GPR119 Agonist for Hypoglycemia in Type 1 Diabetes

NCT04432090 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: 1552172
• Study Type: interventional
• Target: 110
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to test if a specific research medication could increase the response to low blood glucose in people with type 1 diabetes. The response of the body to low blood sugar will be measured in healthy people as a reference point.

Conditions

Diabetes Mellitus, Type 1

Outcome Measures

Primary Outcomes (3)

• Maximal Glucagon Concentration During Hypoglycemia

  Maximal glucagon concentration during insulin induced hypoglycemia. This was measured during the hypoglycemic steady state of the hyper-insulinemic euglycemic-hypoglycemic clamp study.

  Day 14, Day 42

• Total Area Under the Curve (AUC) for Glucagon During Hypoglycemia.

  This outcome was measured during the hypoglycemic steady state of the hyper-insulinemic euglycemic hypoglycemic clamp study. Total area under the curve (AUC) for glucagon was measured during the time points of 120 minutes to 140 minutes of the clamp.

  Day 14, Day 42

• Incremental AUC for Glucagon During Hypoglycemia (Above Baseline Levels During Euglycemia)

  This is the difference between the AUC during the hypoglycemic steady state (time points 120 - 140 mins of clamp) and the baseline glucagon levels during euglycemic steady state (timepoints 60 min - 80 mins of the clamp)

  Day 14, Day 42

Study Arms (3)

MBX-2982 first then placebo- Volunteers with Type 1 diabetes

EXPERIMENTAL

Participants with type 1 diabetes (T1D) will be randomized to either study medication or placebo group. In this arm, participants will receive a pill that contains the study medication (MBX-2982). This will be followed by a wash-out period and a cross over to the second study period in which they will receive a pill that does not contain the medication (placebo).

Drug: Placebo; Drug: Study Medication (MBX-2982)

Healthy Volunteers

ACTIVE COMPARATOR

This group will not receive any medication. It will be studied to establish the norm of the measurement that will be performed to obtain the study outcomes.

Other: No medication for this group

Placebo first then MBX-2982- Volunteers with Type 1 diabetes

EXPERIMENTAL

Participants with type 1 diabetes (T1D) will be randomized to either study medication or placebo group. In this arm, participants will receive a pill that does not contain the medication (placebo). This will be followed by a wash-out period and a cross over to the second study period in which they will receive a pill that contains the study medication (MBX-2982).

Drug: Placebo; Drug: Study Medication (MBX-2982)

Interventions

Placebo DRUG

Each group will receive either a pill that contains the study medication (MBX-2982) or a pill that does not contain the medication (placebo)

Also known as: MBX-2982

MBX-2982 first then placebo- Volunteers with Type 1 diabetes; Placebo first then MBX-2982- Volunteers with Type 1 diabetes

Study Medication (MBX-2982) DRUG

Each group will receive either a pill that contains the study medication (MBX-2982) or a pill that does not contain the medication (placebo)

Also known as: MBX-2982

MBX-2982 first then placebo- Volunteers with Type 1 diabetes; Placebo first then MBX-2982- Volunteers with Type 1 diabetes

No medication for this group OTHER

This group will be studied to establish the norm of the measurement that will be performed to obtain the study outcomes.

Healthy Volunteers

Eligibility Criteria

• Age: 20 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Type 1 diabetes cohort:
• Age 20-60 years
• Diagnosis of T1DM according to American Diabetes Association (ADA) criteria continuously requiring insulin for survival
• Diabetes diagnosis performed more than 5 years before enrollment
• Fasting C-peptide levels \< 0.7 ng/mL with a concurrent plasma glucose concentration \> 90 mg/dL (Labs may need to be repeated if the Plasma glucose is \< 90 mg/dL)
• For female participants: must be \> 6 months post-partum and not lactating and agrees not to become pregnant during the study and for at least 2 weeks after the last dose of the study medication. For male participants: agrees not to donate sperm or not to get a woman pregnant during the study and for at least 2 weeks after the last dose of the study medication.
• Healthy subject cohort:
• Age 20-60 years
• General good health
• Creatinine clearance \>80 mL/min based on CKD-EPI equation
• Fasting blood glucose (FBG) \>70 mg/dL and \<100 mg/dL
• No history of diabetes
• For female participants: must be \> 6 months post-partum and not lactating and agrees not to become pregnant during the study

You may not qualify if:

