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 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.

Study Overview

• Status: Terminated
• Conditions: Hypoglycemia; Type 1 Diabetes
• Intervention / Treatment: Drug: ZT-01 low dose; Drug: ZT-01 high dose; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4G 3E8
      • LMC Manna Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

6

Arms and Interventions

Participant Group / 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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Symptom score during hypoglycemia	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.	During each clamp, up to 12 weeks

Collaborators and Investigators

• Sponsor: Zucara Therapeutics Inc.
• Investigators: Study Director: Richard Liggins, PhD, Zucara Therapeutics Inc.

Study record dates

Study Major Dates

• Study Start (Actual): July 8, 2021
• Primary Completion (Actual): April 12, 2022
• Study Completion (Actual): April 18, 2022

Study Registration Dates

• First Submitted: July 20, 2021
• First Submitted That Met QC Criteria: August 16, 2021
• First Posted (Actual): August 17, 2021

Study Record Updates

• Last Update Posted (Actual): July 12, 2023
• Last Update Submitted That Met QC Criteria: July 11, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: hypoglycemic clamp; glucagon counterregulation
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemia
• Other Study ID Numbers: ZT01-CL-1003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No