ABSTRACT
Chronic liver disease (CLD)‐related thrombocytopenia can limit the feasibility of invasive procedures. Recombinant human thrombopoietin (rhTPO) has demonstrated a favorable safety profile without hepatotoxicity. We evaluated the efficacy and safety of rhTPO in patients with CLD‐related thrombocytopenia who were undergoing elective invasive procedures. In this multicenter, randomized (2:1), double‐blind, placebo‐controlled phase III trial, 120 adult Chinese patients with CLD‐related thrombocytopenia (platelet count < 50 × 109/L) received rhTPO (n = 80) or placebo (n = 40) once daily for up to 5 or 7 days. The primary endpoint was the proportion of patients with sustained platelet counts ≥ 50 × 109/L from 24 h before invasive procedure to 7 days post‐procedure, without requiring emergency bleeding management. The primary endpoint was achieved by 85.0% of patients in the rhTPO group versus 12.5% in the placebo group (p < 0.0001). Preoperatively, platelet counts ≥ 50 × 109/L were achieved in 92.5% and 20.0% of patients in the rhTPO and placebo groups, respectively (p < 0.0001). Platelet transfusion was avoided in 92.5% of rhTPO‐treated patients versus 25.0% of placebo‐treated patients (p < 0.0001). The median duration of platelet counts ≥ 50 × 109/L was significantly longer with rhTPO than with placebo (21.0 vs. 3.0 days, p = 0.0007). Treatment‐related treatment‐emergent adverse events (TEAEs) occurred in 12.5% of patients in both the rhTPO and placebo groups. No treatment‐related serious adverse events were reported. Overall, rhTPO was effective and well tolerated in patients with CLD‐related thrombocytopenia and may represent a viable therapeutic option for those undergoing elective invasive procedures.
Trial Registration: www.chinadrugtrials.org.cn: number CTR20230919.
Keywords: chronic liver disease, efficacy, recombinant human thrombopoietin, safety, thrombocytopenia
1. Introduction
Thrombocytopenia is a common complication of chronic liver disease (CLD), affecting approximately 64%–84% of patients diagnosed with cirrhosis and hepatic fibrosis [1]. Severe thrombocytopenia, characterized as a platelet count < 50 × 109/L, is associated with poor clinical outcomes, including an increased risk of hemorrhage and mortality [2, 3, 4, 5]. Moreover, many patients with CLD and severe thrombocytopenia require multiple diagnostic or therapeutic interventions, including medical and surgical procedures [6].
As invasive procedures are associated with an increased risk of bleeding in patients with CLD, several clinical practice guidelines recommend prophylactic platelet transfusion for selected patients [7, 8, 9, 10, 11]. Although platelet transfusions can reduce the risk of procedure‐related bleeding resulting from thrombocytopenia in patients with CLD undergoing invasive operations [6, 12], their use is associated with several limitations, including transient therapeutic efficacy, transfusion‐related reactions, rare but serious infectious complications, and the possibility of inducing refractoriness to subsequent platelet transfusions [13, 14, 15].
Thrombopoietin receptor agonists (TPO‐RAs) and recombinant human thrombopoietin (rhTPO) are commonly used to manage thrombocytopenia. Currently available TPO‐RAs include eltrombopag, hetrombopag, avatrombopag, lusutrombopag, and romiplostim. However, the use of eltrombopag and hetrombopag in patients with CLD remains limited because their safety profiles have not been fully validated in this population [16, 17]. In addition, evidence supporting the efficacy of romiplostim in hepatitis C virus‐associated thrombocytopenia is limited to small‐sample studies [18].
rhTPO (Shenyang Sunshine Pharmaceutical Co. Ltd.) is a full‐length, fully glycosylated 332‐amino acid glycoprotein produced in Chinese hamster ovary cells using recombinant DNA technology. As it is structurally identical to endogenous thrombopoietin, rhTPO exhibits physiologic thrombopoietic activity. Previous studies have shown that rhTPO significantly increases platelet counts in patients with CLD‐related thrombocytopenia while reducing both the risk of bleeding and the need for platelet transfusions [19, 20].
