NCT01893775已完成1 期
Phase I Study of the Humanized Mik-Beta-1 Monoclonal Antibody Directed Toward IL-2/IL-15R Beta (CD122) That Blocks IL-15 Action In Patients With Refractory Celiac Disease
适应症
干预措施
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 5
- 试验地点
- 1
- 主要终点
- safety of Hu MIK Beta 1 in celiac disease pts
研究概览
简要总结
Background:
- Celiac disease is a condition where the immune system attacks the cells of the small intestine. The intestine becomes inflamed and cannot digest food properly. The disease most often causes a reaction to foods that contain gluten. Most people can treat celiac disease with a gluten-free diet. However, some people have digestion problems even on a gluten-free diet. Researchers want to try a new antibody therapy for celiac disease. The treatment may block the immune reaction that causes the disease. They will test this antibody in people who have celiac disease that has not responded to a gluten-free diet.
Objectives:
- To see if antibody therapy is a safe and effective treatment for celiac disease that has not responded to standard treatments.
Eligibility:
- Individuals at least 18 years of age who have been on a gluten-free diet for 6 to 12 months but still have symptoms of celiac disease.
Design:
- Participants will be screened with a physical exam and medical history. Blood samples will be collected. These samples will help determine if the specific antibody treatment is likely to work.
- Before the start of the study, participants will have a biopsy of the small intestine.
- Participants will receive three doses of the study antibody as injections. These doses will be given 3 weeks apart.
- Treatment will be monitored with blood tests and heart function tests. Participants will also have a second small intestine biopsy within a week after the last dose of the antibody.
详细描述
Background:
- Celiac disease is a complex inflammatory disorder with an autoimmune component characterized by a dramatic expansion of intraepithelial cytotoxic T lymphocytes that usually regress on a gluten-free diet.
- It is estimated that approximately 10% of patients become refractory on a gluten-free diet.
- A subgroup of refractory celiac disease is characterized by expansion of a highly oligoclonal intraepithelial T-lymphocyte population that exhibits a high risk of developing enteropathy associated T-cell lymphoma (EATL).
- There is presently no effective therapy for refractory celiac disease.
- A number of studies indicate that intestinal epithelial derived IL-15 plays a critical role in the disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis that characterizes refractory celiac disease.
- A pivotal role for IL-15 in refractory celiac disease and EATL is further supported by the finding that in two murine models of celiac disease the pathognomonic features were reversed completely by administration of an antibody to CD122 (IL-2/IL-15R beta) that blocks IL-15 transpresentation and action.
- A Phase I clinical trial in patients with T-cell LGL and hematocytopenia using the monoclonal antibody, Hu-Mik-Beta-1 that blocks IL-15 action produced under cGMP conditions by the BDP NCI has been completed in the Metabolism Branch, NCI at the Clinical Center NIH.
Objectives:
Primary Objectives:
- Phase I trial to define the safety of Hu-Mik-Beta-1 infusions to 2 groups of patients each with refractory celiac disease at escalating 0.5 (7 patients) and 1.0 (2 patients) mg/kg doses.
- To define the clinical efficacy of Hu-Mik-Beta-1 infusions in 9 patients with refractory celiac disease and to correlate these findings with celiac disease specific tests.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 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 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •INCLUSION CRITERIA
- •2.1.1.1 Patients must be greater than or equal to 18-years-old.
- •2.1.1.2 All patients must have a pathologically confirmed diagnosis of refractory celiac disease(RCD) defined by internationally accepted criteria of persistent and recurrent symptoms(diarrhea, weight loss, and abdominal pain) associated with intestinal damage, characterized by partial to total villous atrophy with intraepithelial lymphocytes defined by > 25 intraepithelial lymphocytes per 100 epithelial cells.
