Restoration of Hypoglycemia Awareness With Metoclopramide

Metoclopramide is a drug approved by the FDA for gastroesophageal reflux and to relieve symptoms in adults with acute and recurrent diabetic gastroparesis. The objective of this study is to determine whether metoclopramide can improve hypoglycemia awareness and decrease the incidence of hypoglycemia in type 1 diabetes patients with hypoglycemia unawareness.

Study Overview

• Status: Recruiting
• Conditions: Hypoglycemia Unawareness
• Intervention / Treatment: Drug: Metoclopramide; Drug: Placebo

Detailed Description

Hypoglycemia is the most prevalent clinical complication in the daily management of diabetes and is the major obstacle to normalizing blood sugar. For people with Type 1 diabetes mellitus (T1DM), hypoglycemia associated autonomic failure (HAAF) increases the risk for severe hypoglycemia by a factor of 25 or more. A major component of HAAF is hypoglycemia unawareness (perhaps more accurately defined as impaired awareness of hypoglycemia), which involves in the loss/diminution of warning symptoms to hypoglycemia that would normally prompt a corrective behavioral response (e.g., eating food). Approximately 25-40% of people with T1DM report hypoglycemia unawareness. This value is most certainly an underestimation, as even people with diabetes who report having intact hypoglycemia, demonstrate impaired awareness of biochemically confirmed hypoglycemia. Although a major clinical problem for people with T1DM, it remains largely unknown what therapeutic agents could possibly be used to treat hypoglycemia unawareness.

With a goal of identifying existing biological compounds that could restore hypoglycemia awareness, laboratory drug screens were conducted using animal models. It was postulated that an ideal drug would markedly enhance the ability to sense hypoglycemia and trigger a potentially life-saving behavioral response (ie, alert the subject to increase food consumption). The vast majority of tested drugs did not restore hypoglycemia awareness (ie, did not restore blunted food intake response to hypoglycemia). Interestingly, of all the drugs tested, the dopamine antagonist metoclopramide consistently restored hypoglycemia awareness in several preclinical experiments. Additionally, metoclopramide also restored the impaired counterregulatory response to hypoglycemia in the animal model of HAAF.

This pilot phase II clinical trial (with placebo control) will be conducted to determine if FDA approved doses of Metaclopramdide can restore both, 1) hypoglycemia awareness, and 2) the sympathoadrenal response to hypoglycemia in patients with T1DM and hypoglycemia unawareness.

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Simon Fisher, MD, PhD; Phone Number: 859-562-0473; Email: sjfi230@uky.edu
• Study Contact Backup: Name: Karen M Shearer; Phone Number: 859-323-7778; Email: Karen.Shearer@uky.edu

Study Locations

• United States
  • Kentucky
    • Lexington, Kentucky, United States, 40516
      • Recruiting
      • University of Kentucky
      • Contact: Simon Fisher, MD, PhD; Phone Number: 859-562-0473; Email: Simon.Fisher@uky.edu
      • Principal Investigator: Simon Fisher, MD, PhD
      • Contact: Karen Shearer, HIT; Phone Number: 8593237778; Email: Karen.Shearer@uky.edu
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Completed
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Subjects with Type 1 Diabetes Mellitus
• Diabetes duration > 5 years
• Hemoglobin A1c ≤ 9%
• Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines

Exclusion Criteria:

• History of myocardial infarction, cardiac arrhythmia, congestive heart failure and coronary artery insufficiency
• History of stroke or brain disease
• History of genitourinary obstruction or urinary retention
• Advanced liver disease
• Active anemia with hemoglobin less than 11 g/dL
• Female in pregnancy or breastfeeding, or not able to practice effective contraception during the study period
• Uncontrolled mania or active major depressive disorder
• Previous allergic reaction or side effect to heparin use
• Contraindications to metoclopramide or conditions raising the risk for complication development to metoclopramide, such as hypersensitivity to metoclopramide, ongoing mechanical gastrointestinal obstruction, uncontrolled hypertension, pheochromocytoma, seizure disorders, Parkinson's disease, use of neuroleptics or antipsychotics within 6 months, use of benzodiazepines within the last month, active or recent (last 14 days) use of monoamine oxidase inhibitors or opioids, active alcohol or drug abuse, or other sedatives
• Participation in another study evaluating treatment for impaired awareness of hypoglycemia or hypoglycemia-associated autonomic failure in the last 30 days
• Current use of unblinded real-time Continuous Glucose Monitoring System
• Frequent need of acetaminophen administration

