J
Author link: https://covid19-data.nist.gov/pid/rest/local/author/zhou_j
Author Name: Mao, W
Author link: https://covid19-data.nist.gov/pid/rest/local/author/mao_w
Author Name: Chen, T
Author link: https://covid19-data.nist.gov/pid/rest/local/author/chen_t
Author Name: Zhu, Y
Author link: https://covid19-data.nist.gov/pid/rest/local/author/zhu_y
Author Name: Pan, X
Author link: https://covid19-data.nist.gov/pid/rest/local/author/pan_x
Author Name: Mei, H
Author link: https://covid19-data.nist.gov/pid/rest/local/author/mei_h
Author Name: Singh, V
Author link: https://covid19-data.nist.gov/pid/rest/local/author/singh_v
Author Name: Buxbaum, J
Author link: https://covid19-data.nist.gov/pid/rest/local/author/buxbaum_j
Author Name: Doig, G
Author link: https://covid19-data.nist.gov/pid/rest/local/author/doig_g
Author Name: He, C
Author link: https://covid19-data.nist.gov/pid/rest/local/author/he_c
Author Name: Gu, W
Author link: https://covid19-data.nist.gov/pid/rest/local/author/gu_w
Author Name: Lu, W
Author link: https://covid19-data.nist.gov/pid/rest/local/author/lu_w
Author Name: Tu, S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/tu_s
Author Name: Ni, H
Author link: https://covid19-data.nist.gov/pid/rest/local/author/ni_h
Author Name: Zhang, G
Author link: https://covid19-data.nist.gov/pid/rest/local/author/zhang_g
Author Name: Zhao, X
Author link: https://covid19-data.nist.gov/pid/rest/local/author/zhao_x
Author Name: Sun, J
Author link: https://covid19-data.nist.gov/pid/rest/local/author/sun_j
Author Name: Chen, W
Author link: https://covid19-data.nist.gov/pid/rest/local/author/chen_w
Author Name: Song, J
Author link: https://covid19-data.nist.gov/pid/rest/local/author/song_j
Author Name: Shao, M
Author link: https://covid19-data.nist.gov/pid/rest/local/author/shao_m
Author Name: Tu, J
Author link: https://covid19-data.nist.gov/pid/rest/local/author/tu_j
Author Name: Xia, L
Author link: https://covid19-data.nist.gov/pid/rest/local/author/xia_l
Author Name: He, W
Author link: https://covid19-data.nist.gov/pid/rest/local/author/he_w
Author Name: Zhu, Q
Author link: https://covid19-data.nist.gov/pid/rest/local/author/zhu_q
Author Name: Li, K
Author link: https://covid19-data.nist.gov/pid/rest/local/author/li_k
Author Name: Yao, H
Author link: https://covid19-data.nist.gov/pid/rest/local/author/yao_h
Author Name: Wu, J
Author link: https://covid19-data.nist.gov/pid/rest/local/author/wu_j
Author Name: Fu, L
Author link: https://covid19-data.nist.gov/pid/rest/local/author/fu_l
Author Name: Wendi, J
Author link: https://covid19-data.nist.gov/pid/rest/local/author/wendi_j
Author Name: He, Z
Author link: https://covid19-data.nist.gov/pid/rest/local/author/he_z
Author Name: Lin, J
Author link: https://covid19-data.nist.gov/pid/rest/local/author/lin_j
Author Name: Li, B
Author link: https://covid19-data.nist.gov/pid/rest/local/author/li_b
Author Name: Zhihui, T
Author link: https://covid19-data.nist.gov/pid/rest/local/author/zhihui_t
Author Name: Windsor, J
Author link: https://covid19-data.nist.gov/pid/rest/local/author/windsor_j
Author Name: Liu, Y
Author link: https://covid19-data.nist.gov/pid/rest/local/author/liu_y
Author Name: Li, W
Author link: https://covid19-data.nist.gov/pid/rest/local/author/li_w
Author Name: Acute, Chinese
Author link: https://covid19-data.nist.gov/pid/rest/local/author/acute_chinese
sha: 8da0d63c56e5662ef3ed95b72f31d103992bae84
license: medrxiv
source_x: MedRxiv
url: http://medrxiv.org/cgi/content/short/2021.08.09.21261580v1?rss=1
has_full_text: TRUE
Keywords Extracted from Text Content: organ IPN saline pancreatic gastrointestinal NCT02473406 acute pancreatitis Tα1 ANP patients patients Thymosin alpha 1 ANP AP c e midway e v e r e o r g B o l l e n T L cardiovascular c u t e p Province organ AP APACHE II ≥ 8 c r e v i e w Chengdu Tongde Pharmaceutical Co. pancreatic fistula e d enteral venous Tα1 AP 2 COVID-19 Figure3 thymus NCT02473406 pancreas saline AP 11-14 C-reactive Thymosin alpha 1 C l renal biliary https://doi.org/10.1101/2021.08.09.21261580 doi C R P d e n o t e C -r e ANP monocyte human leukocyte antigen-DR Patients B IPN 17 Wuxi, China https://doi.org/10.1101 https://doi.org/10 AP 13 c r e pancreatic necrosis ( P=0.742 left mHLA-DR patients CRP c m gastrointestinal IPN e v c u t e p line pancreatic v e n i s participants c o r e e r blood cultures c t i v lymphocyte c r fine-needle octreotide blood medRxiv medRxiv preprint 0 medRxiv preprint e v e r e d i s c d i s e lymphatic abdominal c e t G gastrointestinal tract human AP lung SciClone c i d e n acute pancreatitis c o capctg.medbit.cn
