Insulin Degludec and Symptomatic Nocturnal Hypoglycaemia
Insulin Degludec and Symptomatic Nocturnal Hypoglycaemia
The purpose of this study is to determine whether insulin degludec compared to insulin
 glargine can reduce the risk of symptomatic nocturnal hypoglycaemia in subjects with the
 greatest potential benefit from optimised insulin treatment, which are patients with type 1
 diabetes and high risk of nocturnal severe 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