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Restoration of Hypoglycemia Awareness With Metoclopramide

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ClinicalTrials.gov Identifier: NCT03970720
Recruitment Status : Recruiting
First Posted : May 31, 2019
Last Update Posted : May 31, 2019
Sponsor:
Collaborator:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
Simon Fisher, University of Utah

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.

Condition or disease Intervention/treatment Phase
Hypoglycemia Unawareness Drug: Metoclopramide Drug: Placebo Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: Restoration of Hypoglycemia Awareness With Metoclopramide
Actual Study Start Date : May 28, 2019
Estimated Primary Completion Date : April 2023
Estimated Study Completion Date : April 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hypoglycemia

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




Primary Outcome Measures :
  1. Change in Blood Glucagon [ Time Frame: 4 weeks ]
    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.

  2. Change in Blood Epinephrine [ Time Frame: 4 weeks ]
    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.

  3. Change in Blood Norepinephrine [ Time Frame: 4 weeks ]
    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. Change in Blood Cortisol [ Time Frame: 4 weeks ]
    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.

  5. Change in Blood Pancreatic Polypeptide [ Time Frame: 4 weeks ]
    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.

  6. Change in Hypoglycemia Symptom Recognition [ Time Frame: 4 weeks ]
    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.


Secondary Outcome Measures :
  1. Ratio of Self-Reported Hypoglycemic Episodes to Total Hypoglycemic Episodes [ Time Frame: 6 weeks ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

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): NCT03970720


Contacts
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Contact: Sally Bradstreet 801-581-4684 sally.bradstreet@hsc.utah.edu
Contact: Simon Fisher, MD 801-581-7755 sfisher@u2m2.utah.edu

Locations
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United States, Utah
University of Utah Recruiting
Salt Lake City, Utah, United States, 84132
Contact: Sally Bradstreet    801-581-4684    sally.bradstreet@hsc.utah.edu   
Sponsors and Collaborators
Simon Fisher
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
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Principal Investigator: Simon Fisher, MD University of Utah

Publications:

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Responsible Party: Simon Fisher, Professor of Medicine and Biochemistry, University of Utah
ClinicalTrials.gov Identifier: NCT03970720     History of Changes
Other Study ID Numbers: IRB_00118549
1R01DK118082-01A1 ( U.S. NIH Grant/Contract )
First Posted: May 31, 2019    Key Record Dates
Last Update Posted: May 31, 2019
Last Verified: May 2019
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
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Simon Fisher, University of Utah:
Type 1 Diabetes Mellitus
Additional relevant MeSH terms:
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Hypoglycemia
Glucose Metabolism Disorders
Metabolic Diseases
Metoclopramide
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Dopamine D2 Receptor Antagonists
Dopamine Antagonists
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action