Phase 2 Study of Avatrombopag in Japanese Patients with Chronic Liver Disease and Thrombocytopenia
Hepatology research : the official journal of the Japan Society of Hepatology. 2022
AIM: Avatrombopag, a thrombopoietin receptor agonist, can reduce the need for platelet transfusions or rescue interventions for bleeding in patients with chronic liver disease (CLD) and thrombocytopenia undergoing scheduled procedures. A model analysis indicated that the effect of avatrombopag on platelet production was reduced in East Asian versus non-East Asian patients; however, the difference was deemed not clinically significant. Furthermore, a subgroup analysis of pooled Phase 3 trials showed similar avatrombopag efficacy across racial subgroups. The aim of this Phase 2 study was to corroborate the efficacy and safety of avatrombopag in Japanese patients with thrombocytopenia due to CLD. METHODS Japanese patients with CLD and thrombocytopenia were randomized to receive placebo or avatrombopag 20, 40, or 60 mg daily for 5 days. The primary endpoint was responder rate in platelet counts at Visit 4 (10-13 days after treatment initiation), defined as the proportion of patients with platelet count ≥50×10(9) /L and ≥20×10(9) /L increase from baseline. RESULTS Thirty-nine patients were randomized and completed the study (placebo, n=11; avatrombopag 20 mg, n=7; 40 mg, n=11; 60 mg, n=10). Avatrombopag treatment was associated with significant increases in responder rate at Visit 4 in the 40 mg (63.6%; P=0.004) and 60 mg (40%; P=0.024) groups versus placebo (9.1%). Avatrombopag was well tolerated and no new safety signals were detected. CONCLUSIONS Efficacy and safety results from this study were consistent with previous studies in patients with CLD and thrombocytopenia undergoing elective procedures, supporting treatment with avatrombopag in the Japanese population. ClinicalTrials.gov identifier: NCT02227693. This article is protected by copyright. All rights reserved.
Impact of prestorage leucoreduction of autologous whole blood on length of hospital stay with a subgroup analysis in bilateral hip arthroplasty
Vox Sanguinis. 2018
BACKGROUND Although prestorage leucoreduction (LR) of blood components for transfusion has gained favour around the world, evidence of its beneficial clinical effects is ambiguous. STUDY DESIGN AND METHODS To reveal whether leucocytes and/or platelets in transfused blood are related to transfusion-related adverse effects, a prospective randomized crossover study was performed on patients who donated autologous blood prior to elective surgery. Among 1487 primary enrolees, a total of 192 patients undergoing two-stage, bilateral total hip arthroplasty were randomized to receive autologous blood that was either prestorage leucoreduced, or not, for the first procedure. For the second procedure, each patient was crossed over to receive alternatively processed autologous blood. Length of hospital stay served as a primary end-point, with perioperative infectious/thrombotic complications, pre- and postoperative laboratory values, and body temperature serving as secondary endpoints. RESULTS No significant differences emerged between prestorage LR and non-LR cohorts in length of hospital stay, as well as perioperative infectious/thrombotic complications, postoperative body temperature and duration of fever. Postoperative laboratory values including white blood cell counts and C-reactive protein levels had no significant differences. CONCLUSION This study could not prove any superiority of prestorage LR over non-LR for autologous whole blood among patients who underwent total hip arthroplasty.
An open-label prospective randomized multicenter study of intensive versus weekly granulocyte and monocyte apheresis in active crohn's disease
BMC Gastroenterology. 2015;15((1)):163.
BACKGROUND Granulocyte and monocyte adsorptive apheresis (GMA) has shown efficacy in patients with active Crohn's disease (CD). However, with routine weekly therapy, it may take several weeks to achieve remission. This study was performed to assess clinical efficacy and safety of intensive GMA in patients with active CD. METHODS In an open-label, prospective, randomized multicentre setting, 104 patients with CD activity index (CDAI) of 200 to 450 received intensive GMA, at two sessions per week (n = 55) or one session per week (n = 49). Clinical remission was defined as a CDAI score <150. Patients in each arm could receive up to 10 GMA sessions. However, GMA treatment could be discontinued when CDAI decreased to <150 (clinical remission level). RESULTS Of the 104 patients, 99 were available for efficacy evaluation as per protocol, 45 in the weekly GMA group, and 54 in the intensive GMA group. Remission was achieved in 16 of 45 patients (35.6 %) in the weekly GMA and in 19 of 54 (35.2 %) in the intensive GMA (NS). Further, the mean time to remission was 35.4 +/- 5.3 days in the weekly GMA and 21.7 +/- 2.7 days in the intensive GMA (P = 0.0373). Elevated leucocytes and erythrocyte sedimentation rate were significantly improved by intensive GMA, from 8005/muL to 6950/muL (P = 0.0461) and from 54.5 mm/hr to 30.0 mm/hr (P = 0.0059), respectively. In both arms, GMA was well tolerated and was without safety concern. CONCLUSIONS In this study, with respect to remission rate, intensive GMA was not superior to weekly GMA, but the time to remission was significantly shorter in the former without increasing the incidence of side effects. UMIN registration # 000003666.
Efficacy of single-dose intravenous immunoglobulin administration for severe sepsis and septic shock
Journal of Intensive Care. 2013;1((1):):4.
BACKGROUND Although some studies conducted outside of Japan have addressed the effectiveness of intravenous immunoglobulins (IVIG) in treating infections, the dosing regimens and amounts used in Japan are very different from those reported. Here, we investigate the effectiveness of single-dose administration of IVIG in sepsis patients in Japan. METHODS We analyzed 79 patients admitted to the intensive care unit (ICU) of a tertiary care institution due to severe sepsis or septic shock. Patients were randomly divided into a group that was administered standard divided doses of IVIG (5 g/day for 3 days, designated the S group) or a group that was administered a standard single dose of IVIG (15 g/day for 1 day, H group); freeze-dried sulfonated human IVIG was used. The longitudinal assessment of procalcitonin (PCT) levels, C-reactive protein (CRP) levels, white blood cell count, blood lactate levels, IL-6 levels, Sequential Organ Failure Assessment (SOFA) score, and Systemic Inflammatory Response Syndrome (SIRS) was conducted. We also assessed mechanical ventilation duration (days), ICU stay (days), 28-day survival rate, and 90-day survival rate. RESULTS The study showed no significant differences in PCT levels, CRP levels, 28-day survival rate, and 90-day survival rate between the two groups. However, patients in the H group showed improvements in the various SIRS diagnostic criteria, IL-6 levels, and blood lactate levels in the early stages after IVIG administration. In light of the non-recommendation of IVIG therapy in the Surviving Sepsis Campaign Guidelines 2012, our findings of significant early post-administration improvements are noteworthy. IVIG's anti-inflammatory effects may account for the early reduction in IL-6 levels after treatment, and the accompanying improvements in microcirculation may improve blood lactate levels and reduce SOFA scores. However, the low dosages of IVIG in Japan may limit the anti-cytokine effects of this treatment. Further studies are needed to determine appropriate treatment regimens of single-dose IVIG. CONCLUSIONS In this study, we investigated the effectiveness of single-dose IVIG treatment in patients with severe sepsis or septic shock. Although there were no significant effects on patient prognoses, patients who were administered single-dose IVIG showed significantly improved IL-6 levels, blood lactate levels, and disease severity scores.
A comparative double-blind randomized trial of activated protein C and unfractionated heparin in the treatment of disseminated intravascular coagulation
International Journal of Hematology. 2002;75((5):):540-7.
A randomized prospective double-blind trial was performed to compare the safety and efficacy of human activated protein C (APC) and unfractionated heparin for the treatment of disseminated intravascular coagulation (DIC). One hundred thirty-two patients with DIC were enrolled in this study: 63 patients received APC (12.5 U [2.5 microg]/kg body wt per hour) and 69 patients received heparin (8 U/kg body wt per hour) by intravenous infusion for 6 days. Forty-nine APC-treated patients and 55 heparin-treated patients were evaluated for efficacy, and 52 APC-treated patients and 55 heparin-treated patients were evaluated for safety. The 2 groups were similar with respect to sex, age, body weight, underlying diseases, and coagulation/fibrinolysis parameters before treatment. Aggravation of bleeding was seen after treatment in 8 patients receiving heparin, but in none of the patients receiving APC. The number of patients who showed alleviation of bleeding was significantly higher in the APC group than the heparin group (P = .009). The effects on DIC-related organ dysfunction were not significantly different between the 2 groups. Fibrinogen-fibrin degradation products, D-dimer, thrombin-antithrombin complex (TAT), and plasmin-plasmin inhibitor complex (PIC) were all significantly decreased by treatment in both groups. Fibrinogen, protein C, and antithrombin were significantly increased in the APC group, whereas only protein C was significantly increased in the heparin group. Platelet count in the nonleukemic group was significantly increased in those patients receiving APC but not increased in those patients receiving heparin. Improvement of coagulation/fibrinolysis was assessed by scoring 4 parameters (soluble fibrin monomers, D-dimer, TAT, and PIC), and the results indicated that the APC group showed significantly greater improvement than the heparin group (P = .046). There was, however, no significant difference in the rate of complete recovery from DIC between the 2 groups. The rate of death from any cause within 28 days after treatment was 20.4% in the APC group, significantly lower than the 40% death rate observed in the heparin group (P < .05). There were no severe adverse events in either group. These results suggest that APC in a relatively small dosage can improve DIC more efficiently than can heparin, without increasing bleeding, and may be a better alternative.