• BMI \>35 kg/m2 and \<18.5 kg/m2 for females and BMI \>35 kg/m2 and \<20 kg/m2 for males.
• Increase or decrease body weight greater than 3kg in the 3 months before enrollment.
• Evidence by history, ECG or exams of clinically significant cardiovascular disease (unstable angina, myocardial infarction or coronary revascularization within 6 months, clinically significant abnormalities on ECG, presence of cardiac pacemaker, implanted cardiac defibrillator)
• Evidence of autonomic neuropathy
• Liver disease (AST or ALT \>2.5 times the upper limit of normal)
• Kidney disease (creatinine \>1.6 mg/dl or estimated GFR \<60 ml/min).
• Dyslipidemia, including triglycerides \>500 mg/dl, LDL \>200 mg/dl or unstable hyperlipidemia. Treatment with a single lipid lowering agents is allowed if stable within the previous 3 months.
• Anemia (hemoglobin \<12 g/dl in men, \<11 g/dl in women)
• Thyroid dysfunction (suppressed TSH, elevated TSH \<10 µIU/ml if symptomatic or elevated TSH \>10 µIU/ml if asymptomatic)
• Uncontrolled hypertension (BP \>160 mmHg systolic or \>100 mmHg diastolic) or treatment with more than 2 antihypertensive medications.
• Current use of beta-adrenergic blocking agents or their use was stopped less than one month before recruitment
• History of cancer within the last 5 years (skin cancers, with the exception of melanoma, may be acceptable)
• History of organ transplant
• History of HIV, active Hepatitis B or C, or Tuberculosis
• Pregnancy, lactation or 6 months postpartum from the scheduled date of screening lab collection

Sponsors & Collaborators

• AdventHealth Translational Research Institute: lead

Study Sites (1)

AdventHealth Translational Research Institute

Orlando, Florida, 32804, United States

Location

Related Publications (18)

• Ekberg JH, Hauge M, Kristensen LV, Madsen AN, Engelstoft MS, Husted AS, Sichlau R, Egerod KL, Timshel P, Kowalski TJ, Gribble FM, Reiman F, Hansen HS, Howard AD, Holst B, Schwartz TW. GPR119, a Major Enteroendocrine Sensor of Dietary Triglyceride Metabolites Coacting in Synergy With FFA1 (GPR40). Endocrinology. 2016 Dec;157(12):4561-4569. doi: 10.1210/en.2016-1334. Epub 2016 Oct 25.

  PMID: 27779915 BACKGROUND

• Flock G, Holland D, Seino Y, Drucker DJ. GPR119 regulates murine glucose homeostasis through incretin receptor-dependent and independent mechanisms. Endocrinology. 2011 Feb;152(2):374-83. doi: 10.1210/en.2010-1047. Epub 2010 Nov 10.

  PMID: 21068156 BACKGROUND

• Lauffer LM, Iakoubov R, Brubaker PL. GPR119 is essential for oleoylethanolamide-induced glucagon-like peptide-1 secretion from the intestinal enteroendocrine L-cell. Diabetes. 2009 May;58(5):1058-66. doi: 10.2337/db08-1237. Epub 2009 Feb 10.

  PMID: 19208912 BACKGROUND

• Li NX, Brown S, Kowalski T, Wu M, Yang L, Dai G, Petrov A, Ding Y, Dlugos T, Wood HB, Wang L, Erion M, Sherwin R, Kelley DE. GPR119 Agonism Increases Glucagon Secretion During Insulin-Induced Hypoglycemia. Diabetes. 2018 Jul;67(7):1401-1413. doi: 10.2337/db18-0031. Epub 2018 Apr 18.

  PMID: 29669745 BACKGROUND

• Segerstolpe A, Palasantza A, Eliasson P, Andersson EM, Andreasson AC, Sun X, Picelli S, Sabirsh A, Clausen M, Bjursell MK, Smith DM, Kasper M, Ammala C, Sandberg R. Single-Cell Transcriptome Profiling of Human Pancreatic Islets in Health and Type 2 Diabetes. Cell Metab. 2016 Oct 11;24(4):593-607. doi: 10.1016/j.cmet.2016.08.020. Epub 2016 Sep 22.

  PMID: 27667667 BACKGROUND

• Bolli G, Calabrese G, De Feo P, Compagnucci P, Zega G, Angeletti G, Cartechini MG, Santeusanio F, Brunetti P. Lack of glucagon response in glucose counter-regulation in type 1 (insulin-dependent) diabetics: absence of recovery after prolonged optimal insulin therapy. Diabetologia. 1982 Feb;22(2):100-5. doi: 10.1007/BF00254837.

