Insulin Degludec and Symptomatic Nocturnal Hypoglycaemia

Background: Insulin degludec is a novel insulin analogue that may reduce the risk of mild nocturnal hypoglycaemia in type 1 diabetes. Patients with type 1 diabetes and recurrent severe hypoglycaemia (high risk patients) are also burdened by nocturnal hyoglycaemia (mild and silent). These episodes may contribute to the developement of hormonal counterregulatory failure and hypoglycaemia unawareness, which in turn increases the risk of further hypoglycaemic episodes, especially epiosdes of severe hypoglycaemia.The effect of insulin degludec on risk of mild nocturnal hypoglycaemia in subjects with type 1 diabetes and high risk of severe hypoglycaemia compared to insulin glargine is to be investigated.

Study design and intervention: A controlled, cross-over multi-centre study in a Prospective, Randomised, Open, Blinded Endpoint (PROBE) design. Each treatment period last for 12 months. Patients will be randomised to treatment with basal-bolus therapy with insulin aspart/degludec or insulin aspart/glargine in random order. Endpoints will be assessed during the last 9 months of each treatment arm.

Subjects: 175 type 1 diabetic patients with a history of one or more episodes of nocturnal severe hypoglycaemia during the proceeding two years.

Method: Patients will record all events of symptomatic (mild), asymptomatic (silent) and severe hypoglycaemia in a diary. All events of symptomatic nocturnal and severe hypoglycaemia must also be reported by telephone within 24 hours. Patients will be instructed to do and record self-monitored blood glucose (SMBG) i.e. 4-point profiles twice per week (blood glucose before breakfast, before lunch, before dinner and before bedtime).

Outcomes: See "Outcome Measures". Concerning the primary endpoint all possible symptomatic nocturnal hypoglycaemic episodes will be adjudicated by an independent endpoint committee consisting of diabetes specialists blinded to the individual patient insulin regimen.

Safety: Adverse reactions

Inclusion criteria

• Type 1 diabetes > 5 years
• One or more episodes of nocturnal severe hypoglycaemia during the preceding two years
• Treated with multiple dose insulin injection (>2) or insulin pump. Both human insulin and insulin analogues are allowed
• Willingness to a once daily (OD) regimen concerning insulin degludec and insulin glargine
• Willingness to do self-monitoring of blood glucose (SMBG) and keep a diary
• Signed informed consent

Exclusion criteria

• History of primary and secondary adrenal insufficiency, growth hormone deficiency, or untreated myxoedema
• History of unstable angina or major cardiovascular events (myocardial infarction, coronary re-vascularisation, transient ischaemic attack, or stroke within the last three months)
• Heart failure, New York Heart Association (NYHA) class IV
• History of malignancy unless a disease-free period exceeding five years
• History of alcohol or drug abuse
• Treatment with glucose lowering agent(s) other than insulin
• Pregnant or lactating women
• Women of childbearing potential who are not using chemical (P-pills or gestagen depots) or mechanical (intra-uterine device) contraception
• Participation in another investigational drug study within the last 3 months
• Inability to understand the informed consent
• HbA1c > 86 mmol/mol (10%)
• Shifting working hours