Randomized Controlled Trial of Insulin Versus Tablets for Latent Autoimmune Diabetes in Adults (LADA)

Randomized, Controlled, Parallel-Group Prospective Study to Investigate the Clinical Effectiveness of Early Insulin Treatment in Patients With Latent Autoimmune Diabetes in Adults

Background: Latent autoimmune diabetes in adults [LADA] is a type 1 diabetes that is slowly developing. This means many people are treated as having type 2 diabetes at diagnosis as they are adults who are not immediately insulin dependent. LADA can be distinguished from type 2 diabetes by antibody tests. Patients who are antibody positive have an autoimmune reaction which is similar to that of type 1 diabetes and is not found in type 2 diabetes. We would like to examine the best way of treating LADA in the early phase of the conditions, with tablets (similar to type 2 diabetes) or with insulin (similar to type 1 diabetes).

Methods/Design: This is an open parallel group prospective randomised trial. Participants need to have a GAD antibody test results of 101 WHO units or more and a diagnosis of diabetes not requiring insulin at diagnosis. Participants will need to have been diagnosed within 12 months and not treated with insulin at study entry. They will be randomised to receive either insulin (NovoMix 30) or tablets (diet treated followed by metformin followed by glitazone (with or without metformin) followed by insulin). Primary outcome assessment will be for change in HbA1c and change in fasting C-peptide over 24 months. Secondary outcome measures will include Quality of life, GAD antibody levels, adverse events, inflammatory markers, insulin resistance, and markers of the metabolic syndrome.

Discussion: This study seeks the best treatment for early LADA in terms of maintaining glycaemic control and maintaining natural insulin production.

Inclusion Criteria:

1. Male, non-fertile female (i.e., post menopausal, post hysterectomy, or sterilized by tubal ligation) or female of childbearing potential using a medically approved birth control method.
2. The patient has a diagnosis of diabetes mellitus according to WHO classification.
3. The patient has a positive GAD antibody test of 101 WHO units or more on two separate occasions.
4. Age 18 +
5. The patient did not start on insulin within 1 month of diagnosis
6. Written informed consent to participate in the study.
7. Ability to comply with all study requirements.

Exclusion Criteria:

1. Pregnant or breast-feeding females and females who plan pregnancy or breast-feeding during the course of the study.

2. A history of:

   Diabetes that is a result of pancreatic injury, or secondary forms of diabetes, e.g., Cushing's syndrome and acromegaly.

   Acute metabolic diabetic complications such as ketoacidosis or hyperosmolar state (coma) within the past 6 months

3. Acute infections, which may affect blood glucose control within 4 weeks prior to visit 1.

4. Malignancy including leukaemia and lymphoma (not including basal cell skin cancer) within the last 5 years.

5. The patient has a known immune deficiency from any disease, or a condition associated with an immune deficiency.

6. The patient is receiving immunosuppressive or immunomodulating agents or cytotoxic therapy, or any medication that, in the opinion of the site investigator, might interfere with the study.

7. Any of the following significant laboratory abnormalities:

   • Patients with severe renal failure as defined previous renal transplant or currently having renal dialysis or GFR <30.
   • Clinically significant laboratory abnormalities, confirmed by repeat measurement, that may interfere with the assessment of safety and/or efficacy of the study drug, other than hyperglycemia and glycosuria at visit 1.
   • Severe ketonuria (+++ on urine sticks testing; ++ on repeated urine sticks testing).

8. The patient is a known or suspected drug abuser.

9. The patient has chronic hepatitis or liver cirrhosis, or any other chronic liver disease.

10. The patient is known to test positive for hepatitis B antigens or hepatitis C antibodies

11. The patient is known to test positive for HIV antibodies.

12. The patient has any significant diseases or conditions, including psychiatric disorders and substance abuse that, in the opinion of the site investigator, are likely to affect the patient's response to treatment or their ability to complete the study.

13. The patient has chronic haematological disease.

14. The patient has had a severe blood loss (>400 mL, e.g., blood donation) within 2 months before the first dosing of the study medication.

15. The patient has known proliferative retinopathy.

16. Patient has had stage 3-4 heart failure.

17. The patient is participating in another research study which may affect the results of this trial.