In a phase I tolerability study, 27 healthy participants received a single subcutaneous injection of rhTPO at 1 of 4 dose levels: 75 U/kg, 150 U/kg, 300 U/kg, and 600 U/kg, with 3, 6, 9, and 9 participants in each group, respectively. A single subcutaneous administration of rhTPO produced a dose‐dependent increase in platelet counts. At doses ranging from 150 to 600 U/kg, the mean platelet counts increased by 24%–52% from baseline, with increases of up to 100% in some participants. Platelet counts peaked between days 10 and 14 after dosing and returned to near‐baseline levels by day 21. One participant experienced transient low‐grade fever and fatigue, while another participant experienced somnolence; all adverse events resolved spontaneously. A transient mild elevation in alanine aminotransferase and aspartate aminotransferase levels was observed in one participant and normalized within 1 week.
This multicenter, randomized (2:1), double‐blind, parallel‐group, placebo‐controlled phase III study evaluated the efficacy and safety of rhTPO in patients with CLD‐related thrombocytopenia who were undergoing scheduled invasive procedures. The primary objective of this study was to determine whether rhTPO was superior to placebo in reducing the need for platelet transfusions in patients with CLD and thrombocytopenia scheduled to undergo invasive procedures, thereby providing an additional therapeutic option for clinical practice.
2. Materials and Methods
2.1. Study Design
This multicenter, randomized, double‐blind, parallel‐group, placebo‐controlled phase III study was conducted at 41 centers across China between May 2023 and February 2024 to evaluate the efficacy and safety of rhTPO in adults with CLD‐related thrombocytopenia who were undergoing scheduled invasive procedures (Figure 1). The study protocol was approved by the institutional review board or an independent ethics committee at each participating center, and written informed consent was obtained from all patients prior to screening. This study was conducted in accordance with the guidelines of the World Medical Association Declaration of Helsinki and Good Clinical Practice guidelines. The clinical trial protocol and the protocol amendment are provided in the Supporting Information. This study was registered with the China Drug Trials Registry (CTR20230919, registered on May 22, 2023).
FIGURE 1.
Study flow diagram.
2.2. Participants
Eligible patients were adults aged ≥ 18 years with CLD‐related thrombocytopenia and a baseline platelet count (BPLT) < 50 × 109/L. Key inclusion criteria included a scheduled invasive procedure between days 8 and 15 after treatment initiation, an anticipated platelet count ≥ 50 × 109/L at the time of the procedure, Model for End‐Stage Liver Disease score ≤ 24, Child–Pugh class A or B, an Eastern Cooperative Oncology Group performance status grade of 0 or 1, and agreement to use an effective method for contraception throughout the study period.
Key exclusion criteria included a history of thrombosis; any malignancy other than hepatocellular carcinoma (HCC); HCC classified as Barcelona Clinic Liver Cancer stage C or D; prior splenectomy, history of liver transplantation, or systemic infection requiring treatment (except viral hepatitis); hematologic disorders; use of heparin, warfarin, nonsteroidal anti‐inflammatory drugs, verapamil, ticlopidine, glycoprotein IIb/IIIa antagonists (e.g., tirofiban), or erythropoiesis‐stimulating agents within 7 days before randomization; and receipt of platelet transfusions or platelet‐containing blood products (excluding packed red blood cells) within 7 days before randomization.
2.3. Procedure
The study consisted of three periods: a screening period of up to 7 days, a treatment period of up to 7 days, and a post‐treatment follow‐up period of 29 days. The maximum duration of the study for each patient was up to 43 days. Individuals who provided written informed consent underwent screening to determine eligibility. Eligible patients were randomized in a 2:1 ratio to receive either rhTPO (treatment group) or placebo (control group). Randomization was stratified according to a BPLT of 30 × 109/L ≤ BPLT < 50 × 109/L or BPLT < 30 × 109/L.
