Clinical trial NCT05007977: Effect of ZT-01 on Glucagon During Hypoglycemia in Type 1 Diabetes Mellitus
Official title: Pharmacodynamic Evaluation of ZT-01 in a Stepped Hypoglycemic Clamp Model in Subjects With Type 1 Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Type 1 Diabetes
Hypoglycemia
Keywords: hypoglycemic clamp
glucagon counterregulation
Lead sponsor: Zucara Therapeutics Inc.
Sponsor class: INDUSTRY
First posted: 2021-08-17
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Subjects will be randomized to the order in which they receive three treatments during consecutive clamps
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Change in glucagon between euglycemia and hypoglycemia
timeFrame: During each clamp, up to 12 weeks
Secondary outcomes:
measure: Insulin infused
timeFrame: During each clamp, up to 12 weeks
measure: Insulin infusion rate
timeFrame: During each clamp, up to 12 weeks
measure: Change in catecholamines between euglycemia and hypoglycemia
timeFrame: During each clamp, up to 12 weeks
measure: Change in growth hormone between euglycemia and hypoglycemia
timeFrame: During each clamp, up to 12 weeks
measure: Change in cortisol between euglycemia and hypoglycemia
timeFrame: During each clamp, up to 12 weeks
Other outcomes:
measure: Symptom score during hypoglycemia
timeFrame: During each clamp, up to 12 weeks
Locations:
city: Toronto
country: Canada
facility: LMC Manna Research
state: Ontario
Study officials:
affiliation: Zucara Therapeutics Inc.
name: Richard Liggins, PhD
role: STUDY_DIRECTOR
References: