Restoration of Hypoglycemia Awareness With Metoclopramide

Study Overview
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Brief Summary
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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
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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.

Official Title
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Restoration of Hypoglycemia Awareness With Metoclopramide

Conditions
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Hypoglycemia Unawareness

Intervention / Treatment
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* Drug: Metoclopramide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: T1DM - Unaware: Metoclopramide<br>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<br>* 10 mg metoclopramide four times a day<br>|
| Placebo Comparator: T1DM - Unaware: Placebo<br>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<br>* 10 mg matching placebo capsules four times a day<br>|
| Placebo Comparator: T1DM - Aware: Placebo<br>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<br>* 10 mg matching placebo capsules four times a day<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 1 Diabetes Mellitus