Effect of ZT-01 on Glucagon During Hypoglycemia in Type 1 Diabetes Mellitus

Pharmacodynamic Evaluation of ZT-01 in a Stepped Hypoglycemic Clamp Model in Subjects With Type 1 Diabetes Mellitus

The study was completed following review of the assumptions underlying the power calculation and it was deemed that enough subjects had been recruited to complete enrollment

The purpose of this study is to determine whether ZT-01 increases the glucagon response to hypoglycemia in type 1 diabetes (T1D). ZT-01 is a specific somatostatin (SST) type 2 receptor antagonist hypothesized to increase the counterregulatory glucagon release during hypoglycemia, which is impaired in diabetes, and may thus reduce the occurrence of hypoglycemia. Approximately 25 participants with well-controlled type 1 diabetes will be recruited to a crossover study and be randomized to the order in which they receive a single administration of placebo, low dose and high dose ZT-01 during three euglycemic-hypoglycemic clamps 2 to 6 weeks apart, with a follow-up visit approximately 1 week after the final clamp. Participants will stay overnight in the clinic before each clamp, and their plasma glucose (PG) will be kept at euglycemic levels with IV insulin and dextrose as needed. The following morning, the clamp will begin and the subject's PG will be kept at 5.5 mmol/L (euglycemia) with variable IV insulin (and dextrose as needed). Study treatment will be administered during this euglycemic period, and then insulin will be increased so that PG falls to a plateau of mild hypoglycemia, and then increased further to clinically significant hypoglycemia. Release of glucagon and other counterregulatory hormones will be measured, and a symptom score will be completed, during euglycemia before and following study treatment, and during each level of hypoglycemia. Following the clamp, the participant's blood glucose will be returned to normal levels prior to leaving the clinic.

Subjects will be randomized to the order in which they receive three treatments during consecutive clamps

The participant, the investigator and site staff conducting all study procedures are masked to treatment administered at each clamp.

Subjects will receive a single administration of each treatment in this order during three consecutive clamps

Subjects will receive a single administration of each treatment in this order during three consecutive clamps

Subjects will receive a single administration of each treatment in this order during three consecutive clamps

Subjects will receive a single administration of each treatment in this order during three consecutive clamps

Subjects will receive a single administration of each treatment in this order during three consecutive clamps

Subjects will receive a single administration of each treatment in this order during three consecutive clamps

The Edinburgh hypoglycemia symptom score assesses the presence and extent (on a scale of 1, not present to 7, present a great deal) of 16 common symptoms which may be experienced by an individual while their blood glucose is low. The score does not indicate any outcome.

Inclusion Criteria: Type 1 diabetes for at least 5 years and receiving insulin as the only T1D therapy HbA1c ≥6.0 and ≤9.0 % BMI ≥18 to ≤27 kg/m^2 Normal thyroid function Exclusion Criteria: Impaired hypoglycemia awareness Severe hypoglycemia or diabetic ketoacidosis (DKA) within 3 months Abnormal blood pressure or ECG, clinically significant cardiovascular, cerebrovascular or peripheral vascular disease History of pheochromocytoma, insulinoma, glucagonoma, acromegaly, Cushing's disease, glycogen storage disease or adrenal insufficiency; ongoing or previous treatment with octreotide, lanreotide or pasireotide Current use of systemic corticosteroids or beta-blockers