Combination Therapy of Romiplostim and Erythropoiesis-stimulating Agents

Background and Rationale Anemia is a common complication of chronic kidney disease (CKD) and is associated with increased mortality and reduced quality of life. Erythropoiesis-stimulating agents (ESAs) have greatly reduced transfusion needs, but up to 20% of patients with CKD anemia are ESA-resistant or ESA-hyporesponsive. ESA resistance is clinically important because it is associated with higher risks of death and cardiovascular events. Treatment options for ESA-resistant anemia remain limited, and many patients eventually require recurrent transfusions. Preclinical studies by our group and others suggest that intensive ESA treatment can deplete early erythroid progenitor cells, contributing to ESA resistance. Thrombopoietin receptor agonists (TPO-RAs), such as romiplostim, can stimulate the expansion of hematopoietic stem cells and early erythroid progenitors, potentially correcting ESA-induced progenitor depletion. Because megakaryocytic and erythroid lineages share a common megakaryocyte-erythroid progenitor (MEP), concomitant ESA therapy may preferentially recruit MEPs into the erythroid lineage and indirectly inhibit platelet production through stem cell competition. This provides a mechanistic rationale for combining a TPO-RA with an ESA to treat ESA-resistant anemia while limiting the risk of thrombocytosis. This Phase 2 study is designed to evaluate the safety and tolerability of adding romiplostim to ongoing ESA therapy in patients with CKD and ESA-resistant anemia. The current protocol focuses on the safety and dose-escalation portion of the study; a planned efficacy evaluation was removed in the current version. Study Design This is a single-center, open-label, Phase 2 dose-escalation trial conducted at the Division of Nephrology, Prince of Wales Hospital, The Chinese University of Hong Kong. The study uses sequential cohorts of four participants each, with a total of 12 participants planned. Romiplostim is administered by subcutaneous injection once weekly for three consecutive weeks at one of three dose levels: 0.2 mg/kg, 0.5 mg/kg, or 1 mg/kg. The 1 mg/kg once-weekly dose is the approved starting dose for immune thrombocytopenic purpura (ITP); lower doses are included because patients with anemia may have higher baseline platelet counts and potentially stronger platelet responses than patients with ITP. The study is open-label, and all participants receive active romiplostim as an add-on to their existing ESA therapy. There is no placebo or control group. No formal interim analysis is planned. Safety oversight is provided by an independent Data and Safety Monitoring Board (DSMB), which reviews serious adverse events, thrombotic events, and bleeding events. Participants and Intervention Participants are adults with CKD receiving chronic hemodialysis who have anemia resistant to ESAs. Only hemodialysis patients are enrolled because the protocol requires relatively frequent blood sampling to monitor platelet responses, which is more feasible in this population than in pre-dialysis patients. All participants continue their pre-study ESA, either darbepoetin alfa or Mircera, together with iron supplementation. ESA doses are initially unchanged. If hemoglobin rises too rapidly, for example by more than 1 g/dL over 2 weeks, ESA dose reduction may be performed according to product labels. Romiplostim is given as three weekly subcutaneous injections. After the 3-week romiplostim dosing period, participants continue their ESA therapy and are monitored through Week 24, with a safety follow-up visit approximately 4 weeks after the End-of-Treatment visit. Assessments and Safety Monitoring Safety is the primary focus of this study. Participants undergo frequent monitoring of platelet counts, hemoglobin, and other hematologic parameters. In the initial weeks, blood sampling is performed weekly; later monitoring occurs every 4 weeks. Safety assessments include adverse event (AE) and serious adverse event (SAE) reporting, clinical laboratory tests, electrocardiograms, vital signs, and physical examinations. Laboratory tests include complete blood counts, liver function tests, renal function tests, and electrolytes. AEs are assessed for severity and relationship to study intervention. SAEs must be reported to the sponsor within 24 hours of investigator awareness. Events of special interest include overdose, suspected abuse or misuse, medication errors, and inadvertent or accidental exposure. Pregnancy is monitored; women of childbearing potential must have negative pregnancy tests and use acceptable contraception during the study. The DSMB reviews safety data at regular intervals, including at least semiannually, and provides recommendations regarding study continuation or modification. Pharmacokinetic/Pharmacodynamic and Biomarker Strategy Blood samples for pharmacokinetic (PK) and pharmacodynamic (PD) analyses are collected together with hematology samples when possible. Biomarkers include erythroferrone (ERFE), hepcidin, ferritin, transferrin, transferrin saturation, total iron, reticulocyte count, mean corpuscular volume, mean corpuscular hemoglobin, hematocrit, and red blood cell count. The PK and PD data will be combined to develop a mechanism-based PK-PD model. Model-based simulations will then be performed to explore optimal dosing regimens and titration strategies for romiplostim combined with ESAs. This in silico approach has previously been used to inform romiplostim dosing in patients with ITP. Statistical Considerations The sample size of 12 participants is considered adequate to characterize the safety of romiplostim in this setting, given that the clinical safety of romiplostim has been previously demonstrated. No formal efficacy hypothesis testing is planned. Descriptive statistics will be used to summarize demographic, baseline, safety, and laboratory variables. Continuous variables will be summarized using mean, median, standard deviation, minimum, and maximum; categorical variables will be summarized using counts and percentages. Time-to-event measures, such as time to platelet counts above the normal range, will be analyzed using Kaplan-Meier methods. AEs will be summarized by treatment dose, severity, and relationship to study intervention. PK and PD data will be summarized by dose and time point, and PK/PD modeling will be conducted. Exploratory analyses will evaluate changes in erythroid response and iron-status biomarkers. Regulatory and Ethical Oversight The trial will be conducted in accordance with the Declaration of Helsinki, International Council for Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements. The protocol, informed consent forms, and other participant materials will be approved by the Institutional Review Board before study initiation. Participation is voluntary, and participants may withdraw at any time without affecting their medical care. Data will be recorded in case report forms and source documents, monitored for quality and compliance, and kept confidential according to institutional and regulatory requirements. The study may be suspended or terminated if unexpected or unacceptable risks are identified, if required by regulators, or if the study cannot be conducted according to protocol requirements.