1. Administrative Information
1.1. Title
Cytokine adsorption in patients with acute-on-chronic liver failure (CYTOHEP)—a single center, open-label, three-arm, randomized, controlled intervention trial
1.2. Trial registration
1.2.1. Trial registry name and trial identifier
ClinicalTrials.gov: NCT05019352
Deutsches Register Klinischer Studien (DRKS): DRKS00026082
1.2.2. Synopsis/World Health Organization Trial Registration Data Set
Data category	Information
Primary registry and trial identifying number	ClinicalTrials.gov: NCT05019352
Date of registration in primary registry	August 24, 2021
Secondary identifying numbers	DRKS00026082
Source(s) of monetary of material support	University of Freiburg, Medical Center, Department of Medicine III, Intensive Care Medicine, Faculty of Medicine, University of Freiburg
Primary sponsor	University of Freiburg, Medical Center, Department of Medicine III - Intensive Care Medicine
Secondary sponsor(s)	None
Contact for public queries	University of Freiburg
Dr. Alexander Supady, MPH	Medical Center Department of Medicine III - Intensive Care Medicine Hugstetter Str. 55 79106 Freiburg Germany Tel.: +49 761 270-73790 Fax: +49 761 270-73792 E-mail: alexander.supady@uniklinik-freiburg.de
Contact for scientific queries Dr. Alexander Supady, MPH	University of Freiburg Medical Center Department of Medicine III - Intensive Care Medicine Hugstetter Str. 55 79106 Freiburg Germany Tel.: +49 761 270-73790 Fax: +49 761 270-73792 E-mail: alexander.supady@uniklinik-freiburg.de
Public title	Cyctokine adsorption in acute-on-chronic liver failure (CYTOHEP trial)
Scientific title	Cytokine adsorption in patients with acute-on chronic liver failure (CYTOHEP) – a single center, open-label, three-arm, randomized, controlled intervention trial
Countries of recruitment	Germany
Health condition(s) or problem(s) studied	Liver cirrhosis; acute-on-chronic liver failure (ACLF)
Intervention(s)	Active comparator: continuous renal replacement therapy with cytokine adsorption for 72 h control comparator: continuous renal replacement therapy without cytokine adsorption control comparator: no continuous renal replacement therapy and no cytokine adsorption
Key inclusion and exclusion	Inclusion criteria • Adult patients (≥ 18 years) admitted to the University Medical Center Freiburg, Germany • Acute-on-chronic liver failure (ACLF) [1] WITH o Acute kidney injury according to Kidney Disease: Improving Global Outcome (KDIGO) criteria stage 3 (≥ 3-fold increase of serum creatine OR increase of serum creatine ≥ 4 mg/dl OR urine output ≤ 0.3 ml/kg/h for ≥ 24 h OR anuria for ≥ 12 h) AND o Serum bilirubin ≥ 5 mg/dl Exclusion criteria • Known patient will against participation in the study or against the measures applied in the study • A decision made prior to inclusion to stop further treatment of the patient within the next 24 h • No complete remission of malignancy including hepatocellular carcinoma within the past 12 months • Patients on the waiting list for liver transplant or the potential option for being listed for liver transplant within the next 6 months • Liver cirrhosis in patients after liver transplantation • Ongoing intermittent or continuous renal replacement therapy before study inclusion All patients that fulfill all inclusion criteria and none of the exclusion criteria, will be considered provisionally eligible. In a subsequent assessment it will be ascertained whether the most responsible clinician(s) (the attending critical care physician and where relevant, the attending nephrologist) are in a position of clinical equipoise with respect to the two renal-replacement therapy initiation strategies that the provisionally eligible patient would receive if he/she was randomized. This will be performed in practice by ascertaining the presence of the following two exclusion criteria: • Clinician(s) caring for the patient believe that immediate renal-replacement therapy is mandated. After fulfilling the above inclusion/exclusion criteria, the study team has to speak to the ICU and/or nephrology attending physician and ask if he/she agrees with the statement: “Renal-replacement therapy must be initiated immediately for this patient.” If the answer is “Yes”, the patient will be excluded but could be re-screened for eligibility, if applicable. • Clinician(s) caring for the patient believe that deferral of renal-replacement therapy is mandated. After fulfilling the above inclusion/exclusion criteria, the study team has to speak to the ICU and/or nephrology attending physician and ask if he/she agrees with the statement: “Renal-replacement therapy must be deferred for this patient.” If the answer is “Yes”, the patient will be excluded, but could be re-screened for eligibility. When on both questions above it will be replied “No” by all of the relevant clinicians, the respective patient will be considered fully eligible for study participation.
