Alpelisib Challenge Test (ACT) for Assessment of Pancreatic β-Cell Reserve, Pilot & Feasibility Study
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 15
- 试验地点
- 2
- 主要终点
- Correlation coefficient between clamp and ACT/MMTT
研究概览
简要总结
The goal of this study is to test a potentially easier method for measuring how much insulin a person is capable of producing than the current gold-standard method, the "hyperglycemic clamp." Participants will come in for a two-day (overnight) visit in which they will first undergo a "hyperglycemic clamp," in which they receive an intravenous (into the vein) infusion of glucose (sugar) in order to measure the maximum amount of insulin their body produces in response. They will then consume a series of three standardized meals throughout the rest of the day. At 23:00, they will take a single dose of alpelisib, a drug that interferes within insulin's actions in the body. Then, the following morning, they will undergo a "Mixed Meal Tolerance Test" in which they consume a standardized liquid nutritional beverage and have blood drawn periodically before and during the test.
详细描述
Type 2 diabetes results from a combination of insulin resistance and failure of pancreatic beta cells to produce sufficient insulin to compensate for it. Beta cell failure is therefore central to type 2 diabetes pathophysiology, and assessment of beta-cell reserve carries prognostic significance for likelihood of progression to type 2 diabetes. Beta-cell reserve may also serve as a useful clinical endpoint for the prevention or treatment of type 2 diabetes. The gold standard for measuring beta-cell reserve is the hyperglycemic clamp technique, which quantifies insulin secretion in response to hyperglycemia induced by exogenous glucose infusion. The hyperglycemic clamp, however, is technically challenging and not suitable for large-scale use, including in many research settings. As such, oral-based methods such as the oral glucose tolerance test (OGTT) and mixed-meal tolerance test (MMTT) have been developed to assess beta-cell reserve. Although these measures are useful, they come with important limitations. The investigators therefore wish to improve upon these oral methods by imposing a near-maximal beta-cell challenge during MMTT. The investigators have designed the Alpelisib Challenge Test (ACT) for this purpose, as alpelisib induces temporary, high-grade insulin resistance that will then allow a more accurate assessment of insulin-secretory capacity during MMTT. Study volunteers will be admitted to the inpatient clinical research unit for one overnight, 30-hour stay. On the morning of Study Day 1, they will undergo the gold-standard hyperglycemic clamp technique to assess beta-cell reserve. Then, at bedtime, they will take a single dose of alpelisib 300 mg followed by measurement of insulin secretion during MMTT on the morning of Study Day 2. This study can therefore determine the potential validity of the ACT by determining correlation coefficients with beta-cell reserve as measured during the hyperglycemic clamp.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Adults aged 18-70 years
- •Able to understand wrifen and spoken English and/or Spanish
- •Body mass index of 18-45 kg/m2 (or 18-42 kg/m2 for those of Asian ancestry)
- •For Lean group: BMI 18.0-24.9 kg/m2 (or 18.0-22.9 kg/m2 for those of Asian ancestry)
- •For Overweight group: BMI 25.0-29.9 kg/m2 (or 23.0-27.4 kg/m2 for those of Asian ancestry)
- •For Obesity group: BMI 30.0-45.0 kg/m2 (or 27.5-42 kg/m2 for those of Asian ancestry)
排除标准
- •Inability to provide informed consent in English or Spanish
- •Unwillingness to fast (except water) for up to 18 hours
- •Unwillingness not to get out of bed and to use bedpan/urinal to void for up to 15 hours
- •Documented weight change of ≥ 5.0% of baseline within the previous 3 months
- •Abnormal blood pressure
- •Systolic blood pressure < 90 mm Hg or > 160 mm Hg, and/or
- •Diastolic blood pressure < 55 mm Hg or > 100 mm Hg
- •Abnormal resting heart rate < 55 bpm or ≥ 110 bpm
- •Sinus tachycardia that has been extensively worked up and considered benign by the recruit's personal physician may be permitted at the PI's discretion
- •Sinus bradycardia between heart rates of 45 and 54 bpm may be permitted at the PI's discretion if in a clinically appropriate setting (e.g., toned athlete, taking beta blockers)
- •Abnormal (i.e., non-regular) heart rhythm detected on physical exam
- •Abnormal screening serum electrolytes judged by the PI to be potentially clinically significant
- •Liver function abnormalities (either of the following)
- •Transaminases (AST or ALT) > 3.0 x the upper limit of normal
- •Total bilirubin > 1.25 x the upper limit of normal
- •Laboratory evidence of diabetes mellitus:
- •Hemoglobin A1c ≥ 6.5%, and/or
- •Fasting plasma glucose ≥ 126 mg dL-1
