Insulin Degludec and Symptomatic Nocturnal Hypoglycaemia

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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

Official Title
-----------------
The Effect of Insulin Degludec on Risk of Symptomatic Nocturnal Hypoglycaemia in Subjects With Type 1 Diabetes and High Risk of Nocturnal Severe Hypoglycaemia

Conditions
-----------------
Type 1 Diabetes Mellitus, Nocturnal Hypoglycemia, Recurrent Severe Hypoglycaemia

Intervention / Treatment
-----------------
* Drug: Insulin aspart/glargine
* Drug: Insulin aspart/degludec


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Insulin glargine<br>Each treatment arm last for 12 months - 3 months of run-in/cross-over and 9 months of maintenance. Patients will be randomised (1:1) to treatment with basal-bolus therapy with insulin aspart/degludec or insulin aspart/glargine in random order. After 12 months of treatment patients will cross-over to the other basal-bolus therapy. Insulin degludec and insulin glargine is administered once daily at the evening meal and insulin aspart is administered three times daily before the main meals. | Drug: Insulin aspart/glargine<br> <br> * Other names: Lantus;|
| Experimental: Insulin degludec<br>Each treatment arm last for 12 months - 3 months of run-in/cross-over and 9 months of maintenance. Patients will be randomised (1:1) to treatment with basal-bolus therapy with insulin aspart/degludec or insulin aspart/glargine in random order. After 12 months of treatment patients will cross-over to the other basal-bolus therapy. Insulin degludec and insulin glargine is administered once daily at the evening meal and insulin aspart is administered three times daily before the main meals. | Drug: Insulin aspart/degludec<br> <br> * Other names: Tresiba;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptomatic nocturnal hypoglycaemia |  | 9 months (3-12) of each treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Severe hypoglycaemia (total, night-time, daytime) |  | 9 months (3-12) of each treatment period | 
| Any nocturnal hypoglycaemia (incl. asymptomatic/silent events) |  | 9 months (3-12) of each treatment period | 
| Any daytime hypoglycaemia (symptomatic, asymptomatic/silent and severe) |  | 9 months (3-12) of each treatment period | 
| Any CGM recorded hypoglycaemia (symptomatic, asymptomatic/silent and severe) |  | 2 x 6 days in each treatment arm | 
| Any in-hospital nocturnal hypoglycaemia (incl. asymptomatic/silent events) |  | 2 overnight stays in each treatment arm | 
| Change in HbA1c |  | From baseline to after 12 months of treatment | 
| Change in glycaemic variability |  | 4 x overnight stays and 4 x 6 days of CGM | 
| Insulin doses |  | End of each treatment period | 
| Quality of life incl. pre-depression scale |  | At baseline, cross-over and after 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Insulin, Diabetes Mellitus, Hypoglycaemia, Glucose Metabolism Disorders, Metabolic Diseases, Endocrine System Diseases, Autoimmune Diseases, Hypoglycaemic Agents, Physiological Effetcs of Drugs