Islet Allotransplantation in Type 1 Diabetes
试验速览
- 阶段
- 1 期
- 状态
- 暂停
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Incidence of hypoglycemia
研究概览
简要总结
Islet transplantation can provide physiologic insulin replacement to patients with type 1 diabetes without the complications associated with whole pancreas transplantation. The purpose of this study is to achieve insulin-independence in patients with type 1 diabetes, thereby eliminating the need for exogenous insulin injections to maintain normal glucose levels, ameliorating severe hypoglycemia and potentially decreasing the development of diabetes-related complications. This study will investigate islet transplantation in subjects who have preserved renal function and subjects who have undergone cadaveric renal transplantation, since the latter subjects are already on immunosuppression.
This is a single center, prospective trial of islet transplantation in subjects receiving islets alone or islets after kidney transplant. This is a phase I study investigating the use of islet transplantation for the treatment of type 1 diabetes. Subjects will be eligible for an islet transplant if they meet all of the inclusion criteria and none of the exclusion criteria outlined in the protocol. In brief, the aims of this study are to establish an islet transplant program at the Ohio State University, determine the safety of islet transplantation in islet alone and kidney transplant recipients, determine whether islet transplantation will reduce the frequency of severe hypoglycemic events, determine whether a novel steroid-free immunosuppressive protocol will prevent rejection in islet transplants and to achieve insulin independence at one year after the final islet transplant.
详细描述
Hypothesis - Insulin independence (insulin injections no longer needed) will be achieved in subjects with type 1 diabetes receiving islet transplantation using the immunosuppressive regimen of cyclosporine and sirolimus. Amelioration of severe hypoglycemia will also be achieved in these groups.
Primary Objective
To determine the safety of islet transplantation in islet alone and in kidney transplant recipients. Safety analyses include:
- Incidence, timing and severity of adverse events and their relationship to the transplant protocol, islet infusion and immunosuppressive medications
- Proportion without protocol-related serious adverse events (SAE) at 1 year
- Incidence, type and severity of infectious complications
- Incidence and severity of procedural-related events, such as bleeding and portal vein thrombosis
- Incidence and severity of liver function test elevations
- Incidence and severity of hypoglycemia
- Incidence and severity of creatinine clearance and urine microalbumin changes
- Incidence and severity of lipid abnormalities
- Proportion of those who develop donor-specific alloantibody
Secondary Objective
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
- 否
入选标准
- •Type 1 diabetes > 5 years
- •First islet transplant
- •Demonstrate intensive efforts to manage diabetes for last 6 months (≥4 SMBG/day, ≥3 injections of insulin/day or use of pump and ≥3 contacts with diabetes care team in last 12 months)
- •Metabolic complications: at least one of the following:
- •Reduced hypoglycemia awareness (inability to sense hypoglycemia until blood glucose falls to < 54 mg/dl or > one hypoglycemic episode in last 12 months requiring outside help and not explained by clear precipitant)
- •≥2 severe hypoglycemic events or ≥2 hospitalizations for diabetic ketoacidosis (DKA) in last year.
- •Ability to provide written informed consent
- •Specific for group 2: All of above (1-6) with renal transplant at least 6 months previous
排除标准
- •Age < 18 years or > 65 years
- •Inability to provide informed consent
- •Body Mass Index > 29 kg/m2
- •Insulin requirement of > 50 units/day
- •Stimulated C-peptide ≥ 0.2 ng/ml
- •Current panel reactive anti-HLA antibodies >20%
- •Cardiovascular instability
- •Previous islet transplant
- •History of malignancy except squamous and basal cell skin cancer unless disease-free for > 2 years determined by independent oncologist
- •Active peptic ulcer disease
- •Condition that may interfere with absorption of medications
- •Hemoglobin A1C > 12%
- •Invasive aspergillus infection within one year
- •Varicella titer index <1.0
- •Rubella titer <10 IU/ml
- •Psychiatric disorder
- •Untreated hyperlipidemia: fasting total cholesterol >240 mg/dl, low density lipoprotein>130 mg/dl, or triglycerides >200 mg/dl
- •Hemoglobin <10 g/dl for females, and <11 g/dl for males, white blood cell count < 3,000/µL, platelet count of <150,000/microliter, CD4+ count <500/microliter
- •Liver function test abnormalities (if any value > 1.5 times normal, candidate will be excluded. If 1-1.5 times normal, test will be repeated. If re-test value remains above normal, candidate will be excluded).
