Development of Agents to Diminish the Risk of Hypoglycemia-induced Brain Injury in Type 1 Diabetes

Study Overview
=================
Brief Summary
-----------------
To determine the effect of re-activation of brain glucose metabolism induced by dichloroacetate (DCA) on cognitive function and counterregulatory hormone responses in patients with type 1 diabetes (T1DM) with recurrent hypoglycemia.

Detailed Description
-----------------
This will be a single center, placebo-controlled, cross-over, randomized clinical pilot study. The screening will take place at the Yale New Haven Hospital Research Unit (HRU) 10th floor, East Pavilion at 20 York St., New Haven, CT. At the screening visit informed consent will be obtained. Medical history and documents will be reviewed to screen potential subjects by inclusion and exclusion criteria. Subjects will receive a physical examination and laboratory blood work (BUN/creatinine, electrolytes, lipid profile, liver function, and HbA1c) as well as urine toxicology screens (to confirm self-report of alcohol, and drug information) to ensure good physical health.

Official Title
-----------------
Development of Agents to Diminish the Risk of Hypoglycemia-induced Brain Injury in Type 1 Diabetes

Conditions
-----------------
Hyperglycaemia (Diabetic)

Intervention / Treatment
-----------------
* Drug: Dichloroacetate
* Drug: Placebo oral capsule


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Group 1: Diagnosed C-peptide-negative T1DM, > 5 years duration, HbA1c of < 7.5% Intensive management, defined by frequent self-monitoring of glucose values and by the administration of 3 or more insulin injections each day (or the use of insulin pump therapy). History of severe hypoglycemia and hypoglycemia unawareness as assessed by the Guy's and Thomas' Minimally Modified Clarke Hypoglycemia Survey, the Gold Score and the Edinburgh Hypoglycemia Survey (see Appendix 1) Willingness to fast and to reduce insulin therapy for a limited time period Group 2: Age, weight, and gender matched to group 1 subjects HbA1c <6% Good general health as evidenced by medical history and blood screening Willing to fast for a limited time period Exclusion Criteria: General criteria: Known allergic reactions to components of the study product(s) Participants carrying polymorphisms known to slow DCA metabolism (e.g. KGM or EGM allele [10]) Treatment with another investigational drug or other intervention Active infection including hepatitis C, hepatitis B, HIV Any past or current history of alcohol or substance abuse Psychiatric or neurological disorders, including need for medications, including anxiolytics, and antidepressants Baseline Hgb < 10.5 g/dL in females, or < 12.5 g/dL in males. Blood donation within 30 days of the study History of coagulopathy or medical condition requiring long-term anticoagulant therapy (low-dose aspirin treatment is allowed) Co-existing cardiac, liver, and kidney disease Abnormal liver function tests GI disorders potentially interfering with the ability to absorb oral medications Women that are post-menopausal, pregnant (as assessed by pregnancy test that will be performed on female participants at reproductive age), or lactating. Any medical condition that, in the opinion of the investigators, will interfere with the safe completion of the study or study outcomes Any medication assumed less than 30 days before the study sessions that, in the opinion of the investigators, will interfere with the safe completion of the study or study outcomes.The list of medications to be avoided includes - but is not limited to - drugs known to influence metabolic and endocrine function (other than insulin in Group 1) and neuroactive medications. Group 1: Detectable C-peptide; Untreated proliferative retinopathy; Creatinine ≥1.5 mg/dl, urinary albumin levels . 300 mg/day Autonomic neuropathy; painful peripheral neuropathy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This will be a single center, placebo-controlled, cross-over, randomized clinical pilot study. At the screening visit informed consent will be obtained. Medical history and documents will be reviewed to screen potential subjects by inclusion and exclusion criteria. Subjects will receive a physical examination and laboratory blood work (BUN/creatinine, electrolytes, lipid profile, liver function, and HbA1c) as well as urine toxicology screens (to confirm self-report of alcohol, and drug information) to ensure good physical health.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: DCA in T1DM with severe hypoglycemia<br>12 T1DM subjects (C-peptide negative, HbA1c <7.5%) with a history of severe hypoglycemia and hypoglycemia unawareness as assessed by the Guy's and Thomas' Minimally Modified Clarke Hypoglycemia Survey, the Gold Score and the Edinburgh Hypoglycemia Survey and as evidenced by interview and glucose log and/or continuous glucose monitoring will receive a single dose of 12.5mg/kg dichloroacetate (DCA). | Drug: Dichloroacetate<br>* Dichloroacetate is an isoform-unspecific inhibitor of four regulatory pyruvate dehydrogenase kinases, which are able to reduce entry of substrates into mitochondria by reducing the conversion of pyruvate to acetyl-CoA. Drug will be administered to subjects with sever hypoglycemia as well as healthy non-diabetic subjects.<br>* Other names: DCA;|
| Placebo Comparator: Placebo in T1DM with severe hypoglycemia<br>12 T1DM subjects (C-peptide negative, HbA1c <7.5%) with a history of severe hypoglycemia and hypoglycemia unawareness as assessed by the Guy's and Thomas' Minimally Modified Clarke Hypoglycemia Survey, the Gold Score and the Edinburgh Hypoglycemia Survey and as evidenced by interview and glucose log and/or continuous glucose monitoring will receive a placebo oral capsule. | Drug: Placebo oral capsule<br>* A Placebo oral capsule identical in shape and color to those with active ingredient.<br>* Other names: Placebo;|
| Active Comparator: DCA in healthy control subjects<br>12 non-diabetic healthy subjects (fasting plasma glucose < 100 mg/dL, HbA1c < 6.0%), who are matched for age, gender, and weight to T1DM subjects, to serve as controls for the study. Each subject will receive a single dose of 12.5mg/kg dichloroacetate (DCA). | Drug: Dichloroacetate<br>* Dichloroacetate is an isoform-unspecific inhibitor of four regulatory pyruvate dehydrogenase kinases, which are able to reduce entry of substrates into mitochondria by reducing the conversion of pyruvate to acetyl-CoA. Drug will be administered to subjects with sever hypoglycemia as well as healthy non-diabetic subjects.<br>* Other names: DCA;|
| Placebo Comparator: Placebo in healthy control subjects<br>12 non-diabetic healthy subjects (fasting plasma glucose < 100 mg/dL, HbA1c < 6.0%), who are matched for age, gender, and weight to T1DM subjects, to serve as controls for the study will receive a placebo oral capsule. | Drug: Placebo oral capsule<br>* A Placebo oral capsule identical in shape and color to those with active ingredient.<br>* Other names: Placebo;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| • Measurement of hormone changes during hypoglycemia | Plasma counterregulatory hormone concentrations will be collected during the controlled insulin-induced hypoglycemic portion of the study. | 1 day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| cognitive function | Performance on a battery of cognitive tests assessing short term memory during controlled hypoglycemia. The Cantab battery of short-term memory tests will be used. | 1 day |