| 1 Jiannipa Phrase III Clinical StudyObjective:The phrase III clinical study was aimed to evaluate safety and effectiveness of the Jiannipai (recombinant humanized monoclonal anti-CD25 antibody injection, one production of Shanghai GuoJian Bio-Tec Institution, Shanghai, China) to prevent acute rejection among kidney transplantation patients.Methods:This study was multi-center, randomized, double-blind, placebo-controlled trial in patients receiving first renal graft transplant. According to the study protocol, the trail was intended to enroll 360 cases, of which 240 cases were experimental group and 120 cases in control group. Organ Transplant Center of Zhujiang Hospitals was responsible to enroll 54 patients (36 cases treatment group, 18 patients control group). Both groups were administered two dose of Jiannipai or placebo intravenously within 24 hours before transplantation and repeated on the 14th day after transplantation, and with cyclosporine A (CsA), mycophenolate mofetil (MMF) and glucocorticoids. All the enrolled patients were followed up for 6 months. The main effect endpoint was incidences of acute rejection (AR) within 3 months and 6 months after transplantation; Secondary efficacy endpoint was the outcome of reverse treatment of AR; the time points of the first occurrence of AR. Graft and patient's 1 year survival rate, serum creatinine (SCr) levels before and after transplantation, the time interval of SCr levels returned to normal, the incidences of delayed graft function (DGF), infection rate within 6 months post-transplant. Safety evaluation index based on adverse events (AE) which the patient complained or doctors observed, the changes in vital signs and laboratory parameters before and after transplantation. Statistical Methods:the populations of full analysis set (FAS) and per-protocol (PP) analysis set were determined by the principle of intention-to-treat (ITT) analysis.Results:Fifty-three patients were enrolled,35 patients were given Jiannipai (treatment group) and 18 patients were given placebo (control group). The Jiannipai and placebo patients were well matched for the baseline characteristics and preoperative conditions.50 patients fulfilled the 24 weeks of follow-up, in which 33 cases in treatment group and 17 in control group. The lost 3 cases caused by serious adverse events (2 in treatment group,1 control group), the loss rates were 5.71% and 5.56%, respectively (x2=0.001, P=0.981)FAS analysis set, the incidences of AR within 3 months were fewer in Jiannipai-treated patients (17.14%) than in placebo-treated patients (50.00%), and 6 months the data was same, and there statistically significant difference (x2=6.324, P =0.015). PP analysis set, the incidences of AR within 3 months, treatment group was 21.21%, control group 47.06% (x2=3.569, P=0.068), the 6 month's data were same.The outcome from AR recovery treatment between the two groups showed no statistical significance. Nearly 90% of first episode of AR occurred within first 4 weeks post-transplant, not reached statistically significant between the two groups. Patients 1 year survival rate in treatment group and control group were 97.14%, 100% (x2=0.514, P=0.473), graft survival was 94.3%,94.4% (x2=0.001, P= 0.981). The SCr level there declined very quickly in both group in the first week post-transplant and in the following several weeks the decline intend goes on, and the downward trend in both groups were similar. The incidences of DGF were 22.86% in treatment group,16.67% in control group (x2=0.028, P=0.866). The incidences of infection in treatment group were 17.14% (6/35) and control group 11.11%(2/18), there was no statistically significant (x2=0.031, P=0.860) in the two groups. The secondary efficacy endpoint was similar in PP or FAS set.All the enrolled patients were very well tolerated with Jiannipai. The incidences of test drug-related AE were nearly the same in the two groups and no statistically significant (Fisher's Exact Test P=0.340). Commonly, the AE included:constipation, nausea, headache, hyperlipidemia, hyperglycemia, hyperuricemia, liver function abnormalities, hypertension, leucopenia, thrombocytopenia, etc., the incidences of AE were no significant difference in the two