Effect of ZT-01 on Glucagon During Hypoglycemia in Type 1 Diabetes Mellitus
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment order: placebo, low dose, high dose Subjects will receive a single administration of each treatment in this order during three consecutive clamps |
Drug: ZT-01 low dose
Single subcutaneous (SC) injection of ZT-01 3 mg during hypoglycemic clamp
Drug: ZT-01 high dose
Single SC injection of ZT-01 20 mg during hypoglycemic clamp
Drug: Placebo
Single SC injection of placebo during hypoglycemic clamp
|
| Experimental: Treatment order: placebo, high dose, low dose Subjects will receive a single administration of each treatment in this order during three consecutive clamps |
Drug: ZT-01 low dose
Single subcutaneous (SC) injection of ZT-01 3 mg during hypoglycemic clamp
Drug: ZT-01 high dose
Single SC injection of ZT-01 20 mg during hypoglycemic clamp
Drug: Placebo
Single SC injection of placebo during hypoglycemic clamp
|
| Experimental: Treatment order: low dose, placebo, high dose Subjects will receive a single administration of each treatment in this order during three consecutive clamps |
Drug: ZT-01 low dose
Single subcutaneous (SC) injection of ZT-01 3 mg during hypoglycemic clamp
Drug: ZT-01 high dose
Single SC injection of ZT-01 20 mg during hypoglycemic clamp
Drug: Placebo
Single SC injection of placebo during hypoglycemic clamp
|
| Experimental: Treatment order: low dose, high dose, placebo Subjects will receive a single administration of each treatment in this order during three consecutive clamps |
Drug: ZT-01 low dose
Single subcutaneous (SC) injection of ZT-01 3 mg during hypoglycemic clamp
Drug: ZT-01 high dose
Single SC injection of ZT-01 20 mg during hypoglycemic clamp
Drug: Placebo
Single SC injection of placebo during hypoglycemic clamp
|
| Experimental: Treatment order: high dose, placebo, low dose Subjects will receive a single administration of each treatment in this order during three consecutive clamps |
Drug: ZT-01 low dose
Single subcutaneous (SC) injection of ZT-01 3 mg during hypoglycemic clamp
Drug: ZT-01 high dose
Single SC injection of ZT-01 20 mg during hypoglycemic clamp
Drug: Placebo
Single SC injection of placebo during hypoglycemic clamp
|
| Experimental: Treatment order: high dose, low dose, placebo Subjects will receive a single administration of each treatment in this order during three consecutive clamps |
Drug: ZT-01 low dose
Single subcutaneous (SC) injection of ZT-01 3 mg during hypoglycemic clamp
Drug: ZT-01 high dose
Single SC injection of ZT-01 20 mg during hypoglycemic clamp
Drug: Placebo
Single SC injection of placebo during hypoglycemic clamp
|
Outcome Measures
Primary Outcome Measures
- Change in glucagon between euglycemia and hypoglycemia [During each clamp, up to 12 weeks]
Mean and peak glucagon level during euglycemia and each hypoglycemic period of the clamp
Secondary Outcome Measures
- Insulin infused [During each clamp, up to 12 weeks]
Insulin administered during euglycemia and each hypoglycemic period of the clamp
- Insulin infusion rate [During each clamp, up to 12 weeks]
Rate of insulin administered during euglycemia and each hypoglycemic period of the clamp
- Change in catecholamines between euglycemia and hypoglycemia [During each clamp, up to 12 weeks]
Epinephrine and norepinephrine during euglycemia and each stable hypoglycemic period of the clamp
- Change in growth hormone between euglycemia and hypoglycemia [During each clamp, up to 12 weeks]
Growth hormone during euglycemia and each stable hypoglycemic period
- Change in cortisol between euglycemia and hypoglycemia [During each clamp, up to 12 weeks]
Cortisol during euglycemia and each stable hypoglycemic period
Other Outcome Measures
- Symptom score during hypoglycemia [During each clamp, up to 12 weeks]
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.
Eligibility Criteria
Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | LMC Manna Research | Toronto | Ontario | Canada | M4G 3E8 |
Sponsors and Collaborators
- Zucara Therapeutics Inc.
Investigators
- Study Director: Richard Liggins, PhD, Zucara Therapeutics Inc.
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- ZT01-CL-1003