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The purpose of this study is to establish the effectiveness of the combined drug approach (anti-thrombin III, infliximab, apotransferrin, human recombinant erythropoietin beta, C1-inhibitor, glutathione, alfa-tocopherol, melatonin and epoprostenol)aimed to reduce ischemia-reperfusion injury during liver transplantation in eligible recipients.
This unicentric, investigator-driven, open-label randomized clinical trial with 2 parallel arms was conducted in Belgium from September 2013 through February 2018, with 1-year follow-up. Adults wait-listed for a first solitary full-size liver transplant were screened for eligibility. Exclusion criteria were acute liver failure, kidney failure, contraindication to treatment, participation in another trial, refusal, technical issues, and death while awaiting transplant. Included patients were enrolled and randomized at the time of liver offer. Data were analyzed from May 20, 2019, to May 27, 2020.
Participants were randomized to a combined drug approach with standard of care (static cold storage) or standard of care only (control group). In the combined drug approach group, following static cold preservation, donor livers were infused with epoprostenol (ex situ, portal vein); recipients were given oral α-tocopherol and melatonin prior to anesthesia and intravenous antithrombin III, infliximab, apotransferrin, recombinant erythropoietin-β, C1-inhibitor, and glutathione during the anhepatic and reperfusion phase.
The primary outcome was the posttransplant peak serum aspartate aminotransferase (AST) level within the first 72 hours. Secondary end points were the frequencies of postreperfusion syndrome, ischemia-reperfusion injury score, early allograft dysfunction, surgical complications, ischemic cholangiopathy, acute kidney injury, acute cellular rejection, and graft and patient survival.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| cases | Active Comparator | the group receives a combination of drugs |
|
| controls | Placebo Comparator | the group do not receive a combination of drugs, but a placebo (sodium chloride solution) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Antithrombin-III | Drug |
| ||
| Infliximab |
| Measure | Description | Time Frame |
|---|---|---|
| Peak Aspartate Aminotransferase Within First 72h Post Transplant | peak AST is defined as the highest value of serum AST within 72 hours following liver transplantation | within 72 hours following liver transplantation |
| Measure | Description | Time Frame |
|---|---|---|
| Graft Loss | graft loss at 3 and 12 months after liver transplantation | 3 and 12 months after liver transplantation |
| Recipient Death | recipient death at 3 and 12 months after liver transplantation |
| Measure | Description | Time Frame |
|---|---|---|
| Intensive Care Unit Length of Stay (Recipient) | Intensive Care Unit stay immediately after liver transplantation (not after rehospitalization) | During hospital stay for liver transplantation |
Inclusion Criteria:
Exclusion Criteria:
Patients who refuse to participate in the study.
History of hypersensitivity to one/several component(s) of the combined drug approach.
Conditions that prevent the use of the combined drug approach:
Mental conditions rendering the subject incapable to understand the nature, scope, and consequences of the trial.
Combined organ transplantation.
Re-transplantation.
Patients that are dialysis-dependent prior to the liver transplantation.
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| Name | Affiliation | Role |
|---|---|---|
| Diethard Monbaliu, MD, PhD | Abdominal transplant surgery - transplant coordination, Abdominal transplant surgery lab (microbiology & immunology Dpt) | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Hospitals Leuven | Leuven | 3000 | Belgium |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 19826248 | Background | Monbaliu D, Vekemans K, Hoekstra H, Vaahtera L, Libbrecht L, Derveaux K, Parkkinen J, Liu Q, Heedfeld V, Wylin T, Deckx H, Zeegers M, Balligand E, Buurman W, van Pelt J, Porte RJ, Pirenne J. Multifactorial biological modulation of warm ischemia reperfusion injury in liver transplantation from non-heart-beating donors eliminates primary nonfunction and reduces bile salt toxicity. Ann Surg. 2009 Nov;250(5):808-17. doi: 10.1097/SLA.0b013e3181bdd787. | |
| 21987442 |
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Of 143 enrolled participants, 93 were randomized.
