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

• ClinicalTrials.gov Identifier: NCT05007977
• Recruitment Status: Terminated
• First Posted: August 17, 2021
• Last Update Posted: July 12, 2023
• Sponsor: Zucara Therapeutics Inc.
• Information provided by (Responsible Party): Zucara Therapeutics Inc.

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
Type 1 Diabetes; Hypoglycemia	Drug: ZT-01 low dose; Drug: ZT-01 high dose; Drug: Placebo	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: Subjects will be randomized to the order in which they receive three treatments during consecutive clamps
• Masking: Double (Participant, Investigator)
• Masking Description: The participant, the investigator and site staff conducting all study procedures are masked to treatment administered at each clamp.
• Primary Purpose: Treatment
• Official Title: Pharmacodynamic Evaluation of ZT-01 in a Stepped Hypoglycemic Clamp Model in Subjects With Type 1 Diabetes Mellitus
• Actual Study Start Date: July 8, 2021
• Actual Primary Completion Date: April 12, 2022
• Actual Study Completion Date: April 18, 2022

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 :

1. Change in glucagon between euglycemia and hypoglycemia [ Time Frame: During each clamp, up to 12 weeks ]
   Mean and peak glucagon level during euglycemia and each hypoglycemic period of the clamp

Secondary Outcome Measures :

1. Insulin infused [ Time Frame: During each clamp, up to 12 weeks ]
   Insulin administered during euglycemia and each hypoglycemic period of the clamp
2. Insulin infusion rate [ Time Frame: During each clamp, up to 12 weeks ]
   Rate of insulin administered during euglycemia and each hypoglycemic period of the clamp
3. Change in catecholamines between euglycemia and hypoglycemia [ Time Frame: During each clamp, up to 12 weeks ]
   Epinephrine and norepinephrine during euglycemia and each stable hypoglycemic period of the clamp
4. Change in growth hormone between euglycemia and hypoglycemia [ Time Frame: During each clamp, up to 12 weeks ]
   Growth hormone during euglycemia and each stable hypoglycemic period
5. Change in cortisol between euglycemia and hypoglycemia [ Time Frame: During each clamp, up to 12 weeks ]
   Cortisol during euglycemia and each stable hypoglycemic period

Other Outcome Measures:

1. Symptom score during hypoglycemia [ Time Frame: 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

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

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

Canada, Ontario

LMC Manna Research

Toronto, Ontario, Canada, M4G 3E8

Sponsors and Collaborators

Zucara Therapeutics Inc.

Investigators

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

More Information

• Responsible Party: Zucara Therapeutics Inc.
• ClinicalTrials.gov Identifier: NCT05007977
• Other Study ID Numbers: ZT01-CL-1003
• First Posted: August 17, 2021
• Last Update Posted: July 12, 2023
• Last Verified: July 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Zucara Therapeutics Inc.:

hypoglycemic clamp; glucagon counterregulation

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemia; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases