Efficacy and Safety of Efepoetin Alfa Versus Darbepoetin Alfa in Anemia Management for Chronic Kidney Disease Patients on Dialysis: A Phase III Randomized Study
- Trial ID
- 2023-503634-50-00
- Protocol
- GX-E4-CKD-002
- Sponsor
- Genexine Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase III, randomized, investigator-blinded, active-controlled study is to evaluate the **efficacy** of **efepoetin alfa** compared to **darbepoetin alfa** in terms of **hemoglobin (Hb) level control** (non-inferiority) in patients with **anemia** due to **chronic kidney disease (CKD)** on **hemodialysis**. This is clinically relevant as maintaining appropriate Hb levels is crucial for managing anemia in CKD patients, potentially improving their quality of life and reducing the risk of cardiovascular complications.
Secondary objectives include:
- Comparing the change from baseline in Hb level over the maintenance period between treatment groups.
- Comparing the proportion of patients who maintained a mean Hb level of 10.0-12.0 g/dL over specified weeks between treatment groups.
- Comparing the proportion of patients with mean Hb ≥10.0 g/dL, averaged over specified weeks between treatment groups.
- Comparing safety between treatment groups.
- Evaluating the mean dose of efepoetin alfa used over the course of the study.
- Evaluating the proportion of patients requiring rescue therapy.
- Comparing the Quality of Life (QoL) in patients with CKD on hemodialysis between treatment groups.
- Evaluating immunogenicity (Anti-Drug Antibody [ADA]).
Participants
The clinical trial involves a total of **207 participants** diagnosed with **anemia in patients with chronic kidney disease on dialysis**. The study population comprises adult males and females aged 18 years and older. Participants are required to have a serum total vitamin B12 concentration at or above the lower limit of normal at screening. The trial includes individuals with stage 4 and 5 chronic kidney disease, as defined by an estimated glomerular filtration rate of 29 mL/min/1.73m² or less, who have been on adequate hemodialysis for a minimum of 12 weeks prior to the start of the study. Participants must be on stable doses of intravenous injections of erythropoiesis-stimulating agents for at least six weeks before the trial commences. The trial population was selected based on specific inclusion criteria, including a mean hemoglobin level between 9.0 g/dL and 12.0 g/dL, serum ferritin levels of at least 100 ng/mL, and transferrin saturation of 20% or higher at screening. Both male and female subjects are included, and the study acknowledges the inclusion of a vulnerable population. The selection process ensures that participants meet the necessary health and treatment stability requirements to evaluate the efficacy of efepoetin alfa compared to darbepoetin alfa in controlling hemoglobin levels.
Plans and Procedures
The clinical trial is a **Phase III**, randomized, investigator-blinded, active-controlled study designed to evaluate the efficacy and safety of **efepoetin alfa** compared to **darbepoetin alfa** in managing anemia in patients with chronic kidney disease on dialysis. The trial employs a randomized, double-blind methodology to ensure unbiased results. Participants will be randomly assigned to receive either efepoetin alfa or darbepoetin alfa, both administered as a solution for injection via intravenous injection. The trial is expected to last approximately 52 weeks, with participant involvement spanning the same duration.
The study will include several key visits: an initial screening visit, regular follow-up visits, and an end-of-study visit. During the screening visit, eligibility criteria will be assessed, including age, serum vitamin B12 levels, and stable doses of erythropoiesis-stimulating agents (ESA). Follow-up visits will occur at regular intervals to monitor hemoglobin levels, assess the need for rescue therapy, and evaluate the overall health status of the participants. The end-of-study visit will involve a final assessment of the primary and secondary endpoints, including the mean change in hemoglobin levels and the proportion of patients maintaining target hemoglobin levels.
Participants are expected to remain in the study for the full 52-week duration unless specific conditions necessitate early termination. These conditions may include adverse reactions to the study drug, withdrawal of consent, or any significant protocol deviations. The primary endpoint of the study is the mean change from baseline in hemoglobin levels averaged over weeks 20 to 28, without the use of rescue therapy. Secondary endpoints include the mean change in hemoglobin levels regardless of rescue therapy, the proportion of patients maintaining target hemoglobin levels, and the mean dose of the investigational product over the specified period.
Treatment
The clinical trial involves the administration of **efepoetin alfa**, marketed under the product name GX-E4, as the experimental medication. GX-E4 is provided as a **solution for injection** and is administered via **intravenous injection**. The dosage form is specified as milligrams per milliliter (mg/ml), with a maximum daily dose of 1 mg/ml and a total maximum dose of 52 mg/ml over a treatment period of 52 weeks. The administration schedule is designed to ensure consistent dosing throughout the trial duration. Participant compliance with the dosing regimen is monitored through regular assessments and documentation.
The comparator treatment in this study is **darbepoetin alfa**, commercially available as Aranesp in various dosages, including 20, 30, 60, and 100 micrograms, each provided as a **solution for injection in pre-filled syringes**. Darbepoetin alfa is also administered via **intravenous injection**. The dosing for Aranesp varies depending on the specific formulation, with maximum daily doses ranging from 0.01 mg/ml to 0.2 mg/ml and total maximum doses from 0.52 mg/ml to 10.4 mg/ml over the same 52-week treatment period. The administration of Aranesp is conducted in a manner consistent with standard clinical practice for managing anemia in patients with chronic kidney disease on dialysis.
Efficacy
The efficacy of **efepoetin alfa** in the treatment of anemia in patients with chronic kidney disease on dialysis will be assessed through a series of primary and secondary endpoints. The primary endpoint is the mean change from baseline in hemoglobin (Hb) levels, averaged over weeks 20 to 28, without the use of rescue therapy such as transfusions or any approved erythropoiesis-stimulating agents (ESAs) within six weeks prior to and during the eight-week evaluation period. The baseline value is defined as the mean of the last screening value and the Day 1 (Visit 2) value.
Secondary endpoints include the mean change from baseline in Hb levels averaged over weeks 20 to 28, regardless of rescue therapy, and the mean change in Hb levels over the maintenance period. Additionally, the proportion of patients maintaining Hb levels between 10.0-12.0 g/dL over weeks 20 to 28 and the maintenance period will be evaluated, irrespective of rescue therapy. The study will also assess the proportion of patients with mean Hb ≥ 10.0 g/dL over the same periods, the proportion of patients requiring rescue therapy, and the time to rescue therapy from the first dose of study treatment. Furthermore, the mean dose of the investigational product over weeks 20 to 28 and the maintenance period will be measured, along with changes in quality of life from Day 1, assessed through the 36-Item Health Survey 1.0 Questionnaire (Rand SF-36).
Inclusion and Exclusion Criteria
Inclusion Criteria
- Adult males and females ≥ 18 years old.
- Patient (or patient’s legally acceptable representative) has voluntarily signed and dated an informed consent form (ICF) approved by an Ethics Committee (EC) or institutional review board (IRB) after the nature of the study has been explained and the patient has had the opportunity to ask questions
- Patient with stage 4 and 5 CKD defined by estimated GFR (eGFR, ≤29 mL/min/1.73m2) on adequate HD for a minimum of 12 weeks prior to Day 1. *CKD staging will be based on the five-stage system for classification of CKD based on KDIGO guidelines.
- Hemodialysis patients with single-pool Kt/V ≥ 1.2 or urea reduction ratio ≥ 65%.
- Patients must be on stable doses of IV injections of ESA (including biosimilars) for at least 6 weeks prior to Day 1. Minimum ESA dose; ✓ Epoetin alfa, epoetin beta, and epoetin kappa: ≥1,500 U/week ✓ Darbepoetin alfa: ≥20 μg/week ✓Mircera®: ≥30 μg/2 weeks
- Mean of the 2 most recent local laboratory Hb screening values obtained at least 6 days apart must be 9.0 g/dL to 12.0 g/dL, inclusive, with a difference of ≤1.5 g/dL between the highest and the lowest value.
- Patients with serum ferritin ≥100 ng/mL at screening.
- Patients with transferrin saturation (TSAT) ≥20% at screening.
- Serum folate concentrations ≥lower limit of normal (LLN) at screening.
- Serum total vitamin B12 concentrations ≥LLN at screening.
Exclusion Criteria
- Active acute or chronic infection, or uncontrolled or symptomatic inflammatory disease other than glomerulonephritis that could impact erythropoiesis (e.g., systemic lupus erythematosus, rheumatoid arthritis, celiac disease), or a C-reactive protein level 40> mg/L (high sensitive C-reactive protein level > 10 mg/L).
- Received a blood transfusion (including RBC transfusion) within the 12 weeks prior to Screening, or blood transfusion is anticipated during the study period (excluding temporary blood transfusion given in case of blood loss due to accident or surgery).
- Immunosuppressive therapy (tacrolimus/cyclosporine, and other than corticosteroids for a chronic condition) within 12 weeks prior to Day 1.
- By history or current clinical evidence, patients with active acute hepatitis B virus (HBV) or hepatitis C virus (HCV) infection should be excluded. Routine screening for HBV, HCV, and human immunodeficiency virus (HIV) infection is not required in this protocol. Chronic HBV/HCV infection with liver function tests (LFT) >3 times of normal are excluded. Known HIV positive patients are excluded.
