hOKT3γ1 (Ala-Ala) Combined With Sirolimus and Delayed Tacrolimus in Type 1 Diabetic Islet Allograft Recipients
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 6
- 试验地点
- 2
- 主要终点
- Safety, tolerability, immune activity, and pharmacokinetics of hOKT3γ1 (Ala-Ala) antibody induction therapy for the prevention of autoimmune destruction and rejection of allogeneic islet transplants as measured by:
研究概览
简要总结
The collective effects of two-layer pancreas preservation, pretransplant islet culture, day -2 pretransplant immunosuppression, and induction immunosuppression with the FcR-nonbinding anti-CD3 monoclonal antibody hOKT3γ1 (Ala-Ala)to facilitate diabetes reversal after single-donor islet transplantation.
详细描述
This is an open-label, one-year follow-up study of type 1 diabetic islet allograft recipients who receive FcR non-binding OKT3 antibody hOKT3γ1 (Ala-Ala) plus sirolimus induction immunotherapy combined with sirolimus and delayed tacrolimus maintenance immunosuppression. Six subjects were transplanted.
The premise behind the proposal is that hOKT3γ1(Ala-Ala) corrects the imbalance between autoreactive and regulatory T cells and consequently prevents autoimmune destruction of transplanted islets. To prevent allorejection, hOKT3γ1(Ala-Ala)was combined with sirolimus and delayed tacrolimus. Additionally, the safety and efficacy of the maintenance immunosuppressive regimen of sirolimus combined with tacrolimus was monitored.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Primary islet allotransplant
- •Type 1 diabetes mellitus, complicated by at least one of the following situations that persist despite intensive efforts in close cooperation with their diabetes care team:
- •Metabolic lability/instability;
- •Reduced awareness of hypoglycemia;
- •Persistently poor glucose control (as defined by HgbA1c>10% at the end of six months of intensive management efforts with the diabetes care team);
- •Progressive secondary complications.
- •Age 18 and older
- •Able to give written informed consent
排除标准
- •Age less than 18 years
- •Body weight greater than75 kg.
- •BMI greater than 26 kg/m2 for male and females
- •Waist-to-hip ratio 0.80 (female) and 0.95 (male)
- •First degree relative with type 2 diabetes
- •Insulin requirement of greater than 0.7 IU/kg/day
- •HbA1C greater than 12%
- •Positive C-peptide response to intravenous arginine stimulation
- •Untreated proliferative retinopathy
- •Macroalbuminuria (urinary albumin excretion greater than 300 mg/24hrs)
- •Creatinine clearance greater than 85 ml/min/1.73 m2 in females, greater than 95 ml/min/1.73 m2 in males
- •Serum creatinine greater than 1.2 mg/dl
- •Previous pancreas or islet transplant
- •Previous OKT3 antibody therapy
- •Presence of history of panel-reactive anti-HLA antibodies greater than 10%
- •Abnormal T4 and TSH despite thyroid replacement therapy
- •Positive pregnancy test, or presently breast-feeding
- •Active infection
- •Negative screen for Epstein-Barr Virus (EBV) by an EBNA method
- •Invasive aspergillus infection within year prior to study entry
- •Any history of malignancy
- •Active alcohol or substance abuse
- •History of non-adherence to prescribed regimens
- •Psychiatric disorder making the subject not a suitable candidate for transplantation
- •Karnofsky performance score greater than 70
- •Baseline Hgb greater than 11.7 g/dl; lymphopenia (greater than 1,000/L), or leukopenia (greater than 4,000 total leukocytes/L), or an absolute CD4+ count <500/L
- •Thrombocytopenia greater than 150 x 109/L
- •Use of warfarin or other anticoagulant therapy (except aspirin) or patient with PT-INR greater than 1.5
- •Severe co-existing cardiac disease
- •Baseline liver function tests outside of normal range
- •Presence of gallstones on baseline ultrasound exam
- •Active peptic ulcer disease
- •Severe unremitting diarrhea or other gastrointestinal disorders potentially interfering with the ability to absorb oral medications
- •Celiac disease
- •Hyperlipidemia (fasting LDL cholesterol greater than 130 mg/dl, treated or untreated; and/or fasting triglycerides greater than 200 mg/dl)
- •Addison's disease.
- •Under treatment for a medical condition requiring chronic use of systemic steroids
- •Any medical condition that, in the opinion of the investigator, will interfere with the safe completion of the trial
结局指标
主要结局
Safety, tolerability, immune activity, and pharmacokinetics of hOKT3γ1 (Ala-Ala) antibody induction therapy for the prevention of autoimmune destruction and rejection of allogeneic islet transplants as measured by:
-Physical examination
-Vital signs
-Body weight
-Adverse events
-Laboratory and diagnostic safety assessments included complete blood counts with differential and platelets, circulating T cell phenotypes, and serum chemistry.
-Immune activity and pharmacokinetic assessments included hOKT3γ1 (Ala-Ala) level and half-life, monoclonal antibody coating and modulation of CD3 on peripheral blood T cells, and anti-hOKT3γ1 (Ala-Ala) antibody responses.
次要结局
- Efficacy of hOKT3γ1 (Ala-Ala) antibody induction therapy for the prevention of autoimmune destruction and rejection of islet transplants as defined by:
- -Proportion of subjects with full islet graft function (insulin independence and HbA1c <7%);
- -Proportion of subjects with partial islet graft function (insulin dependence, basal or arginine-stimulated C-peptide levels of greater or equal to 0.5 ng/ml and HbA1c <7%);
- -Proportion of subjects with slet graft loss will be defined as a return to insulin therapy for >30 days, absence of basal and arginine-stimulated C-peptide, re-transplantation, or patient death;