Patients received rhTPO 15 000 U or placebo from Day 1 via subcutaneous injection once daily. The treatment duration was up to 5 days for patients with BPLT between 30 × 109/L and < 50 × 109/L, and up to 7 days for those with BPLT < 30 × 109/L. From Day 3 to Day 5 (or Day 7 for BPLT < 30 × 109/L), platelet counts were measured prior to each dose. Treatment was discontinued immediately once the platelet count increased to ≥ 50 × 109/L and had increased by ≥ 10 × 109/L from the baseline.
Invasive procedures were performed between Day 8 and Day 15 after the initiation of treatment. Platelet count was assessed within 24 h before surgery (as close to the time of surgery as possible) to determine the need for platelet transfusion. Preoperative platelet transfusion was permitted if the platelet count was < 50 × 109/L. Additionally, physicians were allowed to administer platelet transfusions during or after the procedure at their discretion (e.g., if platelet count fell below 50 × 109/L or excessive bleeding occurred) to prevent or manage bleeding risks. Platelet counts were assessed during the screening period, on Day 1 (prior to the first dose), daily before dosing from Day 3 to Day 7 (if treatment was terminated early, testing was performed on the day of discontinuation), and on Days 8, 10, 12, 14, 16, 22, 29, and 36 or at early termination.
2.4. Randomization and Masking
Randomization numbers for all participants were generated by the Interactive Web Response System (IWRS). Eligible participants were stratified by BPLTs (≥ 30 × 109/L to < 50 × 109/L vs. < 30 × 109/L) and randomized at a 2:1 ratio to receive either rhTPO or placebo. Treatment allocation and randomization codes for each patient were maintained strictly confidential before the database lock and final unblinding. Unblinding at the investigators' request was allowed only in the event of an emergency to determine the appropriate course of therapy.
2.5. Study Endpoints and Assessment
The primary endpoint was the proportion of patients who maintained platelet counts ≥ 50 × 109/L from within 24 h before surgery to 7 days post‐surgery, without requiring emergency bleeding management (including transfusion of whole blood, red blood cells, platelets, plasma, or cryoprecipitate transfusion). Platelet counts were evaluated at four predefined time points: within 24 h preoperatively, and on postoperative days 2, 4, and 7, with success defined as achieving platelet counts ≥ 50 × 109/L at all evaluations. Emergency treatment was defined as transfusion therapy (including whole blood, red blood cells, platelets, fresh frozen plasma, or cryoprecipitate) administered alone or in combination with other therapeutic interventions.
The study also evaluated several secondary outcomes: (1) the proportion of patients who achieved a preoperative platelet count of at least 50 × 109/L; (2) the change in platelet count from baseline to preoperative assessment; (3) the duration during which platelet counts remained at or above 50 × 109/L; (4) the proportion of patients who did not require platelet transfusion throughout the study period; (5) the number of platelet transfusions received and the cumulative dose administered; (6) the incidence of emergency interventions for active bleeding; (7) platelet counts recorded at scheduled follow‐up visits; and (8) changes in platelet counts from baseline in platelet levels at each follow‐up time point.
Safety assessments included treatment exposure, incidence of adverse events (AEs), thrombotic events, laboratory tests, vital signs, electrocardiograms, World Health Organization (WHO) bleeding scale scores, and pregnancy testing. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) and summarized according to System Organ Class (SOC), Preferred Term (PT), and severity grade. AEs of special interest (AESIs) were defined as portal vein thrombosis or embolism.
2.6. Statistical Analysis
Based on data from a phase 1b study (NCT05193201), the proportion of participants who achieved the primary endpoint by postoperative Day 7 was estimated to be 55% in the rhTPO group and 20% in the placebo group. To detect this difference with 90% power at a two‐sided significance level of 0.05, a total of 99 patients (66 in the rhTPO group and 33 in the placebo group) were required. Considering a potential dropout rate of 20%, a total of 120 patients were enrolled (80 in the rhTPO group and 40 in the placebo group).
