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Effects of GRA in Patients With Type 1

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ClinicalTrials.gov Identifier: NCT04779645
Recruitment Status : Not yet recruiting
First Posted : March 3, 2021
Last Update Posted : March 3, 2021
Sponsor:
Collaborator:
REMD Biotherapeutics, Inc.
Information provided by (Responsible Party):
Jeremy Pettus, MD, University of California, San Diego

Brief Summary:
This study will examine the effects a Glucagon Receptor Antagonist (GRA), has on Insulin Sensitivity, Cardiovascular risks (CVD), and Ketone body formation in participants with Type 1 diabetes. The participants will complete blood tests, tests to measure energy expenditure, CVD risks, and insulin resistance. These tests will be performed prior to start of treatment and again after 12-weeks of treatment with the GRA (called REMD-477).

Condition or disease Intervention/treatment Phase
Type 1 Diabetes Drug: REMD-477 Drug: Placebo Phase 2

Detailed Description:

This single-center, double-blind, placebo-controlled, multi-dose study is designed to evaluate the effects of glucagon antagonism on insulin sensitivity, cardiovascular risk and ketogenesis in individuals with Type 1 Diabetes. To accomplish the specific aims proposed, a single clinical trial will be conducted in which a maximum of 30 subjects with T1D, who are otherwise healthy, will be treated with REMD-477 or matching placebo for up to 12 weeks at a dose of 70mg (administered subcutaneously each week) with assessments done pre- and post-therapy. Subjects will be randomized on a 1:1 basis to either the REMD-477 group or placebo group and all subjects will remain on their standard of care insulin therapy throughout the study. There will be 19 study visits as outlined below:

  1. Screening - Complete consenting process, complete medical history and physical exam, review of current medications, collect height/weight, vital signs, and fasting laboratory (blood and urine) tests.
  2. Baseline Visit 1 - Participants that meet screening criteria will complete cardiovascular tests including flow mediated dilation and EndoPat, complete vital signs, weight and laboratory tests for safety and CVD markers.
  3. Baseline Visit 2 - Participants will complete a 2-Step Hyperinsulinemic/Euglycemic clamp with tracer, Indirect Calorimetry, muscle and adipose tissue biopsies.
  4. Baseline Visit 3 - Insulin withdrawal challenge and injection #1 of REMD-477 or placebo. Participants will suspend insulin delivery and remove insulin pump. Blood sugars and ketones will be monitored for up to 8 hours.
  5. Visit 4 - Injection #2 of REMD-477 or placebo and blood collection for safety labs.
  6. Visit 5 - Injection #3 of REMD-477 or placebo.
  7. Visit 6 - Injection #4 of REMD-477 or placebo and blood collection for safety labs.
  8. Visit 7 - Injection #5 of REMD-477 or placebo.
  9. Visit 8 - Injection #6 of REMD-477 or placebo and blood collection for safety labs.
  10. Visit 9 - Injection #7 of REMD-477 or placebo.
  11. Visit 10 - Injection #8 of REMD-477 or placebo and blood collection for safety labs.
  12. Visit 11 - Injection #9 of REMD-477 or placebo.
  13. Visit 12 - Injection #10 of REMD-477 or placebo and blood collection for safety labs.
  14. Visit 13 - Injection #11 of REMD-477 or placebo.
  15. Visit 14 - Injection #12 of REMD-477 or placebo and blood collection for safety labs.
  16. Visit 15 - Repeat cardiovascular tests including flow mediated dilation and EndoPat, complete vital signs, weight and laboratory tests for safety and CVD markers.
  17. Visit 16 - Repeat 2-Step Hyperinsulinemic/Euglycemic clamp with tracer, Indirect Calorimetry, muscle and adipose tissue biopsies.
  18. Visit 17 - Repeat Insulin withdrawal challenge. Participants will suspend insulin delivery and remove insulin pump. Blood sugars and ketones will be monitored for up to 8 hours.
  19. Visit 18 - Safety follow-up visit that includes physical exam, vitals, blood and urine sample collection.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Single-center, double-blind, placebo-controlled, multi-dose study.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double-blind
Primary Purpose: Basic Science
Official Title: The Effects of Glucagon Antagonism on Insulin Sensitivity, Cardiovascular Risk, and Ketogenesis in Type 1 Diabetes
Estimated Study Start Date : April 30, 2021
Estimated Primary Completion Date : December 31, 2024
Estimated Study Completion Date : March 31, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Diabetes Type 1

Arm Intervention/treatment
Experimental: GRA (REMD-477) Group
Once weekly, subcutaneous injection of 70mg REMD-477 (in 1 mL solution) for up to 12 weeks.
Drug: REMD-477
12-Week, once weekly subcutaneous injection with 70mg REMD-477

Placebo Comparator: Placebo Group
Once weekly, subcutaneous injection of 1mL saline solution for up to 12 weeks.
Drug: Placebo
12-Week, once weekly subcutaneous injection with placebo




Primary Outcome Measures :
  1. Metabolic Clearance Rate of Insulin [ Time Frame: 12-Weeks ]
    The change from baseline in calculated metabolic clearance rate of insulin as measured by the 2-step Hyperinsulinemic-Euglycemic Clamp.