- History of alcohol or drug abuse within the past 2 years and inability to avoid consumption of more than >3 alcoholic beverages per day.
- Use of an investigational medication or treatment, participation in an investigational interventional study, or carryover effect of an investigational treatment expected during the study.
- Females of childbearing potential or males who are unable/unwilling to take adequate contraceptive precautions defined by the protocol for the duration of the study and for at least 4 months for male subjects and 7 months for female patients after the end of the study. Females with a positive pregnancy test result within 24 hours prior to study entry, are otherwise known to be pregnant, plan to become pregnant in the next 12 months or are currently breastfeeding.
- Patients who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or patients who are Sponsor or clinical research organization (CRO) employees directly involved in the conduct of the study.
- History or clinical evidence of cardiovascular, hematologic, hepatic, or any physical conditions that, in the opinion of the Investigator, would compromise participation in the study.
- Any of the following laboratory abnormalities at screening visit; • Alanine transaminase (ALT) >3 x upper limit of normal (ULN) • Aspartate aminotransferase (AST) >3 x ULN • Total bilirubin >1.5 x ULN
- Chronic congestive heart failure (New York Heart Association class III or IV).
- Known history of myelodysplastic syndrome, multiple myeloma, hereditary hematologic disease such as thalassemia, sickle cell anemia, pure red cell aplasia, or other known causes for anemia other than CKD, hemosiderosis, hemochromatosis, known coagulation disorder, or hypercoagulable condition.
- High risk for early withdrawal or interruption of the study (due to myocardial infarction, severe or unstable coronary artery disease, stroke, or severe liver disease) within the 12 weeks before Screening or during Screening.
- Uncontrolled hypertension defined as a sitting systolic blood pressure ≥170 mmHg and/or diastolic blood pressure ≥100 mmHg (measure BP in both arms, then the arm that gives the higher reading for subsequent readings).
- History of active malignancy except for cancers determined to be cured or in remission for ≥5 years, curatively resected basal cell or squamous cell skin cancers, or in situ cancer at any site.
- Patients with a history of overt gastrointestinal bleeding or any other bleeding episode associated with a fall in Hb of ≥1 g/dL within the last 8 weeks prior to Screening.
- Any medical condition (patients weighing over 150 kg) that, in the opinion of the Investigator, may pose a safety risk to a patient in this study, may confound efficacy or safety assessment, or may interfere with study participation.
- Any prior functioning organ transplant or a scheduled organ transplantation, or anephric state (one or both kidneys).
- Planned elective surgery that could lead to significant blood loss during the study period.
- Hypoalbuminemia (Serum albumin <2.5 g/dL) at Screening Visit.
- Androgen, deferoxamine, deferiprone, or deferasirox therapy within 12 weeks prior to Day 1.
- Life expectancy of <12 months.
- Cognitive or psychiatric condition rendering the patient unable to be cooperative with and complete study requirements.
- Hypersensitivity to any one of the investigational drugs or its excipients.
- Patients with very limited functional capacity for which a target Hb value of 12 g/dL may have a lower benefit/risk ratio.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Not Yet Recruiting | 05 Feb 2024 | 50 |
 Czechia | Not Yet Recruiting | 05 Feb 2024 | 30 |
 Hungary | Not Yet Recruiting | 05 Feb 2024 | 42 |
 Italy | Not Yet Recruiting | 05 Feb 2024 | 45 |
 Poland | Not Yet Recruiting | 05 Feb 2024 | 55 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
GX-E4 | Test | SOLUTION FOR INJECTION | INTRAVENOUS INJECTION | 1 | 52 | PRD10762829 |
GX-E4 | Test | SOLUTION FOR INJECTION | INTRAVENOUS INJECTION | 1 | 52 | PRD10762831 |
Aranesp 30 micrograms solution for injection in pre-filled syringe | Comparator | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | INTRAVENOUS INJECTION | 0.01 | 52 | PRD378846 |
Aranesp 60 micrograms solution for injection in pre-filled syringe | Comparator | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | INTRAVENOUS INJECTION | 0.2 | 52 | PRD373018 |
Aranesp 20 micrograms solution for injection in pre-filled syringe | Comparator | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | INTRAVENOUS INJECTION | 0.04 | 52 | PRD384843 |
GX-E4 | Test | SOLUTION FOR INJECTION | INTRAVENOUS INJECTION | 1 | 52 | PRD10762830 |
Aranesp 100 micrograms solution for injection in pre-filled syringe | Comparator | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | INTRAVENOUS INJECTION | 0.2 | 52 | PRD382263 |