Primary and secondary endpoint analyses were performed in the intention‐to‐treat (ITT) set, which included all randomized patients and was also used to analyze demographic and baseline characteristics. Safety analysis was performed in the safety set (SS), which included all randomized patients who received at least one dose of rhTPO or placebo.
Descriptive statistics were used to summarize the proportion of patients in each treatment group (BPLT < 30 × 109/L or ≥ 30 × 109/L to < 50 × 109/L) who maintained platelet counts ≥ 50 × 109/L from randomization through postoperative day 7 without requiring emergency treatment for bleeding management. Corresponding 95% confidence intervals (CIs) were calculated using the Clopper–Pearson exact method. Between‐group comparisons were conducted using the Cochran–Mantel–Haenszel (CMH) test adjusted for stratification factors, and between‐group differences with corresponding 95% CIs were reported. Missing data will be populated as “not answered”. A two‐sided p value < 0.05 was considered statistically significant. All statistical analyses were performed using SAS (version 9.4 or higher; SAS Institute, Cary, NC, USA).
3. Results
3.1. Baseline Characteristics
A total of 161 patients were screened for eligibility, and 120 were randomized (80 with rhTPO and 40 with placebo) in this phase III study (Figure 1) conducted between May 2023 and February 2024. All randomized patients received the assigned study treatments. All 80 patients (100.0%) in the rhTPO group completed the full treatment regimen. In the placebo group, 39 patients (97.5%) completed the treatment, whereas 1 patient (2.5%) discontinued the treatment prematurely due to subject request.
Baseline demographics and clinical characteristics are shown in Table 1. The baseline clinical characteristics were well balanced between the rhTPO and placebo groups. The mean BPLTs were 37.6 ± 8.3 × 109/L in the rhTPO group and 39.0 ± 8.0 × 109/L in the placebo group (p = 0.3702). Patients with BPLTs between 30 × 109/L and 50 × 109/L accounted for 83.8% in the rhTPO group and 82.5% in the placebo group, whereas those with platelet counts below 30 × 109/L accounted for 16.3% and 17.5%, respectively. Nearly all patients in the rhTPO group (98.8%) underwent invasive procedures, compared with 47.5% in the placebo group. Among these, procedures with a high bleeding risk accounted for 5.0% and 0.0%, procedures with a moderate bleeding risk accounted for 15.0% and 7.5%, and procedures with a low bleeding risk accounted for 78.8% and 40.0% in the rhTPO and placebo groups, respectively.
TABLE 1.
Demographic and clinical characteristics for patients.
| Placebo (N = 40) | rhTPO (N = 80) | |
|---|---|---|
| Age (years) | 52.5 [45.0, 62.5] | 52.0 [47.5, 57.5] |
| Sex (n, %) | ||
| Female | 8 (20.0) | 22 (27.5) |
| Male | 32 (80.0) | 58 (72.5) |
| BMI (kg/m2) | 25.5 ± 3.8 | 24.3 ± 3.4 |
| Baseline platelet counts (×109/L) | 39.0 ± 8.0 | 37.6 ± 8.3 |
| Baseline platelet‐counts stratification (×109/L) (n, %) | ||
| < 30 | 7 (17.5) | 13 (16.3) |
| 30–50 | 33 (82.5) | 67 (83.8) |
| Type of CLD (n, %) | ||
| Hepatitis B | 31 (77.5) | 61 (76.3) |
| Hepatitis C | 3 (7.5) | 6 (7.5) |
| Alcoholic | 2 (5.0) | 4 (5.0) |
| Autoimmune | 2 (5.0) | 3 (3.8) |
| Drug‐induced liver injury | 1 (2.5) | 0 (0.0) |
| Other | 1 (2.5) | 6 (7.5) |
| Hepatocellular carcinoma (n, %) | 4 (10.0) | 5 (6.3) |
| MELD score | 11.0 [9.0, 13.0] | 10.0 [8.0, 12.0] |
| Child‐Pugh class (n, %) | ||
| A | 26 (65.0) | 55 (68.8) |
