Autoimmune Diabetes Accelerator Prevention Trial - adAPT Stage 1
试验速览
- 阶段
- 4 期
- 状态
- 撤回
- 试验地点
- 5
- 主要终点
- Between group difference in reduction of Homeostatic Model Assessment (HOMAR) of Insulin Resistance (IR, mass units).
研究概览
简要总结
The autoimmune diabetes ACCELERATOR PREVENTION TRIAL (adAPT) is based on the accelerator hypothesis. The trial is designed to establish whether metformin, an oral hypoglycaemic agent that is known to reduce insulin demand in type 2 diabetes (T2D), can do the same in children at risk of type 1 diabetes (T1D) and thereby prevent disease.
The first phase of adAPT will screen participants aged 5-16 years (inclusive) for islet-related autoantibodies who are the siblings or offspring of individuals diagnosed with T1D before the age of 25years in Scotland and England.
There are four principle islet-related antibodies associated with T1D. The presence of two or more confers a 40% risk of developing T1D in five years. While the presence of none or one antibody carries a similar risk for developing T1D to the general population (1 in 500 in 5years).
It is anticipated that 5% of those screened will be identified as double-antibody positive, these participants will be invited to join the intervention phase of the study - randomised controlled trial (RCT). Up to 200 eligible subjects could be identified by screening with a minimum of 90 being enrolled into the RCT phase.
adAPT is a proposed three stage project. The current protocol defines the screening phase, Stage 1 and seamless entry into Stage 2. Screening will identify children and young people at high risk of developing T1D and invite them to participate in Stage 1 which will involve a minimum of 4 months treatment with either metformin/placebo, however Stage1 treatment will run seamlessly into Stage 2. Stage 1/2 treatment will last up to 21 months (to accommodate 15months screening, 4 months treatment and 2 months analysis). Post Stage1 analysis/ late Stage 2 participation will last up to 36 months (participants enrolled early into Stage 1 will have the longest intervention).
During the Stage1 participants will be tested on three occasions (baseline, month 1 and month 4) for metabolic response using a 5-point mixed meal tolerance test (MMTT). Testing will continue in Stage 1/2 with 3 visits further visits at months 8, 12, 18. Late Stage 2 visits will occur on months 24, 30 & 36.
Participants will be invited to continue into Stage 3, taking treatment up to 60 months post analysis of Stage 1 and associated protocol amendment and additional consent.
详细描述
adAPT is a randomised double-blind placebo-controlled Phase IV clinical trial.
Metformin, a licensed medicine but will be tested out with its current license (off-label). Participants will either receive metformin (liquid) or matched placebo in a double blind manner; neither the participant or study team will know the allocation.
Metformin, the study medication, reduces the demand for insulin in Type 2 diabetes (T2D). adAPT will test if metformin can also reduce insulin demand in children at risk of Type 1 Diabetes (T1D). adAPT has an adaptive design with each stage informing the next with progression depend upon the previous stages outcome Stage 1 exposes each participant to metformin or placebo for four months, following which they seamlessly enter Stage 2. However, because recruitment rolls over 15 months many of those recruited early on will have entered Stage 2 before some even reach Stage 1. Accordingly, the protocol and submission also outlines Stages 2.
A successful Stage 1 will lead-on to a clinical outcome trial (Stages 2 and 3) which, if successful, will fundamentally change our understanding of what causes diabetes and how to prevent it. Stage 1 is required to confirm that adAPT trial design is achievable. Outcome evaluation will be undertaken at 21 months. Stage 2 (proof-of-concept) will test if metformin can slow-down the development of diabetes. The outcome data form Stage 1 will allow for power to be calculated to drive the number of participants required for the study for Stages 2 (and 3). It is proposed that once the power and thus population numbers are established for Stage 2 (out with this protocol) that new participants will enter Stage 1 via screening and follow the established trial pathway.
Diabetes biological markers will be measured and formally assessed at the end of Stage 2, after 36 months. Stage 3 will occur if metformin treatment in Stage 2 is proven to be better than placebo for slowing the development of diabetes. Stage 3 will further investigate the development of diabetes between the groups, using biological markers and clinical outcomes at five years.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 5 Years 至 16 Years（Child）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Metformin Hydrochloride
Metformin Hydrochloride Ph Eur oral solution (100mg/1ml) Starting Dose 10mg/Kg body weight once daily for 2 weeks, increasing to 10mg/Kg body weight twice daily if tolerated, increasing to target dose of 20mg/Kg body weight twice daily (max 1000mg twice daily) at Month 1 (4 weeks post randomization).
Down-titration to 10mg/kg twice daily if target dose not tolerated. Stage 1: Dosing for up to 15 months (option to extend to Stage 2: 36 months)
干预措施: Metformin Hydrochloride (Drug)
Placebo
Placebo (100mg/1ml) Starting Dose 10mg/Kg body weight once daily for 2 weeks, increasing to 10mg/Kg body weight twice daily if tolerated, increasing to target dose of 20mg/Kg body weight twice daily (max 1000mg twice daily) at Month 1 (4 weeks post randomization).
Down-titration to 10mg/kg twice daily if target dose not tolerated. Stage 1: Dosing for up to 15 months (option to extend to Stage 2: 36 months)
干预措施: Placebo (Drug)
结局指标
主要结局
Between group difference in reduction of Homeostatic Model Assessment (HOMAR) of Insulin Resistance (IR, mass units).
时间窗: 21 months (Stage1)
Note: study not powered to nominate a primary outcome as feasibility study.
Between group difference in reduction in beta cell demand as measured by serum glucose (mmol/L) and C-peptide (ng/mL)
时间窗: 21 months
Note: study not powered to nominate a primary outcome as feasibility study.
次要结局
- Feasibility of a randomized controlled trial in children who are at high risk of T1D as measured by recruitment rates (%)(21 months)
- Feasibility of a randomized controlled trial in children who are at high risk of T1D as measured by attrition rates (%)(21 months)