- •Prostate specific antigen >4.0 ng/ml
- •Presence of gallstones, liver hemangioma, cirrhosis or evidence of portal hypertension
- •Untreated proliferative diabetic retinopathy
- •Females: positive pregnancy test, intent for future pregnancy, or any subject of reproductive age who is not surgically sterile and is unable or unwilling to use acceptable method of contraception
- •Female subjects who are breast-feeding
- •Adrenal insufficiency: 8am cortisol >19 mcg/dl adequate. Values 19 mcg/dl will be followed by Adreno-Corticotropic Hormone stimulation test
- •Any disease or condition that requires use of chronic steroids
- •Coagulopathy or use of chronic anticoagulation
- •Hyperthyroidism unless treated with radioactive iodine or surgery
- •Thyroid function tests outside normal range
- •Active alcoholism or other substance abuse within the past six months
- •History of non-adherence. Questionable adherence requires agreement entered and compliance demonstrated for at least 3 months
- •Active infection including hepatitis B or C, human immunodeficiency virus positive, positive Mantoux test [unless previously immunized with Bacillus Calmette-Guerin], or X-ray evidence of pulmonary infection
- •Inability to reach hospital within 6 hours of notification
- •Failure to clear psychological or psychiatric screen
- •Medical condition or circumstance that investigator finds will interfere with safe completion of the study
- •Exclusion criteria specific for group 1:
- •Receipt of previous transplant (excluding pancreas)
- •Creatinine clearance <50 ml/minute for females and <60 ml/minute for males or macroalbuminuria (>500 mg/24h)
- •Exclusion criteria specific for group 2:
- •Creatinine clearance <40ml/minute
- •Renal transplant in last 6 months
- •Current use of corticosteroids
研究组 & 干预措施
Subjects with preserved kidney function
Subjects with preserved renal function that have not previously received a kidney transplant will be treated with Human Pancreatic Islets (in the form of islets alone - IA).
干预措施: Human Pancreatic Islets (Drug)
Subjects with prior kidney transplant
Subjects with renal failure secondary to diabetes who have received a prior kidney transplant at least 6 months previously and have stable renal function on a steroid-free immunosuppressive regimen will receive Human Pancreatic Islets (in the form of islets after kidney - IAK).
干预措施: Human Pancreatic Islets (Drug)
结局指标
主要结局
Incidence of hypoglycemia
时间窗: Day 365 post-transplant
Incidence of donor-specific antibody development
时间窗: Day 365 post-transplant
Change in microalbumin level
时间窗: Days 180 and 365 post-transplant
Incidence of adverse events
时间窗: Days 1, 2, 3, 5, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant
Incidence of serious adverse events
时间窗: Days 1, 2, 3, 5, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant
Serious adverse events will be defined (in accordance with FDA Title 21 CFR 312.32) as the following: * Death * Life-threatening and placing the subject at immediate risk of death * Hospitalization * Persistent or significant disability or incapacity * Congenital abnormal/birth defects * Requiring medical or surgical intervention to prevent permanent damage
Incidence of infectious complications
时间窗: Days 1, 2, 3, 5, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant
Incidence of procedural-related events
时间窗: Day 3 post-transplant
Ex. Bleeding or portal vein thrombosis
Incidence of elevated liver function tests
时间窗: Day 365 post-transplant
Incidence of abnormalities in lipids
时间窗: Day 365 post-transplant
Change in measured creatinine clearance
时间窗: Days 180 and 365 post-transplant
次要结局
- Amount of daily insulin units required(Days 1, 2, 3, 5, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant)
- Change in acute insulin response to glucose(Days 180 and 365 post-transplant)
- Change in glycemic lability score(Days 1, 2, 3, 5, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant)
- Measurement of C-peptide(Days 1, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant)
- Incidence of blood glucose level <140mg/dl two hours after oral glucose tolerance tests(Days 180 and 365 post-transplant)
- Change in c-peptide level from fasting following administration of mixed meal(Days 180 and 365 post-transplant)
- Change in Quality of Life(Days 180 and 365 post-transplant)
- Change in hypoglycemia score(Days 1, 2, 3, 5, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant)