Autoimmune Diabetes Accelerator Prevention Trial

NCT02881528 | Withdrawn Phase 4 DMC

• 3 other identifiers: 15/1357632015-000748-4115/ES/0075
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 5

Brief 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.

Conditions

Prediabetic State

Keywords

Type 1 Diabetes; Juvenile Diabetes

Outcome Measures

Primary Outcomes (2)

• Between group difference in reduction of Homeostatic Model Assessment (HOMAR) of Insulin Resistance (IR, mass units).

  Note: study not powered to nominate a primary outcome as feasibility study.

  21 months (Stage1)

• Between group difference in reduction in beta cell demand as measured by serum glucose (mmol/L) and C-peptide (ng/mL)

  Note: study not powered to nominate a primary outcome as feasibility study.

  21 months

Secondary Outcomes (2)

• 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

Other Outcomes (4)

• Percentage response rate of families who choose to participate in the intervention stage when a second sibling in the same family is found to be at high risk of T1D.

  21 months

• Compliance with study medication.

  21 months (Stage1)

• Between group difference in serum vitamin B12

  21 months (Stage1)

Study Arms (2)

Metformin Hydrochloride

EXPERIMENTAL

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)

Drug: Metformin Hydrochloride

Placebo

PLACEBO COMPARATOR

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)

Drug: Placebo

Interventions

Metformin Hydrochloride DRUG

Liquid formula metformin administered by oral syringe in a dose of 10mg/kg body weight once daily for 2 weeks, then to 10mg/Kg twice daily (maximum 500mg twice daily) for a further two weeks during the first month, increasing to 20mg/kg body weight twice daily (maximum 1000mg twice daily) thereafter.

Also known as: Metformin

Metformin Hydrochloride

Placebo DRUG

Liquid formula of placebo administered by oral syringe in an equivalent volume to a metformin dose of 10mg/kg body weight once daily for 2 weeks, then to 10mg/Kg twice daily (maximum 500mg twice daily) for a further two weeks during the first month, increasing to 20mg/kg body weight twice daily (maximum 1000mg twice daily) thereafter.

Placebo

Eligibility Criteria

• Age: 5 Years - 16 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• 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
• 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).

You may not qualify if:

• 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
• 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)

Sponsors & Collaborators

• University of Exeter: lead
• University of Dundee: collaborator
• University of Bristol: collaborator

Study Sites (5)

NHS Ayrshire & Arran

Kilmarnock, Ayrshire, KA2 0BE, United Kingdom

Location

NHS Grampian

Aberdeen, Grampian, AB25 2ZG, United Kingdom

Location

NHS Lanarkshire

Wishaw, Lanarkshire, ML2 0DP, United Kingdom

Location

NHS Tayside

Dundee, Tayside, DD1 9SY, United Kingdom

Location

NHS Greater Glasgow & Clyde

Glasgow, G3 8SJ, United Kingdom

Location

MeSH Terms

Conditions

Prediabetic State; Diabetes Mellitus, Type 1

Interventions

Metformin

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Rob Andrews, Prof

  University of Exeter

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 28, 2016
• First Posted: August 29, 2016
• Study Start: March 30, 2016
• Primary Completion: June 30, 2017
• Study Completion: December 22, 2017
• Last Updated: October 16, 2018

Record last verified: 2018-10

Data Sharing

• IPD Sharing: Will not share

Locations

GB (5)