Abstract
Background
Multiple trials have confirmed that romiplostim could increase platelet count in individuals with primary immune thrombocytopenia (ITP), but no related study has assessed Chinese patients.
Objectives
To assess the effectiveness of romiplostim as a second-line treatment of persistent or chronic ITP in Chinese adults.
Methods
This phase III multicenter, randomized, placebo-controlled, double-blind, then open-label clinical trial (NCT02868099, CTR20150395) was conducted at 28 investigational sites in China. The patients were randomly assigned (3:1) to romiplostim (starting and maximum doses of 1 and 10 μg/kg, respectively) or placebo for 9 weeks (double-blind period), followed by the open-label period (both groups administered romiplostim) to week 22. The primary endpoint was the time (in weeks) during which platelet counts were ≥50 × 109/L in the double-blind period.
Results
In this study, 202 patients (romiplostim, n = 151; placebo, n = 51) started the treatment. The median (range) numbers of weeks with platelet response after 6 weeks of treatment were 2 (0-6) and 0 (0-2) in patients administered romiplostim and placebo, respectively (P < .001). During the double-blind period, the proportions of patients with treatment-emergent adverse events were comparable between the romiplostim and placebo groups (82.8% vs 82.4%). The treatment-emergent adverse event with ≥10% difference in incidence between these 2 groups was injection site bleeding (1.3% vs 11.8%).
Conclusion
Romiplostim significantly increased the time with maintained platelet response in patients with persistent or chronic ITP in comparison with placebo. No new safety signal was observed.
Trial registration
ClinicalTrials.gov, NCT02868099. www.chinadrugtrials.org.cn/clinicaltrials.searchlist.dhtml, CTR20150395
Keywords: primary immune thrombocytopenia, randomized controlled trial, romiplostim, thrombopoietin receptor
Essentials
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Evidence on romiplostim in the immune thrombocytopenia (ITP) population in China is needed.
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This was a phase III multicenter, randomized, placebo-controlled clinical study.
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Longer duration of platelet response was demonstrated in ITP patients treated with Romiplostim.
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No new safety signal of romiplostim was observed.
1. Introduction
The currently applied first-line therapeutic options for immune thrombocytopenia (ITP) include corticosteroids and intravenous immunoglobulin, while second-line and subsequent treatments encompass splenectomy, thrombopoietin receptor agonists (TPO-RAs), rituximab, immunosuppressant drugs (azathioprine, mycophenolate, and cyclosporine), cyclophosphamide, dapsone, and danazol [1,2]. Still, treatment options are lacking for adult patients with persistent or chronic ITP; such patients require continuous treatment, have corticosteroid-dependence, or do not respond to corticosteroids [3,4].
Romiplostim constitutes a TPO-RA mimicking natural human TPO, which was designed to elevate platelet count in patients with clinical ITP [5,6]. In phase III studies outside of China, romiplostim was effective in treating splenectomized and nonsplenectomized patients, regardless of previous corticosteroid use, with limited adverse effects [[7], [8], [9]]. Moreover, a long-term trial showed that romiplostim had an excellent safety profile and maintained efficacy using a stable, continually administered dosage for up to 3 years [10]. At present, romiplostim and fostamatinib are approved as second-line therapies for chronic ITP in the United States of America, the European Union, and Japan, as well as other nations [11,12].
Notwithstanding, there are no reports examining romiplostim in the adult ITP population in China. New treatment options are required for Chinese adults with persistent or chronic ITP to improve patient prognosis. A previous study of eltrombopag showed that ethnicity affects the patient’s drug exposure [13]. A phase I/II trial [14] suggested that the pharmacokinetic features of romiplostim in the Chinese population are consistent with those in other ethnicities, but beyond pharmacokinetic data, the efficacy and safety remain to be confirmed in a phase III trial of romiplostim in China. Therefore, this phase III multicenter, randomized, placebo-controlled clinical study aimed to assess the effectiveness of romiplostim (starting dose of 1 μg/kg) as second-and-later-line treatment in Chinese adults with persistent or chronic ITP.
