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

Study Overview
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Brief Summary
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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.

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

Conditions
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Type 1 Diabetes, Hypoglycemia

Intervention / Treatment
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* Drug: ZT-01 low dose
* Drug: ZT-01 high dose
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Subjects will be randomized to the order in which they receive three treatments during consecutive clamps
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment order: placebo, low dose, high dose<br>Subjects will receive a single administration of each treatment in this order during three consecutive clamps | Drug: ZT-01 low dose<br>* Single subcutaneous (SC) injection of ZT-01 3 mg during hypoglycemic clamp<br>Drug: ZT-01 high dose<br>* Single SC injection of ZT-01 20 mg during hypoglycemic clamp<br>Drug: Placebo<br>* Single SC injection of placebo during hypoglycemic clamp<br>|
| Experimental: Treatment order: placebo, high dose, low dose<br>Subjects will receive a single administration of each treatment in this order during three consecutive clamps | Drug: ZT-01 low dose<br>* Single subcutaneous (SC) injection of ZT-01 3 mg during hypoglycemic clamp<br>Drug: ZT-01 high dose<br>* Single SC injection of ZT-01 20 mg during hypoglycemic clamp<br>Drug: Placebo<br>* Single SC injection of placebo during hypoglycemic clamp<br>|
| Experimental: Treatment order: low dose, placebo, high dose<br>Subjects will receive a single administration of each treatment in this order during three consecutive clamps | Drug: ZT-01 low dose<br>* Single subcutaneous (SC) injection of ZT-01 3 mg during hypoglycemic clamp<br>Drug: ZT-01 high dose<br>* Single SC injection of ZT-01 20 mg during hypoglycemic clamp<br>Drug: Placebo<br>* Single SC injection of placebo during hypoglycemic clamp<br>|
| Experimental: Treatment order: low dose, high dose, placebo<br>Subjects will receive a single administration of each treatment in this order during three consecutive clamps | Drug: ZT-01 low dose<br>* Single subcutaneous (SC) injection of ZT-01 3 mg during hypoglycemic clamp<br>Drug: ZT-01 high dose<br>* Single SC injection of ZT-01 20 mg during hypoglycemic clamp<br>Drug: Placebo<br>* Single SC injection of placebo during hypoglycemic clamp<br>|
| Experimental: Treatment order: high dose, placebo, low dose<br>Subjects will receive a single administration of each treatment in this order during three consecutive clamps | Drug: ZT-01 low dose<br>* Single subcutaneous (SC) injection of ZT-01 3 mg during hypoglycemic clamp<br>Drug: ZT-01 high dose<br>* Single SC injection of ZT-01 20 mg during hypoglycemic clamp<br>Drug: Placebo<br>* Single SC injection of placebo during hypoglycemic clamp<br>|
| Experimental: Treatment order: high dose, low dose, placebo<br>Subjects will receive a single administration of each treatment in this order during three consecutive clamps | Drug: ZT-01 low dose<br>* Single subcutaneous (SC) injection of ZT-01 3 mg during hypoglycemic clamp<br>Drug: ZT-01 high dose<br>* Single SC injection of ZT-01 20 mg during hypoglycemic clamp<br>Drug: Placebo<br>* Single SC injection of placebo during hypoglycemic clamp<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in glucagon between euglycemia and hypoglycemia | Mean and peak glucagon level during euglycemia and each hypoglycemic period of the clamp | During each clamp, up to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin infused | Insulin administered during euglycemia and each hypoglycemic period of the clamp | During each clamp, up to 12 weeks | 
| Insulin infusion rate | Rate of insulin administered during euglycemia and each hypoglycemic period of the clamp | During each clamp, up to 12 weeks | 
| Change in catecholamines between euglycemia and hypoglycemia | Epinephrine and norepinephrine during euglycemia and each stable hypoglycemic period of the clamp | During each clamp, up to 12 weeks | 
| Change in growth hormone between euglycemia and hypoglycemia | Growth hormone during euglycemia and each stable hypoglycemic period | During each clamp, up to 12 weeks | 
| Change in cortisol between euglycemia and hypoglycemia | Cortisol during euglycemia and each stable hypoglycemic period | During each clamp, up to 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hypoglycemic clamp, glucagon counterregulation