Changing the Natural History of Type 2 Diabetes ("CHANGE" Study)
试验速览
- 阶段
- 不适用
- 状态
- 进行中（未招募）
- 入组人数
- 127
- 试验地点
- 1
- 主要终点
- EFFECT SIZE
研究概览
简要总结
Diabetes is a disorder of high blood glucose, that tends to get worse; over time, patients need more and more drugs. This pattern is caused by overwork of the body's insulin-producing β-cells, because patients' glucose levels are typically above normal; if the investigators kept glucose levels normal - reducing β-cell work - the investigators might be able to keep the disease from getting worse. This trial is aimed to show that adjusting the drugs to keep glucose levels normal, can help to preserve β-cell function compared to usual diabetes care, possibly reduce the tendency to develop the eye and kidney complications of diabetes, and might also be more cost-effective than usual care.
详细描述
I. RATIONALE AND SPECIFIC AIMS CHANGING THE NATURAL HISTORY OF TYPE 2 DIABETES - "CHANGE" STUDY
I.A. RATIONALE The investigators will test the hypothesis that maintenance of normoglycemia can prevent the typical worsening of hyperglycemia in early type 2 diabetes (DM) compared to usual care.
Progression of hyperglycemia is mediated by loss of β-cell function, which will be mitigated by normalizing glucose levels, reducing the "excitotoxicity" leading to dedifferentiation and apoptosis. When lifestyle change or Rx reduced progression from prediabetes (PreDM) to DM, there was no "catch-up" after trials ended - cumulative DM remained less than in controls, consistent with a change in the natural history. Reaching normal glucose is beneficial regardless of the intervention: in the Diabetes Prevention Program (DPP), PreDM subjects who achieved normal glucose levels only once, had 56% less DM in the DPP Outcomes Study [DPPOS] - similar in lifestyle change, metformin, and control groups. But if treatment is begun too late, even 10 kg weight loss may not lead to DM remission.
I.B. FEATURES OF THE APPROACH - easy to translate into practice.
This study will be novel: 1) Aim for normal glucose, instead of testing Rx or mechanisms [as in STOP DIABETES, DPP, and RISE], since lowering glucose per se improves β-cell function. 2) Start early in the natural history, instead of late [as in ACCORD, ADVANCE, and VADT], allowing use of Rx with a low risk of hypoglycemia; severe hypoglycemia was unusual in ORIGIN, where DM duration was only 5.5 years. 3) Target early DM instead of PreDM [DREAM, DPP, ACT NOW, and STOP DIABETES], allowing use of Rx FDA approved for DM. 4) Accelerated stepped intensification of Rx to keep glucose normal, vs. < 10% reaching a normal OGTT 3 times in the DPP, only 15% reaching a normal OGTT with metformin over 2 years in RISE, and lack of normalization in other studies.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
盲法说明
While the study is unblinded, investigators will be blinded to the randomization plan. Outcomes assessors (for eye photos and beta cell function) are masked.
入排标准
- 年龄范围
- 40 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •diagnosis of diabetes by OGTT
- •age 40-75 years
- •HbA1c 6.0-7.4%
- •1 hr OGTT glucose >155 mg/dl in each group
排除标准
- •CVD event during the previous year
- •systemic glucocorticoids
- •bariatric surgery
- •stage III-IV congestive heart failure
- •severe angina
- •life expectancy <5 years
- •BMI >40 kg/m2
- •pregnancy
- •pancreatitis
- •family or personal history of multiple endocrine neoplasia 2a
- •an estimated glomerular filtration rate [eGFR] of ≤50 ml/min
- •an alanine aminotransferase (ALT) level >3x the upper limit of the normal range
研究组 & 干预措施
USE OF DIABETES Rx GUIDED LARGELY BY HbA1c LEVELS
Extended-release [ER] metformin will be added if HbA1c is ≥7.0% after 3 months; if already used and maximized, pioglitazone will be begun. Other Rx will be added each time HbA1c reaches ≥7.5%. The sequence of Rx will be the same as in intensive Rx subjects; those using insulin will also do prebreakfast SMBG, aiming for glucose <100 mg/dl.
干预措施: Intensification of diabetes medication based largely on HbA1c levels (Other)
USE OF DIABETES Rx GUIDED BY SELF-MONITORED BLOOD GLUCOSE (SMBG)
- Guidance by SMBG:
- Glucose goals: We will aim for <100 mg/dl premeal (2), <130 postmeal.
- Monitoring will include pre-breakfast 2x/wk, and a 5-point profile 1x/wk (before and 1.5-2.5 hr after breakfast, before lunch, before supper, and bedtime).
- Added Rx will be used if SMBG is >goal ≥3x in 2 consecutive weeks after ≥4 weeks of MOVE! and/or the previous Rx [e.g., any 3 of the 7 goals (<100 mg/dl premeal, <130 post)]. Metformin ER will be given first (if not already on it), and increased to 2000 mg/day if there are no side effects. (If metformin is not tolerated, it will be stopped and the second Rx will become the "first Rx" and given instead. If other Rx are not tolerated, the next Rx will be used. The second Rx will be the TZD pioglitazone, followed by the GLP-1 RA semaglutide, then the SGLT-2 inhibitor empagliflozin. If still above goal, glargine insulin will be added, titrated to keep fasting glucose <100 mg/dl.
干预措施: Intensification of diabetes medication based on glucose levels (Other)
结局指标
主要结局
EFFECT SIZE
时间窗: 2.75 years (includes 3 month washout)
HbA1c DIFFERENCEs, INTENSIVE Rx vs. CONTROLS - PRIMARY OUTCOME #1
β-CELL FUNCTION - PRIMARY OUTCOME #2c.
时间窗: 2.75 years (includes 3 month washout)
β-cell function as the 1 hour OGTT plasma glucose (1hrOGTT).
β-CELL FUNCTION - PRIMARY OUTCOME #2a
时间窗: 2.75 years (includes 3 month washout)
β-cell function from modeling using a 3-hour OGTT with samples for glucose, insulin and C-peptide at 10, -5, 10, 20, 30, 60, 90, 120, 150 and 180 minutes.
β-CELL FUNCTION - PRIMARY OUTCOME #2b
时间窗: 2.75 years (includes 3 month washout)
β-cell function and insulin sensitivity as the oral "OGTT ISI disposition index" (DI), using the "insulinogenic index" \[(Δ insulin/Δ glucose) with 0- and 30-minute insulin (and C-peptide) and glucose levels in the OGTT\] for insulin secretion and \[1/(fasting insulin concentration)\] for insulin action.
次要结局
- RETINOPATHY determined by fundus photographs(2.5 years)
- NEPHROPATHY by eGFR(2.5 years)
- NEPHROPATHY by urine microalbumin/creatinine ratio(2.5 years)
- Point of care glucose by continuous glucose monitoring (CGM)(2.5 years)
- COST EFFECTIVENESS - to be explored only if additional (ancillary) funding can be obtained(2.5 years)
研究者
Mary Rhee, MD
Professor of Medicine, Emory University School of Medicine
Atlanta VA Medical Center