  PMID: 7037510 BACKGROUND

• Gerich JE, Langlois M, Noacco C, Karam JH, Forsham PH. Lack of glucagon response to hypoglycemia in diabetes: evidence for an intrinsic pancreatic alpha cell defect. Science. 1973 Oct 12;182(4108):171-3. doi: 10.1126/science.182.4108.171.

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• Gerich JE. Lilly lecture 1988. Glucose counterregulation and its impact on diabetes mellitus. Diabetes. 1988 Dec;37(12):1608-17. doi: 10.2337/diab.37.12.1608.

  PMID: 3056759 BACKGROUND

• Hypoglycemia in the Diabetes Control and Complications Trial. The Diabetes Control and Complications Trial Research Group. Diabetes. 1997 Feb;46(2):271-86.

  PMID: 9000705 BACKGROUND

• Frier BM. Hypoglycaemia in diabetes mellitus: epidemiology and clinical implications. Nat Rev Endocrinol. 2014 Dec;10(12):711-22. doi: 10.1038/nrendo.2014.170. Epub 2014 Oct 7.

  PMID: 25287289 BACKGROUND

• UK Hypoglycaemia Study Group. Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia. 2007 Jun;50(6):1140-7. doi: 10.1007/s00125-007-0599-y. Epub 2007 Apr 6.

  PMID: 17415551 BACKGROUND

• Cryer PE. Mechanisms of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med. 2013 Jul 25;369(4):362-72. doi: 10.1056/NEJMra1215228. No abstract available.

  PMID: 23883381 BACKGROUND

• Rizza RA, Cryer PE, Gerich JE. Role of glucagon, catecholamines, and growth hormone in human glucose counterregulation. Effects of somatostatin and combined alpha- and beta-adrenergic blockade on plasma glucose recovery and glucose flux rates after insulin-induced hypoglycemia. J Clin Invest. 1979 Jul;64(1):62-71. doi: 10.1172/JCI109464.

  PMID: 36413 BACKGROUND

• Yue JT, Burdett E, Coy DH, Giacca A, Efendic S, Vranic M. Somatostatin receptor type 2 antagonism improves glucagon and corticosterone counterregulatory responses to hypoglycemia in streptozotocin-induced diabetic rats. Diabetes. 2012 Jan;61(1):197-207. doi: 10.2337/db11-0690. Epub 2011 Nov 21.

  PMID: 22106159 BACKGROUND

• Szewczyk JW, Acton J, Adams AD, Chicchi G, Freeman S, Howard AD, Huang Y, Li C, Meinke PT, Mosely R, Murphy E, Samuel R, Santini C, Yang M, Zhang Y, Zhao K, Wood HB. Design of potent and selective GPR119 agonists for type II diabetes. Bioorg Med Chem Lett. 2011 May 1;21(9):2665-9. doi: 10.1016/j.bmcl.2010.12.086. Epub 2010 Dec 22.

  PMID: 21273063 BACKGROUND

• Christensen M, Calanna S, Sparre-Ulrich AH, Kristensen PL, Rosenkilde MM, Faber J, Purrello F, van Hall G, Holst JJ, Vilsboll T, Knop FK. Glucose-dependent insulinotropic polypeptide augments glucagon responses to hypoglycemia in type 1 diabetes. Diabetes. 2015 Jan;64(1):72-8. doi: 10.2337/db14-0440. Epub 2014 Jul 22.

  PMID: 25053587 BACKGROUND

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• Farngren J, Persson M, Schweizer A, Foley JE, Ahren B. Vildagliptin reduces glucagon during hyperglycemia and sustains glucagon counterregulation during hypoglycemia in type 1 diabetes. J Clin Endocrinol Metab. 2012 Oct;97(10):3799-806. doi: 10.1210/jc.2012-2332. Epub 2012 Aug 1.

  PMID: 22855332 BACKGROUND

MeSH Terms

Conditions

Diabetes Mellitus, Type 1

Interventions

MBX-2982

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Results Point of Contact

• Title: Richard Pratley
• Organization: AdventHealth, Orlando

richard.pratley.md@adventhealth.com

407-303-2519

Study Officials

• Richard Pratley, MD

  Study Principal Investigator

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 9, 2020
• First Posted: June 16, 2020
• Study Start: April 21, 2021
• Primary Completion: August 12, 2023
• Study Completion: August 12, 2023
• Last Updated: October 17, 2024
• Results First Posted: October 17, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)