Reasons for exclusion of enrolled participants was :
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| ID | Title | Description |
|---|---|---|
| FG000 | Combined Drug Approach | the group receives a combination of drugs Antithrombin-III Infliximab Apotransferrin Human recombinant erythropoietin C1-Inhibitor Glutathione Alfa-tocopherol Melatonin Epoprostenol |
| FG001 | Controles |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 8, 2016 |
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| Apotransferrin | Drug |
|
| Human recombinant erythropoietin | Drug |
|
| C1-Inhibitor | Drug |
|
| Glutathione | Drug |
|
| Alfa-tocopherol | Drug |
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| Melatonin | Drug |
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| Epoprostenol | Drug |
|
| Sodium chloride solution | Drug |
|
| 3 and 12 months after liver transplantation |
| Early Graft Dysfunction | early graft dysfunction as defined by Olthoff | within first 7 days |
| Number of Participants Developing Biliary Strictures | Biliary strictures are the narrowing of the intrahepatic or extrahepatic biliary ductal system. Here we report the number of participants developing biliary strictures within 12 months post transplantation by MRCP (magnetic resonance cholangiopancreatography) | within 12 months post transplantation |
| Ischemia Reperfusion Injury Score | Ischemia Reperfusion Injury score 1h post reperfusion by using the Suzuki score and Monbaliu et al. The score ranges from 0 (no injury) to 4 (severe injury). | One hour post reperfusion |
| Graft Rejection | a liver biopsy will be taken after transplantation and in case of clinical suspicion of acute rejection | till 1 year after transplantation |
| Patients With at Least 1 Severe Surgical Complications | The ranking of surgical complications will be done by using Clavien-Dindo classification Grade I Any deviation from the normal post-operative course not requiring surgical, endoscopic or radiological intervention. This includes the need for certain drugs (e.g. antiemetics, antipyretics, analgesics, diuretics and electrolytes), treatment with physiotherapy and wound infections that are opened at the bedside Grade II Complications requiring drug treatments other than those allowed for Grade I complications; this includes blood transfusion and total parenteral nutrition (TPN) Grade III Complications requiring surgical, endoscopic or radiological intervention Grade IV Life-threatening complications; this includes CNS complications (e.g. brain haemorrhage, ischaemic stroke, subarachnoid haemorrhage) which require intensive care, but excludes transient ischaemic attacks (TIAs) Grade V Death of the patient A severe surgical complication is defined as Grade III or higher. | within 1 year after liver transplantation |
| Non-anastomotic Biliary Stricture | Non-anastomotic biliary stricture at 1 year | 1 year |
| Acute Kidney Injury Score | An acute kidney injury score of 1 indicates risk; 2, injury; and 3, failure. According to RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) Minimum score is 0 meaning there is no injury, maximum score is 3 meaning failure of the organ. | 48h |
| Post-Reperfusion Syndrome | Post-reperfusion syndrome defined as a 30% decrease of mean systemic blood pressure for more than 1 minute during the first 5 minutes following graft reperfusion | first 5 minutes following graft reperfusion |
| Background |
| Vekemans K, Monbaliu D, Balligand E, Heedfeld V, Jochmans I, Pirenne J, van Pelt J. Improving the function of liver grafts exposed to warm ischemia by the Leuven drug protocol: exploring the molecular basis by microarray. Liver Transpl. 2012 Feb;18(2):206-18. doi: 10.1002/lt.22446. |
| 36853611 | Derived | Meurisse N, Mertens M, Fieuws S, Gilbo N, Jochmans I, Pirenne J, Monbaliu D. Effect of a Combined Drug Approach on the Severity of Ischemia-Reperfusion Injury During Liver Transplant: A Randomized Clinical Trial. JAMA Netw Open. 2023 Feb 1;6(2):e230819. doi: 10.1001/jamanetworkopen.2023.0819. |
the group do not receive a combination of drugs, but a placebo (sodium chloride solution)
Sodium chloride solution
| COMPLETED |
|
| NOT COMPLETED |
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|
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| ID | Title | Description |
|---|---|---|
| BG000 | Combined Drug Approach | the group receives a combination of drugs Antithrombin-III Infliximab Apotransferrin Human recombinant erythropoietin C1-Inhibitor Glutathione Alfa-tocopherol Melatonin Epoprostenol |
| BG001 | Controls | the group do not receive a combination of drugs, but a placebo (sodium chloride solution) Sodium chloride solution |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median | Inter-Quartile Range | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Race (NIH/OMB) | Race data were not collected from participants | Race data were not collected from participants | Count of Participants | Participants |
| ||||||||||||||
| Donor age | Median | Inter-Quartile Range | years |
| |||||||||||||||
| Donor type | Donation after Circulatory Death (DCD) refers to the retrieval of organs for the purpose of transplantation from patients whose death is diagnosed and confirmed using cardio-respiratory criteria. Donation after Brain Death (DBD) refers to retrieval of organs for the purpose of transplantation from patients whose death is diagnosed an confirmed using neurological criteria. | Count of Participants | Participants |
| |||||||||||||||
