The effect of insulin degludec on risk of symptomatic nocturnal hypoglycaemia in adults with type 1 diabetes and high risk of nocturnal severe hypoglycaemia (the HypoDeg trial): study rationale and design

Abstract

Background Hypoglycaemia, especially nocturnal, remains the main limiting factor of achieving good glycaemic control in type 1 diabetes. The effect of first generation long-acting insulin analogues in reducing nocturnal hypoglycaemia is well documented in patient with type 1 diabetes. The effect of the newer long-acting insulin degludec on risk of nocturnal hypoglycaemia remains undocumented in patients with type 1 diabetes and recurrent severe nocturnal hypoglycaemia. The HypoDeg trial is designed to investigate whether insulin degludec in comparison with insulin glargine U100 is superior in limiting the occurrence of nocturnal hypoglycaemia in patients with recurrent nocturnal severe hypoglycaemia. This paper reports the study design of the HypoDeg trial. Methods/design A Danish investigator-initiated, prospective, randomised, open, blinded endpoint (PROBE), multicentre, two-year cross-over study investigating the effect of insulin degludec versus insulin glargine U100 on frequency of nocturnal hypoglycaemia in patients with type 1 diabetes and one or more episodes of nocturnal severe hypoglycaemia during the preceding two years as the major inclusion criteria. Patients are randomised (1:1) to basal therapy with insulin degludec or insulin glargine. Insulin aspart is used as bolus therapy in both treatment arms. Discussion In contrast to most other insulin studies the HypoDeg trial includes only patients at high risk of hypoglycaemia. The HypoDeg trial will compare treatment with insulin degludec to insulin glargine U100 in terms of risk of nocturnal hypoglycaemic episodes in patients with type 1 diabetes with the greatest potential to benefit from near-physiological insulin replacement therapy. www.clinicaltrials.gov : NCT02192450.

Comparison of treatment with insulin degludec and glargine U100 in patients with type 1 diabetes prone to nocturnal severe hypoglycaemia: The HypoDeg randomized, controlled, open‐label, crossover trial

“…At every visit, blood pressure, pulse, and weight were recorded, and HbA1c was measured. At the randomization, crossover, and end‐of‐study visits, we measured fasting blood glucose and C‐peptide 12 . Furthermore, we assessed hypoglycaemia awareness by three validated methods 14‐16 …”

“…The secondary endpoints are the incidence of severe hypoglycaemia (total, night time, daytime) as defined by the American Diabetes Association as an event requiring the assistance of another person to actively administer carbohydrates, glucagon, or to take other corrective actions 18 . Overall glycaemic control, as assessed by the last three HbA1c values in each treatment arm and insulin doses at the end of each treatment period, are accommodated in the secondary endpoints 12 …”

“…Each 1‐year treatment period consisted of 3 months of run‐in or crossover, used for insulin dose adjustment and stabilization of treatment regimens, followed by 9 months of maintenance. A detailed description of the study design has been published previously 12 …”

“…Patients were eligible if they had been diagnosed clinically with type 1 diabetes for more than 5 years, were aged 18 years or older, and reported one or more episodes of nocturnal severe hypoglycaemia in the previous 2 years (defined by the need for treatment assistance from another person). Pertinent exclusion criteria were: history of primary and secondary adrenal insufficiency, growth hormone deficiency or untreated hypothyroidism, unstable macrovascular disease, history of malignancy, drug or alcohol abuse, and HbA1c more than 86 mmol/mol (>10%) 12 . Because the use of continuous glucose monitoring (CGM) was very limited in Denmark at this time we decided only to include people using self‐monitored blood glucose (SMBG) as control of glycaemia.…”

“…We randomized patients to start basal‐bolus therapy with insulin degludec/insulin aspart (Tresiba/NovoRapid) or insulin glargine U100/insulin aspart (Lantus/NovoRapid). A web‐based electronic case report form generating site‐specific randomization lists in blocks of four patients randomized 73 patients to receive insulin degludec first, and 76 patients to receive insulin glargine U100 first 12 …”