Autoimmune Diabetes Accelerator Prevention Trial

• Status: Withdrawn
• Trial end date: 2017-12-22
• Target enrollment: 0
• Participant gender: All

Summary

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.

• Phase: Phase 4
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: University of Exeter
• Collaborators: University of Bristol; University of Dundee
• Treatments: Metformin

Criteria

Inclusion Criteria -For Screening

• Aged 5-16years (inclusive) at time of screening

• Offspring of parents or siblings who themselves developed T1D before the age of 25years

• Parent /Participant is willing and able to give informed consent/assent

Additional Inclusion Criteria for Intervention Phase

• Individuals identified by screening to be sero-positive for at least two of the four islet-related antibodies; Insulin Autoantibodies (IAA), Islet Antigen-2 Autoantibodies (IA-2A), Glutamic Acid Decarboxylase Autoantibodies (GADA), Zinc Transporter 8 Autoantibodies (ZnT8).

Exclusion Criteria for Screening:

• Parent /Participant is unwilling/unable to give informed consent/assent

• Under 5y or over 17y at time of screening

• Offspring of parents or siblings who themselves developed T1D after the age of 25years

• Known to have physician diagnosed diabetes

• Already taking metformin

• Physically or psychologically unable to participate

• Taking medication likely to increase insulin resistance or blood glucose levels (e.g. oral/systemic; steroids, growth hormone, beta-2-agonists, diuretics or angiotensin-converting-enzyme (ACE) -inhibitors.)

• Suffering from anoxia, cardiovascular insufficiency, renal or hepatic disease or sepsis - contraindication to metformin

• Participating in another clinical trial (other than observational trials and registries) concurrently or within 30 days prior to screening for entry into this study

Additional Exclusion Criteria for Intervention Phase:

• Development of diabetes during the screening phase

• Identified by screening to be sero-negative (fewer than two of the four islet-related antibodies (IAA, GAD, IA-2, ZnT8)

• Fasting Blood Glucose of ≥ 7 mmol/L at Month 0

• Postmenarche female participants of childbearing potential who are pregnant or lactating

• Postmenarche female participants of childbearing potential must be sexually abstinent or use another acceptable form of contraception during study participation

• Renal failure or renal dysfunction (creatinine clearance < 60 mL/min)

• Acute conditions with the potential to alter renal function such as, severe infection, shock

• Acute or chronic disease which may cause tissue hypoxia such as: cardiac or respiratory failure, recent myocardial infarction, shock, hepatic insufficiency acute alcohol intoxication, alcoholism

• Known allergies to milk and/or soya

• Hypersensitivity to metformin hydrochloride or any of the excipients:

Parahydroxybenzoates may cause allergic reactions (possibly delayed); Liquid mannitol

• patients with rare hereditary fructose intolerance.