Suppression of Endogenous Glucose Production by Injectable HDV-Insulin Lispro: A Dose Response Study in Human Subjects With Type 1 Diabetes

Single-center, double-blind, random-sequence study assessing the HDV dose-response relationship to Endogenous Glucose Production (EGP), Free Fatty Acids (FFA) and Glucose Disposal Rate (GDR) during a euglycemic clamp procedure following overnight stabilization of blood glucose with intravenous insulin (and, if needed intravenous glucose). EGP and GDR will be determined using established radioisotope methodology. The concentration of Hepatic Directed Vesicles (HDV) in the insulin lispro (LIS) infused during the clamp procedure will be varied such that the percentage of HDV-bound LIS will range from 0%, 1%, 10%, and 100%. Each participant will thus undergo four clamp procedures at the four different HDV levels. LIS will be infused at a constant dose (6 mU/m2/min) for each of the four procedures.

Study Overview

• Status: Not yet recruiting
• Conditions: Type 1 Diabetes
• Intervention / Treatment: Drug: HDV-Insulin Lispro

• Study Type: Interventional
• Enrollment (Estimated): 18
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Todd May, MS; Phone Number: 858-246-2169; Email: tmay@health.ucsd.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Male or female of age 18 to 65 years, inclusive, who:
2. Has at Screening been diagnosed as T1D for at least 12 months; preference will be given to potential participants who currently use continuous subcutaneous insulin infusion (CSII) therapy;
3. Has at Screening C-peptide ≤0.8 ng/mL (single retest allowed);
4. Has at Screening a BMI ≥18.0 kg/m2 and ≤33.0 kg/m2;
5. Has at Screening HbA1c ≥6.5% and ≤8.5 %.

Exclusion Criteria:

1. Has known or suspected allergy to any component of any of the study drugs in this trial;
2. Is, at Screening, pregnant or breast-feeding, or intends to become pregnant at any time during the duration of the study;
3. Has, at Screening, as judged by the Site Investigator, a history or current evidence of any of advance complications of diabetes;
4. Is, at Screening, judged by the Site Investigator to have a current addiction to alcohol or substances of abuse;
5. Is, at Screening, using one or more drugs that may interfere with the interpretation of trial results or are known to cause clinically relevant interference with insulin action, glucose utilization, or recovery from hypoglycemia (e.g., beta blockers, systemic corticosteroids at pharmacologic doses, cancer chemotherapies);
6. Has, within one (1) month prior to Screening, used either oral anti-diabetic medication or noninsulin anti-diabetic injection therapies (e.g. SGLT-2 inhibitors, pramlintide, GLP-1 agonists, etc.);
7. Has, within one (1) month prior to Screening, received any investigational drug;
8. Has, within three (3) months prior to Screening, smoked tobacco or used any smokeless tobacco or nicotine delivery system (inhaled, oral or buccal);

9. Has at Screening, as judged by the Site Investigator, any condition (intrinsic or extrinsic) that could reasonably be expected to interfere with trial participation, confound evaluation of the data, or pose additional risk to adhering to the study protocol. Examples of such conditions include but are not limited to:

   • Clinically significant active disease of the gastrointestinal, cardiovascular, hepatic, neurological, renal, genitourinary, or hematological systems;
   • History of such an illness or disease;
   • Diminished mental capacity, psychological or behavioral dysfunction, unwilling or resistant to protocol requirements, language barriers.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: HDV-bound Lispro 0%; Subjects will receive insulin lispro with 0% bound HDV	Drug: HDV-Insulin Lispro; The name of the investigational drug is Hepatic Directed Vesicles + Insulin Lispro (HDV-bound LIS). It is a nano-carrier-based formulation of insulin which is the active therapeutic ingredient in the product. The nano-carrier component of the formulation contains a hepatic target molecule, biotin phosphatidylethanolamine, which has an affinity for hepatocytes and enables the product to deliver insulin directly to the liver.
Active Comparator: HDV-bound Lispro 1%; Subjects will receive insulin lispro with 1% bound HDV	Drug: HDV-Insulin Lispro; The name of the investigational drug is Hepatic Directed Vesicles + Insulin Lispro (HDV-bound LIS). It is a nano-carrier-based formulation of insulin which is the active therapeutic ingredient in the product. The nano-carrier component of the formulation contains a hepatic target molecule, biotin phosphatidylethanolamine, which has an affinity for hepatocytes and enables the product to deliver insulin directly to the liver.
Active Comparator: HDV-bound Lispro 10%; Subjects will receive insulin lispro with 10% bound HDV	Drug: HDV-Insulin Lispro; The name of the investigational drug is Hepatic Directed Vesicles + Insulin Lispro (HDV-bound LIS). It is a nano-carrier-based formulation of insulin which is the active therapeutic ingredient in the product. The nano-carrier component of the formulation contains a hepatic target molecule, biotin phosphatidylethanolamine, which has an affinity for hepatocytes and enables the product to deliver insulin directly to the liver.
Active Comparator: HDV-bound Lispro 100%; Subjects will receive insulin lispro with 100% bound HDV	Drug: HDV-Insulin Lispro; The name of the investigational drug is Hepatic Directed Vesicles + Insulin Lispro (HDV-bound LIS). It is a nano-carrier-based formulation of insulin which is the active therapeutic ingredient in the product. The nano-carrier component of the formulation contains a hepatic target molecule, biotin phosphatidylethanolamine, which has an affinity for hepatocytes and enables the product to deliver insulin directly to the liver.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of suppression of endogenous glucose production	To establish the dose-response relationship between Hepatic-Directed Vesicles (HDV) and endogenous glucose production at a constant dose of insulin lispro (LIS) during euglycemic clamp procedure	0 through 6 hours

Collaborators and Investigators

• Sponsor: University of California, San Diego
• Collaborators: The Leona M. and Harry B. Helmsley Charitable Trust

Study record dates

Study Major Dates

• Study Start (Estimated): February 1, 2025
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): June 30, 2026

Study Registration Dates

• First Submitted: January 9, 2023
• First Submitted That Met QC Criteria: January 9, 2023
• First Posted (Actual): January 19, 2023

Study Record Updates

• Last Update Posted (Actual): October 10, 2024
• Last Update Submitted That Met QC Criteria: October 7, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin Lispro
• Other Study ID Numbers: DP 01-2022-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: IPD will not be shared

Drug and device information, study documents

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