groups (x2=2.696, P=0.088). Two Jiannipai-treated patients developed serious adverse events (SAE) (5.7%), slimily, one placebo treated patient (5.5%) developed SAE (x2=0.001,P=0.981).4 cases (12.1%) anti-antibodies appeared in the three weeks after administration of Jiannipai, in the six weeks only 1 case (3%) of anti-antibodies are still positive. Neutralizing antibody test, only 1 case was positive in the 3 weeks,6 weeks was negative.Conclusion:The data revealed that the safety and effectiveness of Jiannipai in renal transplantation patients to the prevention of acute rejection was similar with the Zenepax.ChapterⅡ:The extended 3-year follow-up.Objective:To study (1) the long-term affects of 2 dosages Jiannipai as induction therapy in renal transplant patients (2) The role of humoral rejection in graft lost and injury.Methods:We extended the followed-up period to all the enrolled patients to December 31,2009. All enrolled patients was screened the panel reactive antibody (PRA) at lest once during the follow-up, compare PRA level in different prognosis of patients.Results:Median follow-up time was 41.44±8.43 months (1.80-48.70m, n=53). During this period,4 patients died,5 cases lost graft,5 incidences of AR occurred within 6-36 months post transplantation,38 cases with well functional graft at the end of follow-up.(1) The long-term affects of 2 dosages Jiannipai as induction therapy in renal transplant patients.PP analysis set, three Jiannipai treated patients (9.09%) and two placebo treated patients (11.76%) had developed the AR from 6 to 36 m post-transplant, there were no statistical significance (x2=1.000, P= 0.056). Within the whole 36 m post-transplant period, the incidences of AR in treatment group was 30.30% (n=33), were significant lower than the control group (47.06%, n=17), (x2=4.741, P= 0.031). The outcome of AR reverse treatment between the two groups showed no statistical significance.PP analysis set, the incidences of chronic allograft nephropathy (CAN) in the treatment group (10.6%, n=33) were lower than the control group (23.52%, n=17) in 6-36 months period, but not reach statistically significant (x2=0.000, P=1.000).The types of post-transplant complications included:CAN, diabetes, liver dysfunction, hirsutism, infections. There was no difference of the incidences of the post transplantation complication between the two groups.In FAS set, the patients 3-year survival rate of was 94.12% in treatment group, 90.91% in the control group (x2=0.144, P=0.705). Correspondingly, the graft's 3-year survival rate was 82.9%,83.3% (x2=0.549, P=0.498). Censored the death cases with functioning graft, the 3-year graft survival rate was 88.2%,87.9%. (x2=0.619, P=0.431). The leading risk factors contributed to lost graft in two groups were CAN and death with functioning graft.(2) The role of humoral immune factors in the graft injury.In the whole follow up period, one graft was removed due to rupture at 7th day post transplantation.5 cases had developed the chronic allograft failure due to CAN and returned to dialysis, and 6 cases with CAN.45.46% (5/11) Panel reactive antibodies (PRA) positive in the patient with CAN or lost graft due to CAN,80% PRA positive in patients who lost graft due to CAN, while PRA positive were detected only 4 in well-function patients (45.46% vs.10.53%, x2=0.019, P=0.019; 80% vs.10.53%, x2=0.001,P=0.001)There were no statistically significant differences between the CAN and well function group patients in term of preoperative PRA, HLA mismatch, hot and cold ischemic time, immunosuppressive drug regimen, but the post transplantation Diabetes (PTDM) (x2=8.809, P=0.009).Conclusion:1, in the extend follow-up period, the incidences of AR, CAN and other complications were lower in treatment group but no statistical significance, patients/graft 3-year survival rates were similar in both groups. CAN was the leading reason for graft loss in both groups.2, the circulating de novo HLA alloantibody predict adverse short-term and long-term renal allograft outcomes, monitor the sera PRA level may be a key tool to find the ongoing chronic rejection. And PTDM is one of important risk factors leading to graft injury. |
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