Efficacy and Safety of Darbepoetin Alfa in Reducing Intraoperative RBC Transfusion in Liver Transplant Candidates: A Randomized Clinical Trial

Trial ID: 2025-521701-41-00
Protocol: EPO_LT study
Sponsor: Fundacio De Recerca Clinic Barcelona-Institut D’Investigacions Biomediques August Pi I Sunyer

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Diseases & Conditions

Complications of transplanted liver

Objectives

The primary objective of this study is to evaluate the **efficacy** and **safety** of **darbepoetin** (DP) administration in patients on the liver transplant (LT) waiting list. The focus is on reducing intraoperative red blood cell concentrate transfusion. This is clinically relevant as it aims to minimize the need for blood transfusions during liver transplantation, which can reduce associated risks and improve patient outcomes.

Secondary objectives include:

Investigating the increase in **hemoglobin** levels at various intervals post-DP administration or at the time of liver transplantation between intervention and control groups.
Assessing the difference in the percentage of patients receiving intraoperative and early postoperative red blood cell concentrate transfusions between groups.
Evaluating the difference in the percentage of patients undergoing intraoperative massive transfusion between groups.
Comparing the incidence of severe postoperative complications between groups.
Analyzing the overall cost of transplantation from surgery to three months post-transplant between groups.
Evaluating differences in postoperative graft survival at 3, 6, and 12 months between groups.
Investigating differences in postoperative patient survival at 3, 6, and 12 months between groups.
Exploring the impact of DP treatment on the hemostatic profile of patients with chronic liver disease.
Exploring the impact of anemia on complications of portal hypertension and quality of life.
Identifying predictors of poor response to DP treatment.
Exploring the safety in both groups.

Participants

The clinical trial involves participants who are on the **liver transplant** waiting list, with a focus on both male and female subjects. The study population includes adults aged 18 years and older, with a specific requirement for a **hemoglobin** level of 11.5 g/dL or lower. Participants are required to be in generally stable health, as they are awaiting a liver transplant. The trial does not specifically target a vulnerable population. Women of childbearing potential must have a negative pregnancy test prior to inclusion and agree to use highly effective contraceptive methods, excluding hormonal options due to potential adverse effects on liver function. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. The selection criteria ensure that participants are officially listed for liver transplantation, aligning with the study's objective to assess the efficacy and safety of darbepoetin administration in reducing intraoperative red blood cell transfusion requirements.

Plans and Procedures

The clinical trial is designed to evaluate the **efficacy** and safety of **darbepoetin alfa** administration in patients on the liver transplant waiting list, aiming to reduce intraoperative red blood cell concentrate transfusion. This is a randomized, double-blind, controlled trial, with an estimated duration from October 2025 to December 2027. The trial will involve a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (≥18 years), being on the official liver transplant waiting list, and having a hemoglobin level ≤11.5 g/dL. Women of childbearing potential must have a negative pregnancy test and agree to use highly effective contraceptive methods during the study.

Participants will be randomly assigned to either the intervention group receiving **darbepoetin alfa** or a control group. The primary endpoint is the difference in the percentage of patients receiving intraoperative red blood cell transfusions between the two groups. Secondary endpoints include changes in hemoglobin levels, transfusion requirements, postoperative complications, and cost-effectiveness analysis. The trial will also assess graft and patient survival rates at 3, 6, and 12 months post-transplant, as well as the impact of treatment on the hemostatic profile and quality of life.

The study will include follow-up visits at 4, 8, 12, and 16 weeks after the administration of **darbepoetin alfa**, or at the time of liver transplantation, to monitor hemoglobin levels and other health parameters. The end-of-study visit will evaluate the overall outcomes and any adverse events. Participant involvement is expected to last up to 12 months, with conditions for early termination including significant adverse events or withdrawal of consent. The trial is categorized as a Phase 4 low-intervention trial, ensuring rigorous monitoring and adherence to ethical standards throughout its duration.