| B | 14 (35.0) | 25 (31.3) |
| WHO bleeding score grade (n, %) | ||
| Grade 0 | 35 (87.5) | 76 (95.0) |
| Grade 1 | 5 (12.5) | 4 (5.0) |
| Invasive procedures (n, %) | 19 (47.5) | 79 (98.8) |
| Low bleeding risk | 16 (40.0) | 63 (78.8) |
| Endoscopy | 16 (40.0) | 58 (72.5) |
| Gastrointestinal endoscopy | 11 (27.5) | 47 (58.8) |
| Esophageal variceal ligation | 2 (5.0) | 5 (6.3) |
| Gastrointestinal endoscopic therapy | 1 (2.5) | 0 |
| Endoscopic biopsy | 2 (5.0) | 6 (7.5) |
| Abdominal drainage | 0 | 5 (6.3) |
| Moderate bleeding risk | 3 (7.5) | 12 (15.0) |
| Liver biopsy | 0 | 3 (3.8) |
| Breast biopsy | 0 | 1 (1.3) |
| Percutaneous transhepatic portal vein pressure measurement | 0 | 1 (1.3) |
| Bone marrow aspiration | 0 | 1 (1.3) |
| Esophageal variceal injection | 1 (2.5) | 2 (2.5) |
| Therapeutic embolization | 0 | 1 (1.3) |
| Transcatheter arterial chemoembolization | 2 (5.0) | 1 (1.3) |
| Lipoma excision | 0 | 1 (1.3) |
| Inguinal hernia repair | 0 | 1 (1.3) |
| High bleeding risk | 0 | 4 (5.0) |
| Liver ablation | 0 | 2 (2.5) |
| Portal vein shunt | 0 | 2 (2.5) |
Note: Characteristics are expressed as Median [IQR], Mean ± SD, or number (%).
Abbreviations: BMI, body mass index; CLD, chronic liver disease; IQR, interquartile range; MELD, model for end‐stage liver disease; SD, standard deviation; TACE, Transarterial Chemoem‐bolization; TIPS, transjugular intrahepatic portosystemic shunt.
3.2. Efficacy
3.2.1. Primary Efficacy Endpoint
rhTPO was significantly superior to placebo in increasing the proportion of patients with sustained platelet counts ≥ 50 × 109/L from 24 h before the procedure through 7 days afterward without requiring emergency bleeding management. In the ITT population, the primary endpoint was met by 85.0% of patients in the rhTPO group (68/80; 95% CI, 75.3–92.0), compared with 12.5% in the placebo group (5/40; 95% CI, 4.2–26.8). After adjustment for stratification factors using the CMH test, the absolute between‐group difference was 72.2% (95% CI, 59.6–84.9), demonstrating a statistically significant benefit of rhTPO over placebo (p < 0.0001). Subgroup analyses demonstrated a consistent treatment benefit across all predefined subgroups. The treatment effect favored rhTPO regardless of BPLT, age (< 65 years), sex, body mass index, and Child–Pugh class (Figure 2B).
FIGURE 2.
Proportion of patients in the recombinant human thrombopoietin (rhTPO) and placebo groups who achieved meeting the primary efficacy endpoint. (A) Overall proportion of patients who achieved the primary efficacy endpoint. (B) Forest plot of subgroup analysis of the primary efficacy endpoint stratified by baseline platelet count, age, gender, body mass index (BMI), and Child‐Pugh class. [Color figure can be viewed at wileyonlinelibrary.com]
3.2.2. Secondary Efficacy Endpoints
rhTPO also demonstrated significant advantages over placebo across multiple secondary efficacy endpoints (Figure 3). At the preoperative assessment, 92.5% of patients in the rhTPO group (95% CI, 84.4%–97.2%) achieved platelet counts ≥ 50 × 109/L compared with 20.0% of patients in the placebo group (95% CI, 9.1%–35.7%). The absolute between‐group difference was 72.2% (95% CI, 58.8%–85.7%, p < 0.0001) (Figure 3A). The median increase in platelet count from baseline to the preoperative assessment was 46.9 ± 28.8 × 109/L in the rhTPO group and 3.6 ± 12.7 × 109/L in the placebo group (Figure 3B), with a statistically significant difference between the two groups (p < 0.0001).
