Study on Lixisenatide and Counterregulation to Hypoglycemia

The study is a single-center, randomized, placebo-controlled study with a cross-over design and examines the glucagon response during a hyperinsulinemic hypoglycemic phase after a 6-week treatment with lixisenatide (or placebo) as add-on to basal insulin and metformin. The hypothesis of the study is that the glucagon counterregulation to hypoglycemia in patients treated with lixisenatide and basal insulin is not lower than in patients treated with basal insulin.

Inclusion criteria

• Male, non-fertile female or female of childbearing potential using a medically approved birth control method aged >18 years.
• Adult patients with type 2 diabetes treated with basal insulin (NPH insulin, insulin detemir, insulin glargine or insulin degludec) (stable insulin dose (±10%) during the last three months) with concomitant at >3 months stable dose (>1500 mg daily) of metformin.
• HbA1c <10% (DCCT standard; < 83 mmol(mol) at visit 1.

Exclusion criteria

• Treatment with antihyperglycemic agents apart from basal insulin and metformin, i.e., bolus insulin or other antihyperglycemic oral agents apart from metformin
• Type 1 diabetes (including LADA)
• Pregnant or lactating female. Women of childbearing potential with no effective contraceptive method. Acceptable contraceptive include contraceptive sponge; hormonal contraception pills, patches, vaginal rings, injectable contraceptives; and intrauterine devices. Women of childbearing potential (pre-menopausal, not surgically sterile women for at least 3 months prior to the time of screening) must have a confirmed negative serum pregnancy test at screening visit. They must use an effective contraceptive method throughout the study, and agree to repeat pregnancy tests at designated visits. The applied methods of contraception have to meet the criteria for a highly effective method of birth control according to the "Note for guidance on non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals (CPMP/ICH/286/95)"
• A history of any secondary forms of diabetes, e.g., Cushing's syndrome and acromegaly.
• Acute infections which may affect blood glucose control within 4 weeks prior to visit 1
• Any history of recent (<2 weeks) recurrent or severe hypoglycemic episodes or hypoglycemia unawareness
• Donation of one unit (500 ml) or more of blood, significant blood loss equaling to at least one unit of blood within the past 2 weeks or a blood transfusion within the past 8 weeks.
• Treatment with growth hormone and oral or parenteral corticosteroid (> 7 consecutive days of treatment) within 8 weeks prior to visit 1 and thereafter during the whole study period.
• Use of other investigational drugs within 30 days prior to visit 1.
• Laboratory findings at the time of screening, including amylase and/or lipase > 3 times the upper limit of the normal laboratory range (ULN) and P-calcitonin ≥20 pg/ml (5.9 pmol/L).
• Personal or immediate family history of medullary thyroid cancer (MTC) or genetic condition that predisposes to MTC (e.g. multiple endocrine neoplasia syndromes).
• History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy, stomach/gastric surgery
• Allergic reaction to any GLP-1 receptor agonist or to metacresol
• Clinically relevant history of gastrointestinal disease associated with prolonged nausea and vomiting,
• Cardiovascular, hepatic, neurological, or endocrine disease, active malignant tumor or other major systemic disease or patients with short life expectancy making implementation of the protocol or interpretation of the study results difficult.