| Warm ischemia time if Donation after Circulatory Death | The time between withdrawal of mechanical ventilation and abdominal aorta cannulation with initiation of cold preservation | Only livers from Donation after Circulatory Death donors undergo (donor) warm ischemia. So this is only measured and reported in the DCD population (see donor type) | Median | Inter-Quartile Range | minutes |
| |||||||||||||
| Intensive Care Unit Length of stay (donor) | Median | Inter-Quartile Range | days |
| |||||||||||||||
| Donor cause of death | Count of Participants | Participants |
| ||||||||||||||||
| Type of preservation solution | Solutions used to preserve organs during storage and transport to the recipient | Count of Participants | Participants |
| |||||||||||||||
| Brain death duration | The duration of brain death is only measured in Donation after Brain Death donors (see Donor type) | Median | Inter-Quartile Range | hours |
| ||||||||||||||
| Donor hepatectomy duration | Median | Inter-Quartile Range | minutes |
| |||||||||||||||
| Cold ischemia time | Time from start of cold flush until the organ leaves the ice and is placed in the body of the recipient | Median | Inter-Quartile Range | hours |
| ||||||||||||||
| Model for End-Stage Liver Disease score (MELD) | Model for End-Stage Liver Disease score is a score based on bilirubin, creatinine and INR to calculate the severity of liver disease. The score ranges from 6 tot 40 and the higher the number the more likely you are to receive a liver from a deceased donor when an organ becomes available. | Median | Inter-Quartile Range | score on a scale |
| ||||||||||||||
| Indication for liver transplant | Patients can have multiple indications for transplantation | Number | participants |
| |||||||||||||||
| Implantation duration | Implantation duration is the time between the organ leaving the ice box and the restoration of the blood supply in the recipient. | Median | Inter-Quartile Range | Minutes |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Peak Aspartate Aminotransferase Within First 72h Post Transplant | peak AST is defined as the highest value of serum AST within 72 hours following liver transplantation | Posted | Geometric Mean | 95% Confidence Interval | U/L | within 72 hours following liver transplantation |
|
|
| |||||||||||||||||||||||||||||
| Secondary | Graft Loss | graft loss at 3 and 12 months after liver transplantation | Death-censored graft survival | Posted | Count of Participants | Participants | No | 3 and 12 months after liver transplantation |
|
| |||||||||||||||||||||||||||||
| Secondary | Recipient Death | recipient death at 3 and 12 months after liver transplantation | Posted | Count of Participants | Participants | No | 3 and 12 months after liver transplantation |
|
| ||||||||||||||||||||||||||||||
| Secondary | Early Graft Dysfunction | early graft dysfunction as defined by Olthoff | Posted | Count of Participants | Participants | No | within first 7 days |
|
| ||||||||||||||||||||||||||||||
| Secondary | Number of Participants Developing Biliary Strictures | Biliary strictures are the narrowing of the intrahepatic or extrahepatic biliary ductal system. Here we report the number of participants developing biliary strictures within 12 months post transplantation by MRCP (magnetic resonance cholangiopancreatography) | Posted | Count of Participants | Participants | No | within 12 months post transplantation |
|
| ||||||||||||||||||||||||||||||
| Secondary | Ischemia Reperfusion Injury Score | Ischemia Reperfusion Injury score 1h post reperfusion by using the Suzuki score and Monbaliu et al. The score ranges from 0 (no injury) to 4 (severe injury). | Posted | Median | Inter-Quartile Range | score | One hour post reperfusion |
|
| ||||||||||||||||||||||||||||||
| Secondary | Graft Rejection | a liver biopsy will be taken after transplantation and in case of clinical suspicion of acute rejection | Posted | Count of Participants | Participants | No | till 1 year after transplantation |
|
| ||||||||||||||||||||||||||||||
| Secondary | Patients With at Least 1 Severe Surgical Complications | The ranking of surgical complications will be done by using Clavien-Dindo classification Grade I Any deviation from the normal post-operative course not requiring surgical, endoscopic or radiological intervention. This includes the need for certain drugs (e.g. antiemetics, antipyretics, analgesics, diuretics and electrolytes), treatment with physiotherapy and wound infections that are opened at the bedside Grade II Complications requiring drug treatments other than those allowed for Grade I complications; this includes blood transfusion and total parenteral nutrition (TPN) Grade III Complications requiring surgical, endoscopic or radiological intervention Grade IV Life-threatening complications; this includes CNS complications (e.g. brain haemorrhage, ischaemic stroke, subarachnoid haemorrhage) which require intensive care, but excludes transient ischaemic attacks (TIAs) Grade V Death of the patient A severe surgical complication is defined as Grade III or higher. | Posted | Count of Participants | Participants | No | within 1 year after liver transplantation |
| |||||||||||||||||||||||||||||||
| Secondary | Non-anastomotic Biliary Stricture | Non-anastomotic biliary stricture at 1 year | Posted | Count of Participants | Participants | No | 1 year |
|
| ||||||||||||||||||||||||||||||
| Secondary | Acute Kidney Injury Score | An acute kidney injury score of 1 indicates risk; 2, injury; and 3, failure. According to RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) Minimum score is 0 meaning there is no injury, maximum score is 3 meaning failure of the organ. | Posted | Count of Participants | Participants | No | 48h |
|
| ||||||||||||||||||||||||||||||
| Secondary | Post-Reperfusion Syndrome | Post-reperfusion syndrome defined as a 30% decrease of mean systemic blood pressure for more than 1 minute during the first 5 minutes following graft reperfusion | Posted | Count of Participants | Participants | No | first 5 minutes following graft reperfusion |
|
| ||||||||||||||||||||||||||||||
| Other Pre-specified | Intensive Care Unit Length of Stay (Recipient) | Intensive Care Unit stay immediately after liver transplantation (not after rehospitalization) | Posted | Median | Inter-Quartile Range | Days | During hospital stay for liver transplantation |
|
|
Adverse events were collected over the time frame of 1 year starting immediately after transplantation
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Combined Drug Approach | the group receives a combination of drugs Antithrombin-III Infliximab Apotransferrin Human recombinant erythropoietin C1-Inhibitor Glutathione Alfa-tocopherol Melatonin Epoprostenol | 4 | 36 | 6 | 36 | 33 | 36 |
| EG001 | Controles | the group do not receive a combination of drugs, but a placebo (sodium chloride solution) Sodium chloride solution | 3 | 36 | 4 | 36 | 31 | 36 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| General surgical complications | Surgical and medical procedures | Systematic Assessment |
| ||
| Respiratory insufficiency | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
| ||
| Kidney dysfunction | Renal and urinary disorders | Systematic Assessment |
| ||
| Bacterial infection | Infections and infestations | Systematic Assessment |
| ||
| Arrythmia | Cardiac disorders | Systematic Assessment |
| ||
| Portal vein thrombosis | Surgical and medical procedures | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Post-operative delirium | General disorders | Systematic Assessment |
| ||
| Acute kidney injury | Renal and urinary disorders | Systematic Assessment |
| ||
| Respiratory failure post-op | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
| ||
| Urinary tract infections | Renal and urinary disorders | Systematic Assessment |
| ||
| De novo diabetes mellitus | Endocrine disorders | Systematic Assessment |
| ||
| Viral infections | Infections and infestations | Systematic Assessment |
| ||
| Bacterial infections | Infections and infestations | Systematic Assessment |
| ||
| Fungal infection | Infections and infestations | Systematic Assessment |
| ||
| Thrombo-embolitic complications | Blood and lymphatic system disorders | Systematic Assessment |
| ||
| Cardiovascular events | Cardiac disorders | Systematic Assessment |
| ||
| Cerebrovascular events | General disorders | Systematic Assessment |
| ||
| Organ specific complications | Hepatobiliary disorders | Systematic Assessment |
| ||
| Surgical complications - arterial | Injury, poisoning and procedural complications | Systematic Assessment |
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| Surgical complications portal | Injury, poisoning and procedural complications | Systematic Assessment |
| ||
| Surgical complications - general | Injury, poisoning and procedural complications | Systematic Assessment |
| ||
| Biliary problems | Hepatobiliary disorders | Systematic Assessment |
| ||
| Rejections | Immune system disorders | Systematic Assessment |
|
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Diethard Monbaliu | UZLeuven | +32 16 348727 | diethard.monbaliu@uzleuven.be |
| Mar 28, 2023 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D015427 | Reperfusion Injury |
| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D011183 | Postoperative Complications |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D000990 | Antithrombin III |
| D000069285 | Infliximab |
| C028284 | apotransferrin |
| D050718 | Complement C1 Inhibitor Protein |
| D005978 | Glutathione |
| D008550 | Melatonin |
| D011464 | Epoprostenol |
| D012965 | Sodium Chloride |
| ID | Term |
|---|---|
| D058833 | Antithrombin Proteins |
| D015843 | Serpins |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D000510 | Alpha-Globulins |
| D012712 | Serum Globulins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D005916 | Globulins |
| D019774 | Blood Coagulation Factor Inhibitors |
| D001685 | Biological Factors |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
| D007162 | Immunoproteins |
| D006023 | Glycoproteins |
| D006001 | Glycoconjugates |
| D002241 | Carbohydrates |
| D003174 | Complement C1 Inactivator Proteins |
| D003169 | Complement Inactivator Proteins |
| D003165 | Complement System Proteins |
| D009842 | Oligopeptides |
| D014363 | Tryptamines |
| D007211 | Indoles |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D044062 | Prostaglandins I |
| D011453 | Prostaglandins |
| D015777 | Eicosanoids |
| D005231 | Fatty Acids, Unsaturated |
| D005227 | Fatty Acids |
| D008055 | Lipids |
| D012898 | Autacoids |
| D018836 | Inflammation Mediators |
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017670 | Sodium Compounds |
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| HCC |
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| Chronic liver disease |
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| Ethyl |
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| Cholestatic disease |
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| Nonalcoholic Steatohepatitis |
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| Cryptogenic |
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