2. Methods
2.1. Trial design and ethical considerations
The present phase III multicenter, randomized, placebo-controlled, double-blind, then open-label clinical study (NCT02868099) was carried out in 28 Chinese investigational institutions. It was approved by the ethics committees of the respective sites and followed the Declaration of Helsinki as well as Good Clinical Practice’s principles. Each patient or his/her authorized representative provided signed informed consent.
2.2. Patients
Inclusion criteria were 1) ITP diagnosis ≥6 months prior to signing the informed consent form, according to the criteria proposed by the American Society of Hematology [15]; 2) ≥18 years old; 3) no response/relapse following splenectomy or no splenectomy but no response/relapse following at least 1 previous therapy for ITP; 4) a mean platelet count of 3 scheduled tests <30 × 109/L during the screening period, with no value >35 × 109/L; 5) Eastern Cooperative Oncology Group performance status of 0–2; 6) hemoglobin levels ≥9 g/dL during the screening period and absolute neutrophil counts ≥1.5 × 109/L; 7) serum creatinine levels <176.8 μmol/L, serum bilirubin ≤1.5 times the upper limit of normal, and alanine transaminase and aspartate transaminase ≤3 times the respective upper limit of normal; and 8) full understanding of and compliance with the study protocol’s requirements and voluntary signing of informed consent.
Major exclusion criteria were 1) previous bone marrow stem cell disease other than the classical finding of ITP; 2) previously diagnosed arterial (eg, cerebral thrombosis, transient ischemic attack, and myocardial infarction) or venous (eg, deep vein thrombosis and pulmonary embolism) thrombosis or receiving anticoagulant therapy; 3) history of anti–phospholipid antibody syndrome, systemic lupus erythematosus, or secondary ITP; 4) glucocorticoid treatment within 6 weeks of enrollment or not maintaining a stable dose within 4 weeks prior to enrollment, or treatments known to increase platelet (eg, azathioprine, danazol, cyclosporin A, and mycophenolate mofetil, but excluding traditional Chinese medicine) within 4 weeks prior to enrollment or not maintaining a stable dose within 4 weeks prior to enrollment; 5) splenectomy within 12 weeks prior to enrollment; 6) administration of hematopoietic growth factors (eg, granulocyte colony-stimulating factor, macrophage colony-stimulating factor, erythropoietin, and interleukin-11) within 4 weeks preceding enrollment; 7) treatment with MPL stimulation products before enrollment, except participants with discontinued administration of recombinant human TPO or romiplostim administered 4 weeks before enrollment; 8) administration of any anticancer agents for any reason within 8 weeks prior to enrollment; 9) treatment with any monoclonal antibody drug (eg, rituximab) within 14 weeks before enrollment; and 10) prothrombin time and activated partial thromboplastin time exceeding 20% of the respective normal reference ranges (ie, except for ITP, no previous history of coagulation abnormalities).
2.3. Procedures
Figure 1 depicts the trial design. The trial was divided into the double-blind and open-label periods.
Figure 1.
Trial design. The treatment period was from week 1 to week 21. EOT, end of treatment.
First, the participants underwent a 3:1 randomization into the romiplostim and placebo groups, stratified by splenectomy status (with or without), concurrent ITP therapy (with or without), and platelet count at baseline (≥10 × 109/L or not). The participants’ data were entered into the trial’s interactive web response system to confirm eligibility. The system then provided randomization codes corresponding to the drug vials to be administered. The participants received a subcutaneous administration of romiplostim or placebo for 9 weeks. The starting dose was 1 μg/kg, and the dose adjustment algorithm is presented in Supplementary Table S1.
At week 10, the participants entered the open-label period. The participants who were administered placebo in the double-blind period began treatment with romiplostim at a starting dose of 1 μg/kg in case of platelet count <50 × 109/L at week 10. The dose was adjusted as described in Supplementary Table S1. The patients were treated up to week 21. For participants with platelet counts ≥50 × 109/L at week 10, treatment was discontinued. Individuals who received romiplostim in the double-blind period continued romiplostim treatment, with the dose adjusted according to the criteria shown in Supplementary Table S1, up to week 21. In case of platelet count exceeding 200 × 109/L even with the minimum dose (1 μg/kg), the trial drug was discontinued. Administration of the trial drug was resumed at 1 μg/kg with platelet count <50 × 109/L. The participants did not continue to receive romiplostim after the end of the trial and were then managed by their regular physicians.
2.4. Concomitant treatments
During the treatment period, participants could receive oral glucocorticoids, azathioprine, danazol, cyclosporin A, or mycophenolate mofetil with a stable dose in combination with the test drug. In case of intolerable adverse events (AEs) associated with these drugs, dose reduction or suspension was considered. Meanwhile, once the platelet count reached >50 × 109/L, dose reduction or suspension was considered. During the entire trial period, when participants displayed severe bleeding or as determined by the investigators, emergency treatment aiming to increase platelet count could be performed. As an emergency treatment, intravenous immunoglobulin, platelet transfusion, or adrenocorticotropic hormone was recommended. The test drug could be continued even if emergency treatment was needed during the treatment period.
During the trial period, use of the following drugs or therapies was prohibited: ITP therapeutic agents (excluding oral glucocorticoids, azathioprine, danazol, cyclosporin A, or mycophenolate mofetil with a stable dose, in combination with the test drug), drugs known to increase platelet count, spleen removal, Helicobacter pylori eradication therapy, any antitumor agent (eg, cyclophosphamide, mercaptopurine, vincristine sulfate, vinblastine sulfate, or interferon α), therapeutic antibody (eg, rituximab), other drugs with MPL-stimulating effects, any test drug or test device, or elective surgery.
2.5. Efficacy endpoints and assessments
The primary endpoint was the time (in weeks) during which platelet response (platelet count ≥50 × 109/L) took place from weeks 2 to 7 during the double-blind period.
The secondary endpoints included 1) the proportion of participants with platelet count increased by ≥20 × 109/L vs baseline; 2) the proportion of participants administered emergency therapy to elevate platelet count during the double-blind period; 3) the proportion of participants with platelet count ≥100 × 109/L and no bleeding symptoms; 4) the proportion of participants with platelet count increased by >2 times vs baseline (reaching >30 × 109/L) and no bleeding symptoms; 5) changes in platelet count from baseline; 6) the proportion of participants with a platelet response.
2.6. Safety
The safety analysis included the incidence of AEs, antiromiplostim, anti-TPO, vital signs, and laboratory values. A treatment-emergent AE (TEAE) was any AE occurring on or after the first administration of romiplostim or placebo or any AE with an unknown onset date. All AEs were coded and grouped according to the Medical Dictionary for Regulatory Activities and graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events v4.0. Bone marrow examination was planned at baseline and week 22. Immunogenicity and neutralizing antibodies were assessed (Supplementary Materials).
2.7. Statistical analysis
The sample size of this clinical trial was set to achieve at least 90% statistical power. Based on the proportions of participants with a platelet response in the 20030105 and 20030212 trials [8], the minimum numbers of participants with a platelet response from weeks 2 to 7 to achieve 90% statistical power were 27 and 9 for the romiplostim and placebo groups, respectively. From the safety perspective, 149 participants were required to achieve a 95% probability of detecting at least 1 AE with an incidence of >2% in the romiplostim group. Sample size calculation was carried out with SAS 9.4 (SAS Institute).
The safety set encompassed all the patients who were administered ≥1 dose of romiplostim. The full analysis set (FAS) comprised all patients who were administered ≥1 full dose of romiplostim, with 1 or more platelet counts performed after treatment. The FAS was utilized for primary efficacy analysis. The per-protocol (PP) set encompassed all patients who were administered ≥6 weeks of therapy and completed ≥6 weeks of follow-up without major protocol violations. The PP set was used for sensitivity analysis.
Continuous variables were assessed for normality by the Kolmogorov-Smirnov test. Those with normal distribution were presented as mean ± SD; otherwise, medians (ranges) were determined. Platelet response data (primary and secondary endpoints) were compared between the romiplostim and placebo groups by the Wilcoxon rank-sum test. Categorical variables were presented as n (%) and compared by the chi-squared test (secondary endpoints). Two-tailed P < .05 indicated statistical significance.
