Restoration of Hypoglycemia Awareness With Metoclopramide

NCT ID: NCT03970720

Last Updated: 2025-08-11

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 36 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-05-28
• Study Completion Date: 2026-12-31

Brief Summary

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.

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.

Conditions

Hypoglycemia Unawareness

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

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.

Group Type: EXPERIMENTAL

Metoclopramide

Intervention Type: DRUG

10 mg metoclopramide four times a day

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

10 mg matching placebo capsules four times a day

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

10 mg matching placebo capsules four times a day

Interventions

Metoclopramide

10 mg metoclopramide four times a day

Intervention Type: DRUG

Placebo

10 mg matching placebo capsules four times a day

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 20 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

Simon Fisher

OTHER

Sponsor Role: lead

Responsible Party

Simon Fisher

Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Simon Fisher, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Kentucky

Locations

University of Kentucky

Lexington, Kentucky, United States

Site Status: RECRUITING

University of Utah

Salt Lake City, Utah, United States

Site Status: COMPLETED

Countries

United States

Central Contacts

Simon Fisher, MD, PhD

Role: CONTACT

sjfi230@uky.edu

859-562-0473

Karen M Shearer

Role: CONTACT

Karen.Shearer@uky.edu

859-323-7778

Facility Contacts

Simon Fisher, MD, PhD

Role: primary

Simon.Fisher@uky.edu

859-562-0473

Karen Shearer, HIT

Role: backup

Karen.Shearer@uky.edu

8593237778

References

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Reference Type: BACKGROUND

PMID: 24095133 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 23883381 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 1991573 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22314041 (View on PubMed)

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Reference Type: BACKGROUND

PMID: 18290864 (View on PubMed)

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Reference Type: BACKGROUND

PMID: 15343587 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 8243825 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 18387080 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15089796 (View on PubMed)

Other Identifiers

1R01DK118082-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

IRB_00118549

Identifier Type: -

Identifier Source: org_study_id