  2. Rate of Resting Energy Expenditure (REE) [ Time Frame: 12-Weeks ]
    Change from baseline REE as measured by indirect calorimetry.

  3. Change in Beta-hydroxybutyrate (BHB) Level [ Time Frame: 12-Weeks ]
    The change from baseline in peak BHB production as measured by the insulin withdrawal challenge.

  4. Change in Free Fatty Acid (FFA) Level [ Time Frame: 12-Weeks ]
    The change from baseline in peak FFA production as measured by the insulin withdrawal challenge.

  5. Change in mRNA Expression [ Time Frame: 12-Weeks ]
    The change from baseline in gene mRNA expression as measured by adipose and muscle tissue samples.

  6. Change in Peripheral Macrovascular Vasodilation [ Time Frame: 12-Weeks ]
    The change from baseline in post-stimulus vessel diameter as measured by flow mediated dilation.

  7. Change in Peripheral Microvascular Vasodilation [ Time Frame: 12-Weeks ]
    The change from baseline in reactive hyperemia index as measured by reactive hyperemia-peripheral arterial tonometry (RH-PAT).

  8. Change in Cardiovascular Disease (CVD) Risk Markers. [ Time Frame: 12-Weeks ]
    The change in pg/mL from baseline in CVD risk markers (SAA, CRP, VCAM-1 and ICAM-1) as measure by blood samples.

  9. Change in Cardiovascular Disease (CVD) Risk Markers. [ Time Frame: 12-Weeks ]
    The change in ng/mL from baseline in CVD risk markers (Thrombomodulin, ICAM-3, E-Selectin and P-Selectin) as measure by blood samples.



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

Inclusion Criteria:

  1. Men and women between the ages of 18 and 65 years old, inclusive, at the time of screening;
  2. Females of non-child bearing potential must be ≥ 1 year post-menopausal or documented as being surgically sterile. Females of child bearing potential must agree to use two methods of contraception during the entire study and for an additional 3 months after the end of dosing with the investigational product;
  3. Male subjects must be willing to use clinically acceptable method of contraception during the entire study and for an additional 6 months after the end of the treatment period;
  4. Diagnosed with Type 1 diabetes based on clinical history or as defined by the current American Diabetes Association (ADA) criteria for > 5 years;
  5. Treatment with a stable insulin regimen for at least 8 weeks before screening with continuous subcutaneous insulin infusion (CSII) via an insulin pump;
  6. Currently using a Continuous Glucose Monitoring (CGM) system;
  7. HbA1c ≤ 8.5 % at screening;
  8. A minimum weight of 50kg;
  9. eGFR ≥ 60 mL/min/1.73m²
  10. Able to provide written informed consent approved by an Institutional Review Board (IRB).

Exclusion Criteria:

  1. History or evidence of clinically-significant disorder or condition that, in the opinion of the Investigator, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion;
  2. History of pancreatitis, medullary thyroid carcinoma and/or liver disease;
  3. Clinically significant diagnosis of anemia;
  4. Body Mass Index (BMI) < 18.5 kg/m2 and/or weight less than 50kg;
  5. Whole blood donation of 1 pint (500 mL) within 8 weeks prior to Screening. Donations of plasma, packed RBCs, platelets or quantities less than 500 mL are allowed at investigator discretion;
  6. Current or recent (within 1 month of screening) use of diabetes medications other than insulin;
  7. Women who are pregnant or lactating/breastfeeding;
  8. Unable or unwilling to follow the study protocol or who are non-compliant with screening appointments or study visits;
  9. Any other condition(s) that might reduce the chance of obtaining study data, or that might cause safety concerns, or that might compromise the ability to give truly informed consent.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04779645


Contacts
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Contact: Todd May 8582462169 tmay@ucsd.edu

Sponsors and Collaborators
University of California, San Diego
REMD Biotherapeutics, Inc.
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Responsible Party: Jeremy Pettus, MD, Clinical Professor, University of California, San Diego
ClinicalTrials.gov Identifier: NCT04779645    
Other Study ID Numbers: UC-MEDJP-04
First Posted: March 3, 2021    Key Record Dates
Last Update Posted: March 3, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Diabetes Mellitus, Type 1
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
REMD-477
Hypoglycemic Agents
Physiological Effects of Drugs