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: T1DM - Unaware: Metoclopramide; T1DM participants with hypoglycemia unawareness determined by a hypoglycemic clamp study will receive 10 mg metoclopramide four times a day during the four-week intervention period.	Drug: Metoclopramide; 10 mg metoclopramide four times a day
Placebo Comparator: T1DM - Unaware: Placebo; T1DM participants with hypoglycemia unawareness determined by a hypoglycemic clamp study will receive 10 mg matching placebo capsules four times a day during the four-week intervention period.	Drug: Placebo; 10 mg matching placebo capsules four times a day
Placebo Comparator: T1DM - Aware: Placebo; T1DM participants with hypoglycemia awareness determined by a hypoglycemic clamp study will receive 10 mg matching placebo capsules four times a day during the four-week intervention period.	Drug: Placebo; 10 mg matching placebo capsules four times a day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Blood Glucagon	Blood samples will be drawn from study participants during the initial hypoglycemic clamp study (Day 0) and during the second hypoglycemic clamp study (Day 28) following the 4-week intervention period. The average change in blood glucagon level will be compared between the study arms.	4 weeks
Change in Blood Epinephrine	Blood samples will be drawn from study participants during the initial hypoglycemic clamp study (Day 0) and during the second hypoglycemic clamp study (Day 28) following the 4-week intervention period. The average change in blood epinephrine level will be compared between the study arms.	4 weeks
Change in Blood Norepinephrine	Blood samples will be drawn from study participants during the initial hypoglycemic clamp study (Day 0) and during the second hypoglycemic clamp study (Day 28) following the 4-week intervention period. The average change in blood norepinephrine level will be compared between the study arms.	4 weeks
Change in Blood Cortisol	Blood samples will be drawn from study participants during the initial hypoglycemic clamp study (Day 0) and during the second hypoglycemic clamp study (Day 28) following the 4-week intervention period. The average change in blood cortisol level will be compared between the study arms.	4 weeks
Change in Blood Pancreatic Polypeptide	Blood samples will be drawn from study participants during the initial hypoglycemic clamp study (Day 0) and during the second hypoglycemic clamp study (Day 28) following the 4-week intervention period. The average change in blood pancreatic polypeptide level will be compared between the study arms.	4 weeks
Change in Hypoglycemia Symptom Recognition	Participant's self-reported symptoms of hypoglycemia will be obtained during the initial hypoglycemic clamp study (Day 0) and during the second hypoglycemic clamp study (Day 28) following the 4-week intervention period.	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ratio of Self-Reported Hypoglycemic Episodes to Total Hypoglycemic Episodes	Participants will complete a report of all hypoglycemic events during the study surveillance periods. The average ratio of self-reported hypoglycemic episodes to total hypoglycemic episodes recorded by Continuous Glucose Monitoring (CGM) during these periods will be compared between the study arms.	6 weeks

Collaborators and Investigators

• Sponsor: Simon Fisher
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Simon Fisher, MD, PhD, University of Kentucky

Publications and helpful links

General Publications

• Cryer PE. Hypoglycemia-associated autonomic failure in diabetes. Handb Clin Neurol. 2013;117:295-307. doi: 10.1016/B978-0-444-53491-0.00023-7.
• 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.
• Heller SR, Cryer PE. Reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia after 1 episode of hypoglycemia in nondiabetic humans. Diabetes. 1991 Feb;40(2):223-6. doi: 10.2337/diab.40.2.223.
• Schultes B, Schmid SM, Wilms B, Jauch-Chara K, Oltmanns KM, Hallschmid M. Lactate infusion during euglycemia but not hypoglycemia reduces subsequent food intake in healthy men. Appetite. 2012 Jun;58(3):818-21. doi: 10.1016/j.appet.2012.01.022. Epub 2012 Jan 28.
• Schmid SM, Jauch-Chara K, Hallschmid M, Oltmanns KM, Born J, Schultes B. Short-term nocturnal hypoglycaemia increases morning food intake in healthy humans. Diabet Med. 2008 Feb;25(2):232-5. doi: 10.1111/j.1464-5491.2007.02347.x.
• Dewan S, Gillett A, Mugarza JA, Dovey TM, Halford JC, Wilding JP. Effects of insulin-induced hypoglycaemia on energy intake and food choice at a subsequent test meal. Diabetes Metab Res Rev. 2004 Sep-Oct;20(5):405-10. doi: 10.1002/dmrr.471.
• Towler DA, Havlin CE, Craft S, Cryer P. Mechanism of awareness of hypoglycemia. Perception of neurogenic (predominantly cholinergic) rather than neuroglycopenic symptoms. Diabetes. 1993 Dec;42(12):1791-8. doi: 10.2337/diab.42.12.1791.
• Geddes J, Schopman JE, Zammitt NN, Frier BM. Prevalence of impaired awareness of hypoglycaemia in adults with Type 1 diabetes. Diabet Med. 2008 Apr;25(4):501-4. doi: 10.1111/j.1464-5491.2008.02413.x.
• Kubiak T, Hermanns N, Schreckling HJ, Kulzer B, Haak T. Assessment of hypoglycaemia awareness using continuous glucose monitoring. Diabet Med. 2004 May;21(5):487-90. doi: 10.1111/j.1464-5491.2004.1136.x.

Study record dates

Study Major Dates

• Study Start (Actual): May 28, 2019
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: May 29, 2019
• First Submitted That Met QC Criteria: May 29, 2019
• First Posted (Actual): May 31, 2019

Study Record Updates

• Last Update Posted (Actual): March 20, 2026
• Last Update Submitted That Met QC Criteria: March 17, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Type 1 Diabetes Mellitus
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Autoimmune Diseases; Immune System Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Nutritional and Metabolic Diseases; Diabetes Mellitus, Type 1; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Carboxylic Acids; Hydroxy Acids; Hydrocarbons, Aromatic; Amides; Phenols; Benzene Derivatives; Acids, Carbocyclic; para-Aminobenzoates; Aminobenzoates; Benzoates; Hydroxybenzoates; Phenyl Ethers; Benzamides; Chlorobenzoates; Hydroxybenzoate Ethers; Metoclopramide
• Other Study ID Numbers: IRB_00118549; 1R01DK118082-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No