- •2.1.1.3 Persistence of the above signs and symptoms despite strict adherence to a gluten-free diet for 6-12 months
- •2.1.1.4 Patients are to have had circulating antibodies to transglutaminase-1 or similar celiac specific serology
- •2.1.1.5 Patients must have a life expectancy of > 3 months
- •2.1.1.6 Patients must have a creatinine of less than 2.0 mg/dL or if the patient has an elevated creatinine measured creatinine clearance (Ccr) must be > 60 mL/min/1.73m(2)
- •2.1.1.7 Patients must have a serum alkaline phosphatase, ALT (SGPT) and AST (SGOT) less than 3x the upper limits of normal (ULN)
- •2.1.1.8 Patients must have a total bilirubin of less than 2.5 x ULN
- •2.1.1.9 Women of childbearing potential must have a negative beta HCG pregnancy test at initial screening and within 3 days prior to registration
- •2.1.1.10 Patients receiving a stable dose (> 4 weeks) of corticosteroid therapy equal to 20 mg of prednisone per day or less are eligible
- •2.1.1.11 Patients with a history of curatively treated basal cell carcinoma or intraepithelial neoplasia of the uterine surface will be allowed on the study
- •2.1.1.12 Patients must be able to understand and sign an informed consent
排除标准
- •2.1.2.1 Patients enrolled in another therapeutic study
- •2.1.2.2 Patients with a history of venous thrombosis
- •2.1.2.3 Patients with antibodies to Hu-Mik-Beta-1
- •2.1.2.4 A contraindication to monoclonal antibody therapy including adverse events related to prior monoclonal antibody therapy. Patients who have received prior antibody therapy will have permanent medical records reviewed by the study investigator.
- •2.1.2.5 Any uncontrolled or chronic bacterial, mycobacterial or other viral (e.g., herpes virus), fungal, parasitic or protozoal infection
- •2.1.2.6 History of malignancy (active or within the previous 5 years)
- •2.1.2.7 Patients with HIV infection (antibody positive) with positive confirmatory molecular tests
- •2.1.2.8 Patients who have chronic hepatitis B or chronic hepatitis C
- •2.1.2.9 Pregnant or breastfeeding women. Women who not using an acceptable method of contraception. Acceptability of various methods of contraception will be determined by the investigator. Postmenopausal or surgically sterile women who have documentation of postmenopausal status or surgical sterility availability prior to enrollment.
- •2.1.2.10 Patients with significant co-morbidities including uncontrolled hypertension (diastolic B/P > 115 mm/Hg), unstable angina, congestive heart failure (> N.Y.H.A. Class II), poorly controlled diabetes, severe chronic pulmonary disease, coronary angioplasty or myocardial infarction within the last 6 months or uncontrolled atrial or ventricular cardiac arrhythmias.
- •2.1.2.11 Abnormal screening/baseline tests exceeding the limits outlined below:
- •Total white blood cell count (WBC) <300/mm(3)
- •Platelet count <85,000/mm(3)
- •INR greater than or equal to 1.5
- •Serum creatinine level > 1.5 mg/dL
- •Serum alanine transaminase, aspartate transaminase or creatinine kinase > 2 x the upper limits of normal
- •2.1.2.12 Patients with a history of a psychiatric disorder that may interfere with the understanding and compliance with this protocol, and the required follow-up
- •2.1.2.13 Exclusion at the discretion of the PI or delegate if participation in the study is deemed too risky (e.g., clinically significant pleural or pericardial effusion or ascites)
- •2.1.2.14 Inability to give informed consent
- •2.1.2.15 History of diverticulitis
研究组 & 干预措施
1
Experimental
Hu-Mik-Beta-1 every 3 weeks
干预措施: Hu-Mik- Beta-1 (Biological)
结局指标
主要结局
safety of Hu MIK Beta 1 in celiac disease pts
时间窗: end of week 9
Events will be tabulated and reported by grade with evaluationalso of supportive medications and surrogate markers of absorptionsuch as body mass index, albumin and hemoglobin.
次要结局
未报告次要终点
研究者
研究点 (1)
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