3. Results
3.1. Participants
Figure 2 depicts the study flowchart, including the reasons for discontinuation in each phase. Totally 334 patients were enrolled, of whom 203 were included, with 152 and 51 assigned to the romiplostim and placebo groups, respectively. One participant in the romiplostim group withdrew informed consent before the first treatment. Therefore, 202 participants (151 and 51 in the romiplostim and placebo groups, respectively) received one or more doses of romiplostim or placebo. Totally, 189 participants (139 and 50 in the romiplostim and placebo groups, respectively) completed the double-blind phase, and 140 participants (100 and 40 in the romiplostim and placebo groups, respectively) completed the open-label phase. Finally, 95 participants (71 and 24 in the romiplostim and placebo groups, respectively) completed the entire trial. In the PP set at baseline, 187 (92.1%) participants were included, with 140 (92.1%) and 47 (92.2%) in the romiplostim and placebo groups, respectively.
Figure 2.
CONSORT diagram of patient flow through the trial.
3.2. Baseline characteristics
Table 1 summarizes the baseline characteristics. There were more female participants (66.9% and 72.5% in the romiplostim and placebo groups, respectively) than male participants. All participants had received previous treatments for ITP, but the proportion of participants with splenectomy was low in each group (9.3% and 9.8% in the romiplostim and placebo groups, respectively). Six patients received increased steroid doses during the study, which were reported as protocol deviations except one patient who received an increased dose of steroids for the management of a severe AE.
Table 1.
Baseline characteristics of the patients.
| Romiplostim (n = 151) | Placebo (n = 51) | |
|---|---|---|
| Sex, n (%) | ||
| Female | 101 (66.9) | 37 (72.5) |
| Male | 50 (33.1) | 14 (27.5) |
| Age (y), mean ± SD | 42.1 ± 14.0 | 39.7 ± 13.9 |
| Weight (kg), mean ± SD | 65.7 ± 12.3 | 62.7 ± 10.3 |
| Platelet count (109/L), mean ± SD | 13 ± 7 | 13 ± 7 |
| Platelet count (>10 × 109/L), n (%) | 91 (60.3) | 31 (60.8) |
| Splenectomy, n (%) | 14 (9.3) | 5 (9.8) |
| ECOG performance status, n (%) | ||
| 0 | 71 (47.0) | 31 (60.8) |
| 1 | 80 (53.0) | 19 (37.3) |
| 2 | 0 | 1 (2.0) |
| Concomitant ITP therapy, n (%) | ||
| Yes | 88 (58.3) | 29 (56.9) |
| No | 63 (41.7) | 22 (43.1) |
| ITP treatment history, n (%) | ||
| Corticosteroid | 148 (98.0) | 50 (98.0) |
| intravenous immunoglobulin | 67 (44.4) | 27 (52.9) |
| Vincristine/Vinblastine | 33 (21.9) | 12 (23.5) |
| Danazol | 63 (41.7) | 19 (37.3) |
| Cyclophosphamide | 6 (4.0) | 1 (2.0) |
| Azathioprine | 32 (21.2) | 11 (21.6) |
| Rituximab | 16 (10.6) | 6 (11.8) |
| Helicobacter pylori eradication therapy | 6 (4.0) | 4 (7.8) |
| Other | 127 (84.1) | 47 (92.2) |
ECOG, Eastern Cooperative Oncology Group; ITP, immune thrombocytopenia.
3.3. Drug exposure
During the double-blind phase, the romiplostim and placebo groups had comparable median exposure times and total numbers of doses (7.00 vs 7.00 weeks), but the average weekly and cumulative doses of romiplostim/placebo were slightly elevated in the placebo group compared with the romiplostim group (weekly: 3.87 vs 2.97 μg/kg; cumulative: 27.0 vs 20.6 μg/kg). During the trial, participants were administered romiplostim for a median of 20.9 (range, 3.0-21.3) weeks. The mean cumulative romiplostim dose was 88.1 ± 41.3 μg/kg. Fifty-six participants (56/151, 37.1%) received a maximum dose of 10 μg/kg.