FIGURE 3.
Secondary endpoints and additional assessments. (A) Proportion of patients achieving platelet counts ≥ 50 × 109/L at the preoperative assessment. (B) Platelet count change from baseline at the preoperative assessment. (C) Kaplan–Meier analysis of the duration of platelet counts ≥ 50 × 109/L. (D) Proportion of patients not requiring platelet transfusion. (E) Number of platelet transfusions per patient (among those who received transfusions). (F) Platelet transfusion dose in units (among those who received transfusions). (G) Proportion of patients requiring rescue therapy for bleeding events. [Color figure can be viewed at wileyonlinelibrary.com]
In addition, the median duration of platelet counts ≥ 50 × 109/L was 21.0 days (95% CI: 20.0–23.0) in the rhTPO group compared with 3.0 days (95% CI: 2.0–4.0) in the placebo group. The stratified hazard ratio was 0.4 (95% CI: 0.2–0.7), showing a statistically significant difference (p = 0.0007, Figure 3C). As frequent platelet count monitoring to guide dosing may be burdensome in routine clinical practice, in addition to the duration of platelet counts > 50 × 109/L, we analyzed the relationships between the number of rhTPO doses administered and platelet counts, changes in platelet counts, and treatment response rate (defined as a platelet count ≥ 50 × 109/L with an increase > 10 × 109/L). The results are presented in Figures [Link], [Link].
The administration of rhTPO markedly reduced the need for platelet transfusion. Overall, 92.5% of patients in the rhTPO group (95% CI: 84.4%–97.2%) avoided platelet transfusion compared with only 25.0% of patients in the placebo group (95% CI: 12.7%–41.2%), yielding a significant between‐group difference of 67.3% (95% CI: 52.8%–81.8%, p < 0.0001) (Figure 3D). During the study period, three patients in the rhTPO group received platelet transfusions, with a mean of 1.0 ± 0.0 transfusions per patient and a mean transfusion dose of 1.7 ± 0.6 units (Figure 3E). In the placebo group, 14 patients received platelet transfusions, with a mean of 1.4 ± 0.7 transfusions per patient and a mean transfusion dose of 1.7 ± 0.7 units (Figure 3F). Although prophylactic platelet transfusions were significantly higher in the placebo group, the incidence of actual severe bleeding events that required emergency treatment after platelet transfusion was not high. The proportion of patients who required emergency treatment for bleeding was 2.5% in the rhTPO group (2/80, 95% CI: 0.3–8.7) and 2.6% in the placebo group (1/39, 95% CI: 0.1–13.5), with no statistically significant difference (p = 0.9901) (Figure 3G).
In the rhTPO group, the mean platelet count began to increase by day 5 after treatment initiation, showed a marked increase by day 7, and continued to rise, reaching a peak on day 14 (111.4 ± 37.8 × 109/L). This peak represents a mean increase of 73.8 ± 37.0 × 109/L from baseline. Platelet counts subsequently declined gradually and returned to approximately baseline levels by day 29. From days 7 through 22 after treatment initiation, the mean platelet count in the rhTPO group remained above 50 × 109/L. By contrast, no apparent increase in the mean platelet count was observed at any post‐treatment visit in the placebo group (Figure 4).
FIGURE 4.
