An Exploratory, Open Label Study of Anti-inflammatory Therapy With Anakinra in Children With Newly Diagnosed Type 1 Diabetes Mellitus
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 15
- 试验地点
- 1
- 主要终点
- Effect of Anakinra Treatment on PBMC Gene Expression for Patients
研究概览
简要总结
The purpose of this study is to determine whether control of inflammatory pathways mediated by IL-1 beta using the IL-1 receptor antagonist anakinra will yield measurable decreases in expression of genes that are otherwise overexpressed as a consequence of IL-1 beta effects in children with newly diagnosed type 1 diabetes. Ultimately, we believe that control of IL-1 beta pathways will be associated with preserved insulin secretory capacity.
详细描述
Type 1 diabetes mellitus (T1D) is caused by autoimmune and autoinflammatory destruction of the insulin-producing beta cells in the pancreatic islets of Langerhans. Historically, treatment for this condition has consisted of insulin replacement therapy and dietary modification. Recent studies have demonstrated the potential benefits of immunomodulatory therapy in patients with newly diagnosed T1D to prevent further immune-mediated damage. Thus far, there has been a paucity of completed research using agents that target pro-inflammatory cytokines dysregulated in T1D.
IL1B, the gene encoding the proinflammatory cytokine interleukin-1β (IL-1β) is significantly overexpressed in peripheral blood mononuclear cells (PBMC) in patients with newly diagnosed T1D compared to healthy controls. There is ample precedent to support the involvement of IL-1β in the pathogenesis of diabetes. In particular, incubation of human or animal islets or insulinoma cell lines with IL-1β inhibits insulin secretion and leads to apoptosis of beta cells.
Additionally, the IL-1 receptor antagonist protein, anakinra, improves glycemic control and insulin secretory capacity in patients with type 2 diabetes.However, no data have been published regarding efficacy of agents targeting IL-1β in modifying the course of the disease in patients with T1D. Anti-Interleukin-1 in Diabetes Action (AIDA) is a randomized, placebo controlled clinical trial of anakinra in 160 adults with newly diagnosed type 1 diabetes. This trial is currently recruiting subjects. Review of clinicaltrials.gov demonstrates two other planned trials of IL-1 agents in newly diagnosed T1D, one using canakinumab, a monoclonal antibody directed at IL-1β, and another using rilonacept, a cytokine trap targeting IL-1β. To assess the effectiveness of these drugs in future studies and in clinical practice, it will be valuable to identify biomarkers that allow us to monitor their therapeutic effects. However, to the best of our knowledge, the pattern of changes in gene expression induced by IL-1β in normal PBMC has not been systematically studied, making it difficult to identify candidate biomarkers for validation studies.
In this exploratory study, we aimed to determine which of the characteristic changes in gene expression from patients with newly diagnosed T1D are IL-1β-mediated, using both in vitro and in vivo approaches. We also determined the effect size of a short course of anakinra therapy on glycemic control, insulin dosing, and C-peptide area under the curve during mixed-meal tolerance testing (MMTT). Finally, we evaluated the tolerability of anakinra in children and adolescents with newly diagnosed T1D.
Methods In vitro studies To determine the effects of IL-1β on gene expression in peripheral blood mononuclear cells (PBMC), blood samples were collected from 7 healthy adult volunteers under an IRB-approved protocol.
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
- 6 Years 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Newly diagnosed type 1 diabetes (by ADA criteria) within 1 week of diagnosis.
- •Age 6-18 years.
- •Males and females will be recruited.
- •Subjects and families must be English and/or Spanish-speaking.
排除标准
- •Patients with other autoimmune conditions or any other condition (including asthma) necessitating treatment with systemic or inhaled corticosteroids or chronic NSAIDs. Patients cannot have received such therapy in the three months prior to enrollment. Hashimoto's thyroiditis is not an exclusion criterion.
- •Patients with active bacterial infections must be cured prior to entry into the study protocol.
- •Serum creatinine > 1.5 mg/dL or greater than 1.5x the upper limit of normal for age
- •Serum ALT or AST > 3 times the upper limit of normal for the lab
- •Platelet count < 100,000/mm3
- •WBC count < 3,000 cells/mm3
- •Hemoglobin, Hematocrit or Red blood cell count outside 30% of the upper or lower limits of normal for the lab
- •Any medication that, in the opinion of the investigator, is being administered for immunomodulatory purposes, including but not limited to systemic or inhaled corticosteroids and chronic NSAIDs
- •Subject is currently enrolled in another investigational device or drug trial(s), or subject has received other investigational agent(s) within 28 days of baseline visit
- •Treatment in the past with anakinra
- •Patients with known hypersensitivity to E. coli-derived proteins, anakinra, or any components of anakinra.
- •Must not have received immunosuppressive agents (including systemic or inhaled corticosteroids and scheduled/chronic NSAIDs) for at least three months prior to enrollment
- •Known HIV-positive status or known history of any other immunodeficiency state.
- •Any mycobacterial disease
- •Active severe infections within 4 weeks before screening visit, or between the screening and baseline visits.
- •Severe comorbidities (congestive heart failure of any severity, myocardial infarction, cerebrovascular accident or transient ischemic attack within 3 months of screening visit, unstable angina pectoris, uncontrolled hypertension (sitting systolic BP <80 mm Hg or > 160 or diastolic BP > 100 mm Hg), oxygen-dependent severe pulmonary disease, history of cancer within 5 years [other than resected cutaneous basal or squamous cell carcinoma or in situ cervical cancer])
- •History of tuberculosis or tuberculosis exposure, chronic hepatitis B or hepatitis C, or systemic lupus erythematosus.
- •Pregnant or lactating females
- •Use of a live vaccine 90 days prior to, or during this study
- •Any condition judged by the patient's physician to cause this clinical trial to be detrimental to the patient
- •History of non-compliance with other therapies
研究组 & 干预措施
Anakinra
After study enrollment, all subjects started anakinra (Kineret™; Amgen, Thousand Oaks, CA, USA) as a subcutaneous daily injection. Subjects weighing >25 kg at the time of enrollment received 100 mg daily, whereas those weighing <25 kg received 50 mg daily. Anakinra was continued for 28 d with no dose adjustment.
干预措施: Anakinra (Drug)
结局指标
主要结局
Effect of Anakinra Treatment on PBMC Gene Expression for Patients
时间窗: 1 month
Expression data at baseline and after treatment were available on 10 patients who had received anakinra. These were compared to similarly-timed samples from 10 patients from control group B. Several attempts have been made to contact the PI to verify information, but were unsuccessful. Unable to verify if 10 or 12 patients were analyzed.
次要结局
- C-peptide Secretory Capacity(7 months)