3.4. Efficacy in the double-blind period
Platelet response data are summarized in Table 2. The median times during which a platelet response was observed were 2.0 (range, 0-6) and 0 (range, 0-2) weeks in the romiplostim and placebo groups, respectively (P < .001). Supplementary Table S2 presents the subgroup analyses of the primary endpoint. Participants with baseline platelets >10 × 109/L appeared to have a longer-lasting response than those with baseline platelets <10 × 109/L (median [range]: 3 [0-6] vs 0 [0-5] weeks). In the PP set, the median times with a platelet response were 2.0 (0-6) and 0 (0-2) weeks in the romiplostim and placebo groups, respectively (P < .001). The proportion of patients with a platelet response was significantly elevated in the romiplostim group compared with the control group (50.0% vs 2.5%, P < .001).
Table 2.
Efficacy outcomes in the double-blind period (full analysis set).
| Romiplostim | Placebo | P | |
|---|---|---|---|
| Primary endpoint | |||
| Duration of platelet response (platelet count ≥50 × 109/L), wk, median (min, max) | 2.0 (0, 6) | 1.0 (0, 2) | <.001 |
| (N = 151) | (N = 51) | ||
| Secondary efficacy endpoints following 6 weeks of therapy | |||
| Proportion of cases with platelet count increase ≥20 × 109/L from baseline, n (%) | 94 (67.1) (N = 140) |
5 (10.9) (N = 46) |
<.001 |
| Proportion of patients requiring emergency treatment to increase platelet count, n (%) | 2 (1.4) (N = 147) |
1 (2.0) (N = 50) |
>.999 |
| Proportion of patients with platelet count ≥100 × 109/L and no bleeding, n (%) | 21 (15.0) (N = 140) |
1 (2.2) (N = 46) |
.017 |
| Proportion of patients with platelet count ≥30 × 109/L and ≥2 fold increase from baseline showing no bleeding, n (%) | 69 (49.3) (N = 140) |
2 (4.3) (N = 46) |
<.001 |
| Change values of platelet count from baseline, mean ± SD | 42.8 ± 41.3 ×109/L (41.3) (N = 140) |
6.6 ± 28.5 ×109/L (28.5) (N = 46) |
<.001 |
| Proportion of patients with platelet response, n (%) | 70 (50.0) (N = 140) |
1 (2.2) (N = 46) |
<.001 |
P-value: Wilcoxon rank-sum test.
For the secondary endpoint following 6 weeks of treatment, the rate of participants with platelet counts increased by ≥20 × 109/L from baseline and was higher in the romiplostim group than in the placebo group (67.1% vs 10.9%, P < .001). The rate of participants with platelet counts ≥30 × 109/L (increased by ≥2 times vs baseline) and absence of bleeding was higher in the romiplostim group than in the placebo group (49.3% vs 4.3%, P < .001). The proportion of participants with platelet counts ≥100 × 109/L and no bleeding symptoms was slightly elevated in the romiplostim group (15.0% vs 2.2%, P < .001).
For the secondary endpoints in the PP set, the proportions of participants with platelet counts increased by ≥20 × 109/L after 6 weeks of treatment from baseline were 90 (67.7%) and 2 (4.7%) in the romiplostim and placebo groups, respectively. The proportions of participants requiring emergency treatment to increase the platelet count were 1.4% (n = 2) and 2.1% (n = 1), respectively. The proportions of participants with platelet counts ≥100 × 109/L and no bleeding were 20 (15.0%) and 0 (0.0%), respectively. The proportions of participants with platelet counts ≥30 × 109/L (increased by ≥2 times vs baseline) and no bleeding were 66 (49.6%) and 0 (0.0%), respectively. The changes in platelet count from baseline were 43 ± 42 × 109/L and 2 ± 8 × 109/L, respectively. Finally, the proportions of participants with platelet response were 66 (49.6%) and 0 (0.0%), respectively.
3.5. Efficacy in the entire trial
Of the participants who completed the trial in the FAS, 81 (85.3%) showed platelet counts increased by ≥20 × 109/L at week 22 compared with baseline. A tendency of increase in the rate of participants whose platelet counts were ≥50 × 109/L was observed in the romiplostim group each week compared with the placebo group until around week 10 (18.5%-60.4%). The proportions were stable up to week 22, around 58.8% to 84.3%, respectively. A tendency of increase in the rate of participants whose platelet counts were ≥100 × 109/L with no bleeding symptoms was observed in the romiplostim group each week until around week 10 (2.9%-26.0%). This was stable up to week 22, approximately 27.9% to 42.6%.
3.6. Changes in platelet counts
The changes in platelet count are presented in Figure 3. For the romiplostim group, individual and mean values of platelet counts increased following romiplostim initiation with dosing time and reached a plateau from week 10 to week 22, although a few potential outliers were observed.
Figure 3.
(A) Platelet counts during the double-blind period. (B) Platelet counts during the open-label period. Error bars represent SDs.
Based on the highest platelet values during treatment and the lowest value after discontinuation, 100% and 98.0% of patients in the romiplostim and placebo groups, respectively, had decreased platelet counts after treatment discontinuation; when using the lowest platelet count during treatment, these proportions were 72.2% and 72.5% in the romiplostim and placebo groups, respectively.
3.7. Safety
Table 3 and Supplementary Tables S3 and S4 summarized the safety data. During the double-blind period, the romiplostim and placebo groups had proportions of participants who experienced TEAEs (82.8% vs 82.4%). TEAEs reported in ≥10% of participants were upper respiratory tract infection (n = 37, 24.5%) and petechiae (n = 17, 11.3%) in the romiplostim group, and upper respiratory tract infection (n = 10, 19.6%), ecchymosis (n = 9, 17.6%), gingival bleeding (n = 7, 13.7%), injection site hemorrhage (n = 6, 11.8%), and petechiae (n = 6, 11.8%) in the placebo group. The TEAE for which there was at least a 10% difference in incidence between the romiplostim and placebo groups was injection site hemorrhage (1.3% vs 11.8%). During the trial period, the commonest TEAEs in the romiplostim group included upper respiratory tract infection (n = 56, 37.1%), subcutaneous hemorrhage (n = 32, 21.2%), and gingival bleeding (n = 31, 20.5%), while the commonest TEAEs included upper respiratory tract infection (n = 12, 24.0%), ecchymosis (n = 9, 18.0%), and petechiae (n = 8, 16.0%) in the placebo group.
Table 3.
Adverse events.
| Double-blind period |
Open-label period |
|||
|---|---|---|---|---|
| Romiplostim N = 151 |
Placebo N = 51 |
Romiplostim N = 151 |
Placebo-romiplostim N = 50 |
|
| Any TEAEs, n (%) | 125 (82.8) | 42 (82.4) | 143 (94.7) | 40 (80.0) |
| Any drug-related TEAEs, n (%) | 69 (45.7) | 21 (41.2) | 97 (64.2) | 24 (48.0) |
| TEAEs found in ≥10% of cases in either treatment group, n (%) | ||||
| Gingival bleeding | 12 (7.9) | 7 (13.7) | 31 (20.5) | 7 (14.0) |
| Injection site hemorrhage | 2 (1.3) | 6 (11.8) | 0 | 0 |
| Upper respiratory tract infection | 37 (24.5) | 10 (19.6) | 56 (37.1) | 12 (24.0) |
| Petechiae | 17 (11.3) | 6 (11.8) | 30 (19.9) | 8 (16.0) |
| Ecchymosis | 13 (8.6) | 9 (17.6) | 25 (16.6) | 9 (18.0) |
| Subcutaneous bleeding | 0 | 0 | 32 (21.2) | 5 (10.0) |
| Thrombocytopenia | 0 | 0 | 21 (13.9) | 6 (12.0) |
| Arthralgia | 0 | 0 | 25 (16.6) | 2 (4.0) |
| Dizziness | 0 | 0 | 18 (11.9) | 4 (8.0) |
| Epistaxis | 0 | 0 | 17 (11.3) | 2 (4.0) |
| Any SAEs, n (%) | 12 (7.9) | 5 (9.8) | 31 (20.5) | 7 (14.0) |
| Incidence of SAEs (≥2 cases in either treatment group), n (%) | ||||
| Thrombocytopenia | 0 | 0 | 6 (4.0) | 1 (2.0) |
| Platelet counts decreased | 2 (1.3) | 3 (5.9) | 12 (7.9) | 4 (8.0) |
| Cerebral hemorrhage | 2 (1.3) | 0 | 2 (1.3) | 0 |
| Hemorrhage | 1 (0.7) | 0 | 3 (2.0) | 0 |
| Lung infection | 1 (0.7) | 0 | 2 (1.3) | 0 |
| Thromboembolism events | 2 (1.3) | 0 | 0 | 1 (2.0) |
| Death, n (%) | 2 (1.3) | 0 | 2 (1.3) | 0 |
SAE, serious adverse event; TEAE, treatment-emergent adverse event.
Three participants (1.5%) receiving romiplostim developed TEAEs, including 1 with calf muscle vein thrombosis and 1 with superior mesenteric and portal vein thrombosis that led to bowel necrosis, postoperative infection, multiorgan dysfunction, and death, and one with acute cerebral infarction (Table 3 and Supplementary Material). Six participants (3.0%) experienced myelofibrosis events possibly related to romiplostim, all mild in severity (Supplementary Table S3). One participant had a TEAE of platelet rebound (defined as a platelet count 4 weeks after discontinuing romiplostim 10 × 109/L lower than the baseline value). One patient had femoral head osteonecrosis that was possibly unrelated to the study drug (Supplementary Materials).
Two deaths (1.3%) occurred in the romiplostim group throughout the trial period, both during the double-blind trial. The multiple organ dysfunction syndrome mentioned above resulted in death; it was judged to be possibly related to romiplostim. Another participant died due to decreased platelet count, and the direct cause of death was possibly an exacerbation of intracranial hemorrhage due to a low platelet count, which was determined by the investigators as definitely unrelated to romiplostim.
3.8. Antiromiplostim and anti-TPO antibodies
No patient developed antiromiplostim antibodies after treatment. One patient in the romiplostim group showed antiromiplostim antibodies at baseline but none at week 10. No participants had anti-TPO antibodies. Two participants in the romiplostim group showed anti-TPO antibodies from baseline to study end. Of these, one participant showed neutralizing activity to TPO during the study, and the other did not.
4. Discussion
Romiplostim increases platelet count in clinical primary ITP [5,6], but there are no available phase III trials performed in Chinese patients. The results revealed that romiplostim can significantly increase platelet count and duration of platelet response in persistent or chronic ITP compared with placebo. No new safety signal was observed.
The weekly exposure was similar in both groups to that of a long-term safety analysis of romiplostim in ITP (4.2 μg/kg/week) [16]. The primary endpoint was the time (in weeks) with a platelet response (platelet count ≥50 × 109/L), and the results showed that romiplostim was superior to placebo, as supported by previous western studies of romiplostim in adult [9,[17], [18], [19]] and pediatric [20] patients with ITP. The proportion of cases in the romiplostim group with a platelet response during 21 weeks of continuous administration was 81.9%, and a platelet response was found in 74.7% at 22 weeks, corroborating published results [4].
In subgroup analyses, romiplostim showed efficacy in ITP cases regardless of splenectomy or concurrent treatment but was more effective at high platelet counts (>10 × 109/L) at baseline, as supported by previous studies [8,9,17,19,21]. A clinical trial of continuous administration for 24 weeks [8] showed that from weeks 7 to 25, the percentages of participants with a platelet response were 49% to 73% and 61% to 82% among splenectomized and nonsplenectomized participants, respectively.
During the double-blind period, both groups showed similar incidence rates for TEAEs. Most of these TEAEs were mild and resolved without treatment. The commonest (≥5.0%) TEAEs related to romiplostim included joint pain and dizziness, while dizziness and muscle pain were observed in the placebo group. Still, the TEAEs observed in this study corroborated the safety profile of romiplostim reported by other studies outside China [10,17,[19], [20], [21]], and no new safety signals were identified. In this trial, 2 participants in the romiplostim group died. One participant developed a pulmonary infection and respiratory failure and died due to multiple organ failure. The investigators suggested that romiplostim might have caused superior mesenteric vein thrombosis, which resulted in partial intestinal ischemia and necrosis. Thus, this death was considered to be related to romiplostim treatment. Another cause of death was severe thrombocytopenia, which was determined to be unrelated to romiplostim.