- •Positive qualitative β-hCG (i.e., pregnancy test) in women of childbearing potential
- •Women currently pregnant
- •Women currently breastfeeding
- •History of having met any of the American Diabetes Association's definitions of diabetes mellitus (i.e., overt diabetes):
- •Hemoglobin A1c ≥ 6.5%, or rapid rise in documented HbA1c values causing clinical concern for evolving insulin deficiency
- •Plasma glucose ≥ 126 mg/dL after 8-h fast
- •Plasma glucose of ≥ 200 mg/dL at 2 h after ingestion of a 75-g glucose load
- •Random plasma glucose ≥ 200 mg/dL associated with typical hyperglycemic symptoms, diabetic ketoacidosis, or hyperglycemic-hyperosmolar state
- •History of gestational diabetes mellitus within the previous 5 years
- •Use of most antidiabetic medications within the 90 days prior to screening
- •Exceptions: thiazolidinediones, sulfonylureas, meglitinides, DPP4 inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors, amylin mimetics, acarbose, insulin
- •Metformin is acceptable provided that recruits meet all of the inclusion criteria at screening
- •Clinical concern for absolute insulin deficiency (e.g., type 1 diabetes, pancreatic disease)
- •Cardiovascular diseases (N.B. uncomplicated hypertension is not exclusionary)
- •Atherosclerotic cardiovascular disease
- •Stable or unstable angina
- •Myocardial infarction
- •Ischaemic or hemorrhagic stroke
- •Peripheral arterial disease (claudication)
- •Use of dual antiplatelet therapy (aspirin + P2Y12 inhibitor)
- •History of percutaneous coronary intervention
- •Congestive heart failure (NYHA Class ≥ 2)
- •Severe valvular heart disease (e.g., aortic stenosis)
- •Pulmonary hypertension
- •Advanced or severe liver disease, including but not limited to:
- •Advanced liver fibrosis, as determined by non-invasive testing
- •Cirrhosis of any etiology
- •Autoimmune hepatitis or other rheumatologic disorder affecting the liver
- •Biliopathy (e.g., progressive sclerosing cholangitis, primary biliary cholangitis)
- •Chronic liver infection (e.g., viral hepatitis, parasitic infestation)
- •Hepatocellular carcinoma
- •Infiltrative disorders (e.g., sarcoidosis, hemochromatosis, Wilson disease)
- 另有 25 项未显示
研究组 & 干预措施
Lean (healthy control) group
Healthy volunteers with body mass index of 18.0-24.9 kg/m2, hemoglobin A1c < 6.5%, and fasting plasma glucose < 126 mg/dL
干预措施: Alpelisib 300 mg (Drug)
Lean (healthy control) group
Healthy volunteers with body mass index of 18.0-24.9 kg/m2, hemoglobin A1c < 6.5%, and fasting plasma glucose < 126 mg/dL
干预措施: Alpelisib Challenge Test (ACT): Mixed Meal Tolerance Test (MMTT) after taking alpelisib (Diagnostic Test)
Lean (healthy control) group
Healthy volunteers with body mass index of 18.0-24.9 kg/m2, hemoglobin A1c < 6.5%, and fasting plasma glucose < 126 mg/dL
干预措施: Hyperglycemic clamp (Diagnostic Test)
Overweight group
Volunteers with body mass index of 25.0-29.9 kg/m2, hemoglobin A1c < 6.5%, and fasting plasma glucose < 126 mg/dL
干预措施: Alpelisib Challenge Test (ACT): Mixed Meal Tolerance Test (MMTT) after taking alpelisib (Diagnostic Test)
Overweight group
Volunteers with body mass index of 25.0-29.9 kg/m2, hemoglobin A1c < 6.5%, and fasting plasma glucose < 126 mg/dL
干预措施: Hyperglycemic clamp (Diagnostic Test)
Overweight group
Volunteers with body mass index of 25.0-29.9 kg/m2, hemoglobin A1c < 6.5%, and fasting plasma glucose < 126 mg/dL
干预措施: Alpelisib 300 mg (Drug)
Obesity group
Volunteers with body mass index of 30.0-45.0 kg/m2, hemoglobin A1c < 6.5%, and fasting plasma glucose < 126 mg/dL
干预措施: Alpelisib Challenge Test (ACT): Mixed Meal Tolerance Test (MMTT) after taking alpelisib (Diagnostic Test)
Obesity group
Volunteers with body mass index of 30.0-45.0 kg/m2, hemoglobin A1c < 6.5%, and fasting plasma glucose < 126 mg/dL
干预措施: Hyperglycemic clamp (Diagnostic Test)
Obesity group
Volunteers with body mass index of 30.0-45.0 kg/m2, hemoglobin A1c < 6.5%, and fasting plasma glucose < 126 mg/dL
干预措施: Alpelisib 300 mg (Drug)
结局指标
主要结局
Correlation coefficient between clamp and ACT/MMTT
时间窗: Up to 17 hours after dosing alpelisib
Determination of utility of Alpelisib Challenge Test as measure of pancreatic beta-cell reserve based on correlation of insulin/C-peptide levels and/or insulin secretion rates during MMTT portion of ACT versus gold-standard hyperglycemic clamp
次要结局
- Serum insulin level(After 2-3 hours of hyperglycemic clamp and up to 17 hours after alpelisib dose)
- Serum C-peptide level(After 2-3 hours of hyperglycemic clamp and up to 17 hours after alpelisib dose)
- Insulin secretion rate (ISR)(After 2-3 hours of hyperglycemic clamp and up to 17 hours after alpelisib dose)
- Insulin clearance rate (ICR)(After 2-3 hours of hyperglycemic clamp and up to 17 hours after alpelisib dose)
研究者
Joshua Cook
Assistant Professor of Medicine
Columbia University