Treatment

The clinical trial involves the administration of **darbepoetin alfa**, an experimental medication, to patients on the liver transplant waiting list. **Darbepoetin alfa** is a **solution for injection** and is administered via the **subcutaneous** route. The dosing regimen for this trial specifies a maximum daily dose of **1.5 µg/kg** and a maximum total dose of **6.2 µg/kg** over a treatment period of up to **3 weeks**. The medication is produced using gene technology in hamster ovary cells, ensuring a high degree of purity and consistency in the protein-based formulation. The trial aims to assess the efficacy and safety of **darbepoetin alfa** in reducing the need for intraoperative red blood cell concentrate transfusion in liver transplant candidates.

In addition to the experimental treatment, the study may include standard-of-care therapies as deemed necessary by the clinical investigators. These therapies will be administered according to established medical guidelines and will serve as a baseline for evaluating the effects of **darbepoetin alfa**. Participant compliance with the dosing schedule will be closely monitored throughout the trial to ensure adherence to the protocol and to accurately assess the outcomes related to the experimental treatment.

Efficacy

The efficacy of **darbepoetin alfa** in patients on the liver transplant waiting list will be assessed through a series of primary and secondary endpoints. The primary endpoint is the difference in the percentage of patients receiving intraoperative red blood cell transfusions between the intervention group and the control group. Secondary endpoints include absolute differences from baseline in hemoglobin levels at various time points (4, 8, 12, or 16 weeks after administration of darbepoetin alfa, or at the time of liver transplantation), differences in the percentage of patients receiving intraoperative and early postoperative red blood cell transfusions, and differences in the percentage of patients receiving massive transfusions intraoperatively.

Additional secondary endpoints involve the assessment of severe postoperative complications using the Comprehensive Charlson Index, overall cost analysis of transplantation, and evaluation of graft and patient survival at 3, 6, and 12 months post-transplantation. The impact of darbepoetin alfa on the hemostatic profile will be evaluated by measuring changes in specific coagulation and fibrinolysis markers at baseline and 4 weeks post-administration. The trial will also explore the impact of anemia on portal hypertension complications and quality of life, as well as predictors of poor response to treatment. The proportion and severity of treatment-related adverse events will be monitored throughout the study period.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Age ≥ 18 years old
Patients on the oficial liver transplant waiting list
Hemoglobin (Hb) level ≤ 11.5 g/dL
Women of child-bearing potential* must have a negative pregnancy test in serum before the inclusion in the study and agree to use highly effective contraceptive methods during the study. Highly effective contraceptive methods will include: intrauterine device, bilateral tubal occlusion, vasectomized partner and sexual abstinence** (only if refraining from heterosexual intercourse during the period of twelve months).Hormonal contraceptive methods will be avoided due to the risk of adverse events and impairment of liver function. * A woman will be considered of childbearing potential, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as 0 menses for 12 months without an alternative medical cause. A high follicle stimulating hormone level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single follicle stimulating hormone measurement is insufficient. ** Sexual abstinence should only be used as a contraceptive method if it is in line with the subjects’ usual and preferred lifestyle. Periodic abstinence (calendar, symptothermal, postovulation methods) is not an acceptable method of contraception.

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Exclusion Criteria

Acute/subacute liver failure (see appendix 7)
Patients with acute-on-chronic liver failure grade III and/or MELD > 35
History of thrombosis, including portal vein thrombosis
Significant coronary artery disease (requiring angioplasty and/or coronary stent)
Serum ferritin > 800 ng/mL and SAT > 50%
Anticoagulant/antiplatelet therapy
History of seizures
Uncontrolled hypertension (requiring ≥2 antihypertensive drugs)
Active infection/sepsis (see appendix 8)
Lack of patient consent
Pregnancy or breastfeeding.
Patients included in other clinical trials in the month before inclusion.
Patients with mental incapacity, language barrier, bad social support or any other reason considered by the investigator precluding adequate understanding, cooperation or compliance in the study.