This is a phase 3b, multi-center, randomized, Standard of Care (SOC)-controlled, open-label, 52-week treatment study to compare romiplostim to medical SOC for Idiopathic Thrombocytopenia Purpura (ITP), with a 6-month Safety Follow-up. Patients randomized to romiplostim must complete the taper or discontinuation of medical SOC for ITP as soon as medically feasible after the initiation of romiplostim. After the completion or discontinuation of the study treatment period, any participant who does not transfer in to another romiplostim study will complete a 6-month Safety Follow-up period.
BACKGROUND: Chronic ITP is an autoimmune disease characterized by low platelet counts due to both increased platelet destruction and suboptimal platelet production. Conventional ITP therapies that target the immune system have variable response rates and issues regarding toxicity. Romiplostim is an Fc-peptide fusion protein (peptibody) that increases platelet counts by a mechanism similar to thrombopoietin, and has recently been approved in the EU, US, Canada, and Australia for the treatment of chronic ITP. Aims. To evaluate the ability of romiplostim versus medical standard of care (SOC) to reduce the incidence of splenectomy and treatment failures in adult nonsplenectomized ITP patients during a 52-week treatment period. DESIGN AND METHODS: Patients provided informed consent and were randomized (2:1) to romiplostim or SOC and stratified by geographic region. Eligible patients either had a platelet count <50x109/L or had their platelet count fall to <50x109/L during or after a clinically-indicated taper or discontinuation of current ITP therapy. Once-weekly subcutaneous romiplostim was administered with dose adjustments based on platelet count. SOC treatments were prescribed by the investigator according to standard institutional practices or therapeutic guidelines; the only treatments not allowed were investigational agents (rituximab was allowed) or other thrombopoietic agents. The first primary endpoint was the incidence of splenectomy or study discontinuation. The second primary endpoint was the incidence of treatment failure (defined as: platelet count 20x109/L for 4 consecutive weeks at the highest recommended dose and schedule, or major bleeding event, or change in therapy due to intolerable side-effect or bleeding symptoms) or study discontinuation. RESULTS: In total, 234 patients were randomized (SOC, 77; romiplostim, 157). In romiplostim treated patients, there was a significantly lower incidence of splenectomy or study discontinuation (OR, 0.169; 95% CI: 0.081, 0.351; p<0.0001) and treatment failure or study discontinuation (OR, 0.374; 0.188, 0.744; p=0.0039) than in patients receiving SOC. A sensitivity analysis, applied to patients who did not discontinue the study, showed a consistent trend in the incidence of splenectomy and treatment failure with both of the primary endpoint results. Safety analyses included all patients who received ≥1 dose of romiplostim or 1 type of SOC for ITP. Adverse events were experienced by 92% (69/75) of patients receiving SOC and by 95% (146/154) of patients receiving romiplostim. The most common adverse events in the SOC group were epistaxis (23%), nasopharyngitis (19%), and contusion (19%); and in the romiplostim group were headache (35%), fatigue (27%), and nasopharyngitis (23%). Treatment-related serious adverse events were reported by 8% (6/75) of SOC and 5% (7/154) of romiplostim patients. Three patients died during the 52-week treatment period: 2 SOC patients (cardio-respiratory arrest, hepatic failure), and 1 romiplostim patient (pneumonia). None of the deaths were deemed related to study treatment. Bleeding events with grade ≥3 severity were reported by 8% (6/75) of patients in the SOC group, compared with 3% (5/154) in the romiplostim group. CONCLUSIONS: Romiplostim significantly reduced incidences of splenectomy and treatment failure in nonsplenectomized ITP patients compared to standard of care. The safety profile was comparable between patients receiving romiplostim and those receiving SOC.
Introduction: Romiplostim is a novel peptibody that increases platelet counts by a mechanism similar to endogenous thrombopoietin, and is approved for the treatment of chronic ITP. ITP is characterized by low platelet counts due to increased platelet destruction and suboptimal platelet production. The response rate to ITP therapies is variable and may be associated with substantial adverse effects. Splenectomy is commonly used as a treatment for ITP because it removes the major site of platelet destruction. A recent consensus report (Provan et al., 2010, 168-86) recommends delaying splenectomy for 6-12 months, in keeping with the new definition for chronic ITP (Rodeghiero et al., Blood 2009, 2386-93); therefore, we evaluated patients who had been diagnosed with ITP 1 year who participated in a recent study of romiplostim versus standard of care (SOC). Methods: A randomized, open-label study was conducted in nonsplenectomized adult patients with ITP. The co-primary study endpoints were the incidence of treatment failure and the incidence of splenectomy. Treatment failure was defined as: platelet count 20 x 109/L for 4 consecutive weeks at the highest recommended dose and schedule of romiplostim or SOC, or major bleeding event, or change in therapy due to intolerable side-effect or bleeding symptoms. The secondary endpoints included platelet counts and safety. Patients who discontinued treatment were considered to have met both primary endpoints. To assess the impact of study discontinuation on the primary endpoints, the actual incidence of treatment failure and splenectomy were also determined (“sensitivity analysis”). An ad hoc analysis of the study endpoints was conducted in those study patients who had been diagnosed with ITP for 1 year. Results: Eighty-five of 234 enrolled patients had ITP for 1 year; 29 received SOC and 56 received weekly subcutaneous injections of romiplostim. Patient characteristics were similar between treatment groups, as was the distribution of time since ITP diagnosis (romiplostim, 7 - 327 days; SOC 4 - 363 days). The mean (±SD) age was 53 (±20) years and 47% of the patients were male. The mean baseline platelet counts were similar in the romiplostim (26 ± 14 x 109/L) and SOC (23 ± 16 x 109/L) groups. The mean platelet count was higher in the romiplostim arm than the SOC arm at every weekly evaluation until the end of treatment (52 weeks). The incidence of treatment failure was lower in the romiplostim group (9%, 5/56) than in the SOC group (24%, 7/29) [OR, 0.34; 0.10 - 1.14; p= 0.0649]. Similarly, the incidence of splenectomy was significantly lower in the romiplostim group (7%, 4/56) than the SOC group (45%, 13/29) [OR, 0.10; 0.03 - 0.35; p<0.0001]. In addition, romiplostim-treated patients had a significantly longer time to splenectomy than SOC patients (p=0.0001) (Figure). The sensitivity analysis showed that the actual incidence of treatment failure was similar between treatment groups (romiplostim, 5%, 3/56; SOC, 10%, 3/29) [p=0.5589] and the actual incidence of splenectomy was significantly lower in romiplostim-treated patients (4%, 2/56) than in SOC-treated patients (35%, 10/29) [p=.0002]. The percentage of patients experiencing a serious bleeding event was similar (romiplostim, 6%; SOC, 4%). Serious adverse events occurred in 24% (13/55) of romiplostim patients and 46% (13/28) of SOC patients with the most common event being thrombocytopenia. No adverse events led to study withdrawal. Thromboembolic events occurred in one romiplostim-treated patient (pulmonary embolism) and one SOC patient (cerebral microangiopathy). There were no reports of increased reticulin, and no patients tested positive for neutralizing antibodies to romiplostim or TPO. (Figure presented) Conclusion: The results from this ad-hoc analysis of this subgroup indicate romiplostim may reduce the incidence of treatment failure and splenectomy in patients who have been diagnosed with ITP for 1 year or less, although the enrollment of patients with platelet counts >20 x 109/L may have contributed to reduced differences in the rates of treatment failure per the study definition. Romiplostim was well-tolerated in this patient population, and findings were similar to those previously reported for the study population overall (Kuter et al., ASH 2009, #679).
ANTECEDENTES: El romiplostim, un mimético de la trombopoyetina, aumenta el recuento de plaquetas en pacientes con trombocitopenia inmune, con pocos efectos adversos. MÉTODOS: En este estudio abierto, de 52 semanas de estudio, se asignó aleatoriamente a 234 pacientes adultos con trombocitopenia inmune, que no habían sido sometidos a esplenectomía, para recibir el tratamiento estándar (77 pacientes) o inyecciones subcutáneas semanales de romiplostim (157 pacientes). Los desenlaces primarios fueron la incidencia de fracaso del tratamiento y la esplenectomía. Los puntos finales secundarios incluyeron la tasa de respuesta de las plaquetas (un recuento de plaquetas> 50 x 10 (9) por litro en cualquier visita programada), los resultados de seguridad y la calidad de vida. RESULTADOS: La tasa de respuesta de las plaquetas en el grupo de romiplostim fue 2,3 veces mayor que en el grupo estándar de atención (95% intervalo de confianza [IC], 2,0 a 2,6, P <0,001). Los pacientes que recibieron romiplostim tuvo una incidencia significativamente menor de fracaso del tratamiento (18 de 157 pacientes [11%]) que los que recibieron el tratamiento estándar (23 de las 77 pacientes [30%], P <0,001) (odds-ratio con romiplostim, 0,31; 95% IC, 0,15 a 0,61). La esplenectomía también se llevó a cabo con menos frecuencia en los pacientes que recibieron romiplostim (14 de 157 pacientes [9%]) que en aquellos que recibieron el tratamiento estándar (28 de 77 pacientes [36%]; p <0,001) (odds ratio, 0,17; 95% IC, 0,08 a 0,35). El grupo de romiplostim tuvieron una menor tasa de episodios de sangrado, menos transfusiones de sangre, y mayores mejoras en la calidad de vida que el grupo estándar de atención. Los acontecimientos adversos graves en el 23% de los pacientes (35 de 154) que recibieron romiplostim y 37% de los pacientes (28 de 75) que recibieron el tratamiento estándar. Conclusiones: Los pacientes tratados con romiplostim tuvieron una tasa más alta de una respuesta plaquetaria, una menor incidencia de fracaso del tratamiento y la esplenectomía, menos sangrado y menos transfusiones de sangre, y una mejor calidad de vida de los pacientes tratados con el estándar de cuidado. (Número en ClinicalTrials.gov, NCT00415532.).