Mean platelet counts over time in the recombinant human thrombopoietin (rhTPO) and placebo groups. [Color figure can be viewed at wileyonlinelibrary.com]
3.3. Safety
Treatment exposure was similar between the rhTPO and placebo groups (5.1 ± 1.0 vs. 5.1 ± 1.2 days). Treatment‐emergent AEs (TEAEs) were comparable between the rhTPO and placebo groups (81.25% vs. 87.50%) (Table 2). Most TEAEs were mild (grade 1) or moderate (grade 2). Among them, treatment‐related TEAEs occurred in 12.5% of patients in both groups. No treatment‐related serious adverse events (SAEs) were reported. The incidence of AESI was 1.3% (1/80) in the rhTPO group, representing a single case of portal vein thrombosis that was not classified as a serious AE, and 0% (0/40) in the placebo group. The incidence of grade ≥ 3 treatment‐related TEAEs was 1.25% (1/80) in the rhTPO group and 0% (0/40) in the placebo group, with the specific events comprising two grade 3 decreases in neutrophil count and one grade 3 decrease in white blood cell count. No treatment‐related TEAEs resulted in treatment discontinuation. No deaths were reported during the study period.
TABLE 2.
Summary of treatment‐emergent adverse events by category.
| AEs (n, %) | Placebo (N = 40) | rhTPO (N = 80) |
|---|---|---|
| TEAEs | 35 (87.5) | 65 (81.3) |
| Treatment‐related TEAEs | 5 (12.5) | 10 (12.5) |
| TEAEs in > 3% of patients | ||
| Diarrhea | 3 (7.5) | 3 (3.8) |
| Constipation | 0 (0.0) | 5 (6.3) |
| Abdominal pain | 2 (5.0) | 3 (3.75) |
| Abdominal pain, upper | 2 (5.0) | 1 (1.25) |
| Nausea | 0 (0.0) | 4 (5.0) |
| Fibrin D dimer increased | 2 (5.0) | 4 (5.0) |
| Insomnia | 0 (0.0) | 4 (5.0) |
| Dizziness | 0 (0.0) | 3 (3.8) |
| TEAEs with CTCAE Grade ≥ 3 | 10 (25.0) | 28 (35.0) |
| Treatment‐related TEAEs with CTCAEs Grade ≥ 3 | 0 (0.0) | 1 (1.3) |
| SAEs | 2 (5.0) | 4 (5.0) |
| Treatment‐related SAEs | 0 (0.0) | 0 (0.0) |
| AESIs | 1 (2.5) | 4 (5.0) |
| Treatment‐related AESIs | 0 (0.0) | 1 (1.25) |
| TEAEs leading to study withdrawal | 0 (0.0) | 2 (2.5) |
| Treatment‐related TEAEs leading to study withdrawal | 0 (0.0) | 0 (0.0) |
| TEAEs leading to death | 0 (0.0) | 0 (0.0) |
Note: Characteristics are expressed as number (%).
Abbreviations: AEs, adverse events; AESIs, adverse events of special interest; CTCAEs, common terminology criteria for adverse events; SAEs, serious adverse events; TEAEs, treatment‐emergent adverse events.
4. Discussion
This phase III study demonstrated the superiority of rhTPO over placebo for the management of thrombocytopenia in patients with CLD undergoing invasive procedures. A key strength of this study was its more comprehensive primary endpoint, which required patients to maintain platelet counts ≥ 50 × 109/L from the preoperative assessment through 7 days after the procedure without requiring rescue therapy for bleeding. This composite endpoint was designed to rigorously assess sustained efficacy throughout the entire high‐risk periprocedural period rather than at a single timepoint or based solely on the avoidance of a single intervention. Even under these more stringent criteria, rhTPO demonstrated robust efficacy, with 85.0% of patients achieving the primary endpoint compared with 12.5% in the placebo group. These findings are not numerically inferior to those of previous studies on TPO‐RAs for CLD‐related thrombocytopenia [21, 22]. Furthermore, although a higher proportion of patients in the rhTPO group underwent invasive procedures than that in the placebo group (98.8% vs. 47.5%) and moderate‐to‐high‐bleeding‐risk procedures were more common in the rhTPO group (20.0% vs. 7.5%), this greater procedural burden did not reduce the likelihood of achieving the primary endpoint in the rhTPO group, further supporting the efficacy of rhTPO treatment.