Study type	Interventional Allocation: randomized; Intervention model: parallel assignment; Masking: open-label Primary purpose: treatment of severe acute-on-chronic liver failure Post-approval/pivotal study
Date of first enrollment	December 12, 2021
Target sample size	51
Recruitment status	Recruitment phase
Primary outcome(s)	Serum bilirubin reduction after 72 h
Key secondary outcomes	• Survival time (days) from baseline • Interleukin-6 after 72 h • Liver function parameters (72 h): Quick/INR, AST, ALT, AP, g-GT • Blood lactate (72 h) • Clinical scores: CLIF-SOFA-score, MELD score, SOFA score, SAPS II and FIPS score (72 h) • Ventilator free days (VeFD) in the first 30 days after randomization, where each day on invasive mechanical ventilation (IMV), non-invasive ventilation (NIV), or ECMO is defined as ventilator day. VeFD=0, if the patient dies in the first 30 days after randomization • Vasopressor free days (VaFD) in the first 30 days after randomization, where each day with any dose of epinephrine, norepinephrine, dobutamine, argipressin or terlipressin is defined as vasopressor day. VaFD=0, if the patient dies in the first 30 days after randomization • Dialysis free days (DFD) in the first 30 days after randomization, where each day on renal replacement therapy (RRT) is defined as dialysis day. DFD=0 if the patient dies in the first 30 days after randomization • A biomarker panel of pro- and anti-inflammatory cytokines (blood samples will be frozen and stored for later analyses, panel will be determined at the time of analysis)
1.3. Protocol version
Version 1.3, 27.01.2022 Revision chronology:
	• Version 1.0; submitted to IRB for approval (02.07.2021); revision requested by IRB (05.08.2021) • Version 1.1; revised version, considering previous request by IRB (09.08.2021); IRB approval (17.08.2021) • Version 1.2.; amendment submitted to IRB (04.10.2021); addition of trial registration information, specification of randomization tool; IRB approval (19.10.2021)
1.4. Trial status Recruitment phase. Recruiting started December 12, 2021. Estimated trial completion by December 31, 2023. 1.5. Protocol reporting guidelines This clinical trial protocol is following SPIRIT reporting guidelines (see checklist in the supplement) [1]. 1.6. Funding The study is financed by internal funds from the University of Freiburg Medical Center, Department of Medicine III - Intensive Care Medicine. A grant from the Faculty of Medicine, Freiburg University within the funding program for clinical trials will be applied for. 1.7. Roles and responsibilities ASe, ASu and DB designed the trial and wrote the first draft of the study protocol. EW and EG performed the sample size estimation and set up and wrote the statistical analysis plan. EP advised for specifics related to renal replacement therapy. EP and TW revised the manuscript and added important content. All co-authors reviewed and approved the final version of the manuscript. 1.7.1. Sponsor-investigator/Principal Investigator Dr. Alexander Supady, MPH University of Freiburg Medical Center Department of Medicine III - Intensive Care Medicine Hugstetter Str. 55 79106 Freiburg Germany Tel.: +49 761 270-73790 Fax: +49 761 270-73792 E-mail: alexander.supady@uniklinik-freiburg.de 1.7.2. Co-Principal Investigator PD Dr. Dominik Bettinger University of Freiburg Medical Center Department of Medicine II Hugstetter Str. 55 79106 Freiburg Germany Tel.: +49 761 270-34010 or -32440 E-mail: dominik.bettinger@uniklinik-freiburg.de 1.7.3. Co-Principal Investigator Dr. Asieb Sekandarzad University of Freiburg Medical Center Department of Medicine III - Intensive Care Medicine Hugstetter Str. 55 79106 Freiburg Germany Tel.: +49 761 270-33322 E-mail: asieb.sekandarzad@uniklinik-freiburg.de 1.7.4. Cooperating investigator Dr. Eric Peter Prager University of Freiburg Medical Center Department of Medicine IV Hugstetter Str. 55 79106 Freiburg Germany Tel.: +49 761 270-34140 E-mail: eric.peter.prager@uniklinik-freiburg.de 1.7.5. Trial statistician Dr. Erika Graf University of Freiburg Institute of Medical Biometry and Statistics (IMBI) Stefan-Meier-Straße 26 79104 Freiburg Germany Tel.: +49 761 270-83743 E-mail: erika.graf@uniklinik-freiburg.de 1.7.6. Role of study sponsor and funders The study will be financed from internal funds from the University of Freiburg, Medical Center, Department of Medicine III - Intensive Care Medicine and the University of Freiburg Faculty of Medicine. The sponsor-investigator/principal investigator is an employee of University of Freiburg Medical Center. The sponsor-investigator/principal investigator is independently responsible for collection, management, analysis, and interpretation of data, writing of the report(s) and the decision to submit the report for publication.