Official Title: “Effect of Metformin On Glycaemic Control and Non-Glycaemic Cardiovascular Risk-Factors in Patients With Type-1 Diabetes, With Long-Standing Inadequate Glycaemic Control by Insulin and Diet”

Ninety percent of patients with type-1-diabetes will develop late-diabetic complications in the eyes, kidneys, nervous- or cardiovascular-system. Poor glycaemic control is an important risk-factor for development of these late-diabetic complications. The Diabetes Control and Complications Trial (DCCT)-study showed, that improved glycaemic control can prevent the development and progression of these late-diabetic complications. Until now treatment with insulin- and diet-therapy has been the only treatment-modalities available to improve the glycaemic control in patients with type-1-diabetes. A substantial number of these patients still have long-standing poor glycaemic control despite intensive treatment with insulin- and diet-therapy. The antidiabetic drug metformin has shown to be able to improve the glycaemic control in combination with insulin and furthermore reduce both mortality and the risk of developing cardiovascular disease in patients with type-2-diabetes.

Only few small studies have investigated the effect of treatment with metformin in patients with type-1-diabetes. These studies have suggested a positive effect of metformin in these patients too.

Method:

100 patients with type-1-diabetes with persistent poor glycaemic control i.e. HbA1c > 8.5% during the last 12 months are eligible. Patients are treated for one month with placebo.

Hereafter half of the patients will be treated with metformin and the other half continues with placebo for 12 months both as add-on therapy. All patients are continuing ongoing treatment with insulin throughout the study. Before and after the start of treatment with metformin the effect on glycaemic control and other known risk-factors for development of cardiovascular disease i. e. blood-pressure, fasting lipids, urine-albumine-excretion, endothelial dysfunction, inflammation, fibrinolysis etc. is assessed.

This study will show if treatment with metformin can improve the glycaemic control and hereby the prognosis of patients with type-1-diabetes with persistent poor glycaemic control despite intensive treatment with insulin- and diet-therapy. This group of patients suffers the highest risk of developing late-diabetic complications with reduced quality of life and life-expectancy as a consequence.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Efficacy Study

Study Primary Completion Date: August 2006

Intervention(s) in this Clinical Trial

• Drug: Metformin
  • Tablet Metformin 500 mg, Dosage: 1000 mg two times daily (2000 mg total daily dose).
• Drug: Placebo.
  • Tablet Placebo (corresponding to 500 mg metformin). Dosage: 1 tablet per day.
• Drug: Placebo.
  • Tablet Placebo (corresponding to 500 mg metformin). Dosage: 2 tablets two times daily.

Arms, Groups and Cohorts in this Clinical Trial

• Placebo Comparator: 1
  • Single-blind placebo run-in period. Duration one month.
• Active Comparator: 2
  • Metformin 2000 mg, double-masked randomized during 12 months.
• Placebo Comparator: 3
  • Placebo, double-masked randomized during 12 months.

Primary Measures

• HbA1c - difference between final visit and baseline.

Secondary Measures

• Absolute HbA1c
• Number of mild and severe hypoglycaemia with or without measurements of blood-glucose.
• Insulin-dose
• The following parameters are measured at baseline and at the final visit after 12 months of intervention:
• Plasma-PAI-antigen and -activity, t-PA-antigen- and activity.
• Plasma-fibrinogen
• Serum-albumin
• Markers of endothelial dysfunction: Von Willebrand Factor, ICAM, VCAM, Amadori-protein, selectin and endothelin.
• Plasma-homocysteine
• Asymmetric DiMethylArginine - ADMA
• Urine-albumin-excretion in three 24 hour urine-collections
• Blood-pressure in the sitting position after 10 minutes of rest.
• Fasting lipid-profile (total-cholesterol, LDL-cholesterol, HDL-cholesterol, VLDL-cholesterol and triglycerides), small-dense-LDL, Lp(a) and Apo-B100.
• Weight, BMI and Waist-hip-ratio
• White blood-cell-count, hs-CRP, Interleukin-6 and TNF-alfa.
• Serum-creatinine, sodium, potassium, ASAT, alkaline phosphatase, Factor 2, 7, 10, Cobalamin, Erythrocyte-folate and Haemoglobin-concentration.
• Extra blood- and urine-samples will be stored at -80 degrees Celsius for potential extra analyses after closure of the study. DNA will be stored for later pharmaco-genetic analysis.

Inclusion Criteria:

• HbA1c > 8.5% for more than one year prior to enrolment.
• Diabetes-duration > 5 years.
• Age at onset of diabetes < 35 years
• Fasting C-peptide < 300 pmol/l
• Age > 18 years at enrolment.

Exclusion Criteria:

• Clinical or biochemical signs of kidney-, liver- or heart-failure.
• Other coexisting serious morbidity, which will affect the study-participation or outcome of the study i.e. cancer.
• Known abuse of any medication or alcohol
• Hypoglycaemia unawareness.
• Pregnancy or planned pregnancy in the study-period.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Steno Diabetes Center

Overall Clinical Trial Officials and Contacts

Allan A Vaag, M.D., chief physician Study Chair Steno Diabetes Center  

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00118937

Study ID Number: Type-1-Metformin

ClinicalTrials.gov Identifier: NCT00118937

Health Authority: Denmark: Danish Medicines Agency