Children aged 5 to 16 on entry to the RCT with the presence of two or more islet-related autoantibodies which confers a 40% risk of developing type 1 diabetes in five years. MedDRA version: 18.0 Level: LLT Classification code 10036481 Term: Pre-diabetes System Organ Class: 100000004861
Conditions
Interventions
Trade Name: Metformin Hydrochloride
Product Name: Metformin Hydrochloride
Pharmaceutical Form: Oral liquid
INN or Proposed INN: Metformin Hydrochloride
CAS Number: 1115-70-4
Current Sponsor code: N/
Sponsors
University of Exeter
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: FOR SCREENING PHASE (approx. ~3500) -Children/Adolescents aged 5-16 years at time of screening who are siblings of people whose T1D developed before the age of 25 years -Children/Adolescents aged 5-16 years who are the offspring of parents who themselves developed T1D before the age of 25 years -Parent/Participant is willing and able to give informed consent/assent -Multiple family members meeting eligibility criteria. FOR RCT PHASE (~ n= 90-200) - Children/adolescents identified by screening to be sero-positive for at least two of the four islet-related antibodies (IAA, GAD, IA-2, ZnT8). Are the trial subjects under 18? yes Number of subjects for this age range: 90 F.1.2 Adults (18-64 years) no F.1.2.1 Number of subjects for this age range 0 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range 0
Exclusion criteria
Exclusion criteria: For Screening Phase: -Parent /Participant is unwilling/unable to give informed consent/assent -Under 5y or over 16y at time of screening -Sibling or child of person who developed T1D after the age of 25y -Known to have physician diagnosed diabetes -Already taking metformin -Physically or psychologically unable to participate -Taking medication likely to increase insulin resistance (e.g. oral/systemic steroids or growth hormone) -Contraindication to metformin – anoxia, cardiovascular insufficiency, renal or hepatic disease, sepsis -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 exclusions for RCT 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) -Pregnant or lactating -Known allergies to milk and soya For Randomisation: -fasting blood glucose (laboratory sample) greater than or equal to 7mmol/L
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Can metformin, a drug known to reduce insulin demand in type 2 diabetes, reduce insulin demand in children at increased risk of developing type 1 diabetes (T1D)and prevent disease? Stage 1 (pilot) - Study and Participant Outcome Measures Feasibility of a randomised controlled trial in children who are at high risk of T1D comparing metformin and placebo. Specific outcome measures will include (1) recruitment rate, (2) attrition rate, (3) standard deviation of proposed participant outcome measures which are: Biomarker outcomes for HOMAR-IR (measures of insulin resistance), beta cell demand (glucose and c-peptide) and immunological down regulation in T-cell response to islet related antigens. Stage 2 (proof of concept) will continue with these outcomes measures. Outcome Measures will inform sample size for the fully powered trial (Stage 2 & 3). Stage 3 (definitive trial) will focus on the efficacy of Metformin to reduce HOMA2-IR. For purposes of assessing effect size, the HOMA2-I;Secondary Objective: Secondary exploratory outcomes will include: Response rate of families to screening Response of families to participate in the intervention stage when a second sibling in the same family is found to be at high risk of T1D. Compliance with liquid formula metformin. Serum vitamin B12 as a fall in vitamin B12 levels have been reported in adults, currently no data for children. With safety endpoints: Haemoglobin (Hb) and Full Blood Count (FBC) Renal function tests: urea and electrolytes Liver function tests ;Primary end point(s): 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. Stage 1 (pilot) which will test 1. Study Outcome Measures: Feasibility of a randomised controlled trial in children who are at high risk of T1D comparing metformin and placebo. Specific outcom | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Stage 1 Secondary exploratory objectives are screening response rates, response to participate in the treatment study when a second child in the same family is found to be at high risk of T1D (double-antibody positive) and are compliance of liquid metformin/placebo and review of Vitamin B12 serum levels. ;Timepoint(s) of evaluation of this end point: Similarly secondary outcome of Stage 1 can only be known after all participants have completed 4 months treatment. We plan that by month 21, feasibility and efficacy secondary outcomes will be established. Stages 2 and 3 will review outcomes at 36 and 60 months (respectively) of intervention. | — |
Countries
United Kingdom
Contacts
Public ContactDr Roberta Littleford
Tayside Clinical Trials Unit
Outcome results
None listed