Extracted Text Content in Record: First 5000 Characters:Infected pancreatic necrosis (IPN) is a highly morbid complication of acute pancreatitis (AP). Since there is evidence of immunosuppression in the early phase of AP, immune enhancement using Thymosin alpha 1 (Tα1), which stimulates both innate and adaptive immunity, may be a therapeutic strategy to prevent IPN. Our aim was to assess the efficacy of early Tα1 treatment on the development of IPN. We conducted a multicenter, randomized, double-blind, placebo-controlled trial in patients with predicted severe acute necrotizing pancreatitis (ANP). ANP patients with an APACHE II score≥8 admitted within seven days of the advent of symptoms were considered eligible. Enrolled patients were assigned to receive a subcutaneous injection of Tα1 1.6 mg, every 12 hours for the first 7 days and 1.6 mg once a day for the subsequent 7 days or matching placebo (normal saline). The primary outcome was the development of IPN during the index admission. RESULTS Mar 2017 through Dec 2020, 508 patients were randomized at 16 hospitals, of whom 254 were assigned to receive Tα1 and 254 placebo. During the index admission, 40/254 (15.7%) patients in the Tα1 group developed IPN compared with 46/254 patients (18.1%) in the placebo group (difference -2.4% [95%CI -7.4% to 5.0%]; p=0.47). The results were similar in four predefined subgroups. There was no difference in other major complications, including new-onset organ failure (10.6% vs. 15.0%; p=0.15), bleeding (6.3% vs. 3.5%; p=0.15), and gastrointestinal fistula (2.0% vs. 2.4%; p=0.75) during the index admission. The immune-enhancing Tα1 treatment of patients with predicted severe ANP did not reduce the incidence of IPN during the index admission. Clinicaltrials.gov registry: NCT02473406. The annual global incidence of acute pancreatitis (AP) is estimated to be 34 per 100,000 individuals 1 . A smaller subgroup of patients with AP(5-10%) develop acute necrotizing pancreatitis (ANP) 2 and can experience a more prolonged disease course and increased morbidity and mortality, especially if infected pancreatic necrosis (IPN) develops 3, 4 . The bacteria responsible for IPN are often translocated from the gastrointestinal tract and reach the pancreas through several different transmission routes, including hematogenous, lymphatic, and transcoelomic 5, 6 . Attempts to reduce the risk of infection in ANP have included the use of prophylactic antibiotics 7 and enteral probiotics 8 . The former is no longer recommended because of issues like antibiotic resistance, methodological quality in previous studies, and fungal superinfection 9, 10 . The latter is controversial, as a prominent randomized controlled trial found an increased risk of gastrointestinal necrosis associated with probiotic treatment 8 . Given that there is evidence of immunosuppression in the early phase of AP 11-14 , a theoretical strategy to reduce the risk of IPN is to boost the host defense (immune enhancement) against bacterial infection 15 . Thymosin alpha 1 (Tα1), a polypeptide hormone isolated from the thymus, stimulates both innate and adaptive immunity 16 . In a pilot study of patients with AP, Tα1was effective in reducing the risk of developing IPN 17 . Based on this preliminary data, we conducted a multicenter randomized clinical trial to determine the efficacy of early Tα1 treatment on the development of IPN. This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial to assess the efficacy of Tα1 in addition to standard care on the development of IPN in patients with predicted severe ANP. The trial was approved by the local hospital ethics committees of all the participating sites and registered on the ClinicalTrials.gov Registry (NCT02473406) before enrollment commenced. The trial All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 10, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 protocol was published in 2020 18 . This study was funded by the Science and Technology Project of Jiangsu Province of China (no. SBE2016750187) and partly supported by SciClone Pharmaceuticals Holding Limited, which provided trial drugs and support for meetings during the study period. The funders were not involved in the trial's design, data collection, interpretation, or manuscript preparation. Patients diagnosed with AP aged 18 to 70 years and with an APACHE II score≥8 and CT severity score 19 ≥ 5 admitted to any of the participating sites within seven days of the onset of abdominal pain were eligible for inclusion. The diagnosis of AP was based on the Revised Atlanta Classification (RAC) criteria 2 . Patients were excluded if they were pregnant, had a history of chronic pancreatitis, had underlying malignancy, received treatment for pancreatic necrosis prior to enrollment, had a known his
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