To facilitate a comparison with the existing clinical evidence, a key secondary endpoint, the avoidance of preoperative platelet transfusion, was also evaluated. In this study, 92.5% of patients in the rhTPO group avoided platelet transfusion, a result that is numerically consistent with the rates reported for avatrombopag (75.8%) [23] and lusutrombopag (79.2%) [24]. In addition to achieving high response rates, rhTPO significantly prolonged the median duration during which platelet counts remained ≥ 50 × 109/L to 21.0 days, compared with 3.0 days in the placebo group. This duration was comparable to the results reported in two phase III trials of lusutrombopag (19.2 and 21.9 days) [22, 25]. However, given that rhTPO requires daily injections and lacks the convenience of an existing oral agent, the most appropriate treatment should be selected based on the clinical scenario.
The clinical context of this trial adds further specificity to its findings. The enrolled population predominantly consisted of Chinese patients with hepatitis B virus (HBV)‐related CLD (76.3%), in contrast to the etiological profile of previous global TPO‐RA trials, which predominantly included patients with hepatitis C virus infection, alcohol‐related liver disease, or non‐alcoholic steatohepatitis. Given that pathophysiological differences in the underlying etiology of CLD may influence treatment responses, this study provides dedicated phase III evidence in a large and clinically distinct population of patients with HBV‐related liver disease, thereby addressing an important gap in the existing evidence base.
Thrombotic events remain an important safety concern with thrombopoietic agents, including TPO‐RAs and rhTPO, particularly when used to increase platelet counts in patients with CLD. In the present study, treatment‐related AESIs, specifically portal vein thrombosis, occurred in only one patient in the rhTPO group and was not classified as a serious adverse event. This incidence did not exceed the 2.8% rate reported in a meta‐analysis of patients with CLD‐related thrombocytopenia undergoing elective invasive procedures and treated with TPO‐RAs [26].
This study has several limitations. The permitted use of platelet transfusions in both groups likely contributed to the low observed incidence of major bleeding events, thereby limiting the ability to detect between‐group differences in bleeding rates. In addition, the exclusion of patients with Child‐Pugh class C cirrhosis and the preponderance of low‐bleeding‐risk procedures may limit the generalizability of these findings to patients with more advanced liver disease or those undergoing higher‐risk interventions.
5. Conclusions
In conclusion, this study confirms that rhTPO is an effective and safe therapeutic option for the periprocedural management of thrombocytopenia in patients with CLD.
Funding
This work was supported by the Prevention and Control of Emerging and Major Infectious Diseases‐National Science and Technology Major Project, 2025ZD01906300 & 2025ZD01906303. Beijing iGandan Foundation, No. iGandanF‐1082025‐RGG024.
Ethics Statement
All participating sites obtained institutional review board approval and the study was conducted in accordance with the principles of the Declaration of Helsinki.
Consent
All patients provided informed consent.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Data S1: Supporting Information.
Data S2: Supporting Information.
Figure S1: Relationship between platelet count and baseline platelet count.
Figure S2: Relationship between change in platelet count and baseline platelet count.
Figure S3: Relationship between treatment response rate and baseline platelet count.
Acknowledgments
We would like to acknowledge Shenyang Sunshine Pharmaceutical Co. Ltd. for their provision of rhTPO to clinical trial participants. We are grateful to all patients and their families and all members of the study gry.
Contributor Information
Yanyan Yu, Email: yyy@bjmu.edu.cn.
Xiaoyuan Xu, Email: xiaoyuanxu6@163.com.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1: Supporting Information.
Data S2: Supporting Information.
Figure S1: Relationship between platelet count and baseline platelet count.
Figure S2: Relationship between change in platelet count and baseline platelet count.
Figure S3: Relationship between treatment response rate and baseline platelet count.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.