The Effects of Glucagon Antagonism on Insulin Sensitivity, Cardiovascular Risk, and Ketogenesis in Type 1 Diabetes
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Metabolic Clearance Rate of Insulin
研究概览
简要总结
This study will examine the effects a Glucagon Receptor Antagonist (GRA), has on Insulin Sensitivity, Cardiovascular risks (CVD), and Ketone body formation in participants with Type 1 diabetes. The participants will complete blood tests, tests to measure energy expenditure, CVD risks, and insulin resistance. These tests will be performed prior to start of treatment and again after 12-weeks of treatment with the GRA (called REMD-477).
详细描述
This single-center, double-blind, placebo-controlled, multi-dose study is designed to evaluate the effects of glucagon antagonism on insulin sensitivity, cardiovascular risk and ketogenesis in individuals with Type 1 Diabetes. To accomplish the specific aims proposed, a single clinical trial will be conducted in which a maximum of 30 subjects with T1D, who are otherwise healthy, will be treated with REMD-477 or matching placebo for up to 12 weeks at a dose of 70mg (administered subcutaneously each week) with assessments done pre- and post-therapy. Subjects will be randomized on a 1:1 basis to either the REMD-477 group or placebo group and all subjects will remain on their standard of care insulin therapy throughout the study. There will be 19 study visits as outlined below:
- Screening - Complete consenting process, complete medical history and physical exam, review of current medications, collect height/weight, vital signs, and fasting laboratory (blood and urine) tests.
- Baseline Visit 1 - Participants that meet screening criteria will complete cardiovascular tests including flow mediated dilation and EndoPat, complete vital signs, weight and laboratory tests for safety and CVD markers.
- Baseline Visit 2 - Participants will complete a 2-Step Hyperinsulinemic/Euglycemic clamp with tracer, Indirect Calorimetry, muscle and adipose tissue biopsies.
- Baseline Visit 3 - Insulin withdrawal challenge and injection #1 of REMD-477 or placebo. Participants will suspend insulin delivery and remove insulin pump. Blood sugars and ketones will be monitored for up to 8 hours.
- Visit 4 - Injection #2 of REMD-477 or placebo and blood collection for safety labs.
- Visit 5 - Injection #3 of REMD-477 or placebo.
- Visit 6 - Injection #4 of REMD-477 or placebo and blood collection for safety labs.
- Visit 7 - Injection #5 of REMD-477 or placebo.
- Visit 8 - Injection #6 of REMD-477 or placebo and blood collection for safety labs.
- Visit 9 - Injection #7 of REMD-477 or placebo.
- Visit 10 - Injection #8 of REMD-477 or placebo and blood collection for safety labs.
- Visit 11 - Injection #9 of REMD-477 or placebo.
- Visit 12 - Injection #10 of REMD-477 or placebo and blood collection for safety labs.
- Visit 13 - Injection #11 of REMD-477 or placebo.
- Visit 14 - Injection #12 of REMD-477 or placebo and blood collection for safety labs.
- Visit 15 - Repeat cardiovascular tests including flow mediated dilation and EndoPat, complete vital signs, weight and laboratory tests for safety and CVD markers.
- Visit 16 - Repeat 2-Step Hyperinsulinemic/Euglycemic clamp with tracer, Indirect Calorimetry, muscle and adipose tissue biopsies.
- Visit 17 - Repeat Insulin withdrawal challenge. Participants will suspend insulin delivery and remove insulin pump. Blood sugars and ketones will be monitored for up to 8 hours.
- Visit 18 - Safety follow-up visit that includes physical exam, vitals, blood and urine sample collection.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Double-blind
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
- •Men and women between the ages of 18 and 65 years old, inclusive, at the time of screening;
- •Females of non-child bearing potential must be ≥ 1 year post-menopausal or documented as being surgically sterile. Females of child bearing potential must agree to use two methods of contraception during the entire study and for an additional 3 months after the end of dosing with the investigational product;
- •Male subjects must be willing to use clinically acceptable method of contraception during the entire study and for an additional 6 months after the end of the treatment period;
- •Diagnosed with Type 1 diabetes based on clinical history or as defined by the current American Diabetes Association (ADA) criteria for > 5 years;
- •Treatment with a stable insulin regimen for at least 8 weeks before screening with continuous subcutaneous insulin infusion (CSII) via an insulin pump;
- •Currently using a Continuous Glucose Monitoring (CGM) system;
- •HbA1c ≤ 8.5 % at screening;
- •A minimum weight of 50kg;
- •eGFR ≥ 60 mL/min/1.73m²
- •Able to provide written informed consent approved by an Institutional Review Board (IRB).
排除标准
- •History or evidence of clinically-significant disorder or condition that, in the opinion of the Investigator, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion;
- •History of pancreatitis, medullary thyroid carcinoma and/or liver disease;
- •Clinically significant diagnosis of anemia;
- •Body Mass Index (BMI) < 18.5 kg/m2 and/or weight less than 50kg;
- •Whole blood donation of 1 pint (500 mL) within 8 weeks prior to Screening. Donations of plasma, packed RBCs, platelets or quantities less than 500 mL are allowed at investigator discretion;
- •Current or recent (within 1 month of screening) use of diabetes medications other than insulin;
- •Women who are pregnant or lactating/breastfeeding;
- •Unable or unwilling to follow the study protocol or who are non-compliant with screening appointments or study visits;
- •Any other condition(s) that might reduce the chance of obtaining study data, or that might cause safety concerns, or that might compromise the ability to give truly informed consent.
研究组 & 干预措施
GRA (REMD-477) Group
Once weekly, subcutaneous injection of 70mg REMD-477 (in 1 mL solution) for up to 12 weeks.
干预措施: REMD-477 (Drug)
Placebo Group
Once weekly, subcutaneous injection of 1mL saline solution for up to 12 weeks.
干预措施: Placebo (Drug)
结局指标
主要结局
Metabolic Clearance Rate of Insulin
时间窗: 12-Weeks
The change from baseline in calculated metabolic clearance rate of insulin as measured by the 2-step Hyperinsulinemic-Euglycemic Clamp.
Rate of Resting Energy Expenditure (REE)
时间窗: 12-Weeks
Change from baseline REE as measured by indirect calorimetry.
Change in Beta-hydroxybutyrate (BHB) Level
时间窗: 12-Weeks
The change from baseline in peak BHB production as measured by the insulin withdrawal challenge.
Change in Free Fatty Acid (FFA) Level
时间窗: 12-Weeks
The change from baseline in peak FFA production as measured by the insulin withdrawal challenge.
Change in mRNA Expression
时间窗: 12-Weeks
The change from baseline in gene mRNA expression as measured by adipose and muscle tissue samples.
Change in Peripheral Macrovascular Vasodilation
时间窗: 12-Weeks
The change from baseline in post-stimulus vessel diameter as measured by flow mediated dilation.
Change in Peripheral Microvascular Vasodilation
时间窗: 12-Weeks
The change from baseline in reactive hyperemia index as measured by reactive hyperemia-peripheral arterial tonometry (RH-PAT).
Change in Cardiovascular Disease (CVD) Risk Markers.
时间窗: 12-Weeks
The change in ng/mL from baseline in CVD risk markers (Thrombomodulin, ICAM-3, E-Selectin and P-Selectin) as measure by blood samples.
次要结局
未报告次要终点
研究者
Jeremy Pettus, MD
Clinical Professor
University of California, San Diego