Romiplostim increases platelet counts and reduces the risk of bleeding in patients with immune thrombocytopenia (ITP). This post hoc analysis compared the effect of romiplostim versus medical standard of care (SOC) on clinically relevant bleeding-related episodes (BREs) in a 52-week open-label study of patients with ITP. BREs were defined as actual bleeding events and/or use of rescue medication. Nonsplenectomized adult patients with ITP were randomized to receive weekly subcutaneous injections of romiplostim (n = 157) or SOC (n = 77). The rate of all BREs (per 100 patient-weeks) was lower in patients treated with romiplostim (3.1) than in those treated with SOC (9.4); the relative rate (romiplostim/SOC) was 0.33 (95 % CI 0.27-0.40). The rate of BREs associated with immunoglobulin (Ig) rescue medication was also lower for romiplostim (0.2) than SOC (4.8); the relative rate (romiplostim/SOC) was 0.05 (95 % CI 0.03-0.08). BRE rates were lower in patients with platelet counts ≥50 × 10(9)/L, and patients treated with romiplostim spent more time with platelet counts ≥50 × 10(9)/L than did patients treated with SOC. Bleeding-related hospitalizations were rare in both groups. Thus, romiplostim treatment provided greater reductions in all BREs, as well as BREs involving Ig rescue medications, than did SOC.
A safety analysis of pooled data from clinical studies of romiplostim, a thrombopoietin (TPO) receptor agonist, in which patients with immune thrombocytopaenia (ITP) received romiplostim, placebo, or medical standard of care (SOC) Rodeghiero et al. (Eur J Haematol 91:423-436, 2013), has been updated. Included are data from 14 trials spanning 2002-2011; placebo- and SOC-arm data are pooled. Most patients (n = 1059) were female (61 %) and Caucasian (85 %); 38 % had undergone splenectomy; 23 were children. Mean (SD) baseline platelet count was 20.6 (16.5) × 10(9)/L. Mean (SD) weekly dose of romiplostim was 4.2 (2.8) µg/kg; total exposure was 1520 patient-years. Overall, 921 patients received romiplostim only, 65 received placebo/SOC only, and 73 received placebo/SOC followed by romiplostim. Rates of haemorrhage (romiplostim, 205/100 patient-years; placebo/SOC, 263/100), thrombosis (both, 5.5/100 patient-years), haematological malignancy/myelodysplastic syndrome (romiplostim, 0.5/100 patient-years; placebo/SOC, 2.7/100), and non-haematological tumours (romiplostim, 2.2/100 patient-years; placebo/SOC, 3.6/100) were comparable among groups. Bone marrow reticulin was reported in 17 patients and collagen in one patient receiving romiplostim; one patient receiving placebo/SOC had reticulin reported. Three patients developed neutralizing antibodies to romiplostim, but not to endogenous TPO. This integrated analysis of the safety profile of romiplostim in patients with ITP is consistent with previously reported studies; no new safety concerns emerged.
This is a phase 3b, multi-center, randomized, Standard of Care (SOC)-controlled, open-label, 52-week treatment study to compare romiplostim to medical SOC for Idiopathic Thrombocytopenia Purpura (ITP), with a 6-month Safety Follow-up. Patients randomized to romiplostim must complete the taper or discontinuation of medical SOC for ITP as soon as medically feasible after the initiation of romiplostim. After the completion or discontinuation of the study treatment period, any participant who does not transfer in to another romiplostim study will complete a 6-month Safety Follow-up period.
Diseño del estudio»Ensayo controlado aleatorizado (ECA)