Except for the participants who died and one case of femoral head necrosis, all serious adverse events (SAEs) during the trial were isolated events, and most patients with SAEs recovered well. SAEs associated with romiplostim have been reported in previous clinical trials [8,[21], [22], [23]], but osteonecrosis has not been reported previously. This case experienced right thigh soreness in the double-blind phase when administrated placebo and was confirmed with osteonecrosis 2 weeks later in the open-label phase. Owing to the absence of a related finding in previous literature and unclear chronological order, the researchers judged the event unrelated to romiplostim. Indeed, femoral head osteonecrosis might be related to corticosteroid use, as previously described in the literature [24,25].
Previous clinical studies reported that the main risks after administering romiplostim include bleeding after discontinuation, bone marrow fibrosis, and thromboembolic events [18,26]. In this trial, 7 participants experienced bleeding events after discontinuation, which were mild-to-moderate and well-tolerated. A few participants had mild myelofibrosis, which was diagnosed by bone marrow biopsy. None of them had abnormal cell counts or morphology, or other clinical symptoms. Myelofibrosis is observed in approximately 3% of patients administered a TPO-RA, and this AE is usually reversible and increases with romiplostim dose [27,28]. In addition, 3 participants experienced romiplostim-related thromboembolic disorders, eg, deep vein thrombosis and cerebral infarction. In a previous phase III clinical study [18], severe thromboembolic events related to romiplostim were reported. In this trial, the occurrence of common AEs after the administration of romiplostim corroborated previous clinical studies.
This trial had several limitations. The treatment duration and follow-up were short. There were no comparisons with other TPO-RAs because no other TPO-RA has been approved in China when the present trial was designed. The inclusion of the Chinese population exclusively might limit the generalizability of the results due to the disparity of sociocultural, medical, economic, and genetic determinants between difference races. The duration of ITP was not recorded, but all patients were diagnosed at least 6 months before signing the informed consent form. Importantly, a relatively high proportion of participants did not complete the follow-up (weeks 22 to 26), although the treatment was completed. Because the patients did not continue to receive romiplostim during follow-up and the tests mainly included routine blood tests, some out-of-town patients were not willing to visit the designated study centers for routine blood tests. HIV and hepatitis C virus infections were not assessed during screening, which might decrease platelet counts [29]. Finally, the quality of life was not examined. Studies with longer treatment periods and various comparators are necessary.
In conclusion, this phase III multicenter, randomized, placebo-controlled, double-blind study showed that romiplostim is effective, safe, and well-tolerated in Chinese adults with persistent or chronic ITP, with no new safety signals. Osteonecrosis might warrant further investigation in the future.
Acknowledgments
The authors acknowledge the participants for their invaluable participation.
Funding
The trial was sponsored by Kyowa Kirin China Pharmaceutical Co., LTD, which had no roles in the study design, experiment execution, data analysis and interpretation, and decision to submit the manuscript.
Ethics statement
This study had approval from the institutional review boards or independent ethics committees of various sites, and followed the Declaration of Helsinki.
Author contributions
All investigators participated in trial design, patient recruitment, participant visits, and data collection. Z.H. drafted the manuscript. All authors read and approved the submitted manuscript.
Relationship Disclosure
The authors had no conflicts of interest.
Informed patient consent
Each participant or his/her authorized representative provided written consent before enrollment.
Data availability
The datasets generated and/or assessed in the trial sponsored by Kyowa Hakko Kirin China Pharmaceutical Co., LTD will be uploaded to the Vivli repository (https://vivli.org/ourmember/kyowa-kirin).
Footnotes
Handling Editor: Pantep Angchaisuksiri
The online version contains supplementary material available at https://doi.org/10.1016/j.rpth.2023.100192
Contributor Information
Huacong Cai, Email: caihc@pumch.cn.
Yongqiang Zhao, Email: 13581933359@139.com.
Supplementary material
References
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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 Availability Statement
The datasets generated and/or assessed in the trial sponsored by Kyowa Hakko Kirin China Pharmaceutical Co., LTD will be uploaded to the Vivli repository (https://vivli.org/ourmember/kyowa-kirin).