Back to resultsDevelopment of Agents to Diminish the Risk of Hypoglycemia-induced Brain Injury in Type 1 Diabetes
Primary Purpose
Hyperglycaemia (Diabetic)
Status
Completed
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Dichloroacetate
Placebo oral capsule
Sponsored by
About this trial
This is an interventional treatment trial for Hyperglycaemia (Diabetic)
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
Sites / Locations
- Yale New Haven Hospital
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Active Comparator
Placebo Comparator
Active Comparator
Placebo Comparator
Arm Label
DCA in T1DM with severe hypoglycemia
Placebo in T1DM with severe hypoglycemia
DCA in healthy control subjects
Placebo in healthy control subjects
Arm Description
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).
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.
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).
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.
Outcomes
Primary Outcome Measures
• Measurement of hormone changes during hypoglycemia
Plasma counterregulatory hormone concentrations will be collected during the controlled insulin-induced hypoglycemic portion of the study.
Secondary Outcome Measures
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03356457
Brief Title
Development of Agents to Diminish the Risk of Hypoglycemia-induced Brain Injury in Type 1 Diabetes
Official Title
Development of Agents to Diminish the Risk of Hypoglycemia-induced Brain Injury in Type 1 Diabetes
Study Type
Interventional
2. Study Status
Record Verification Date
January 2021
Overall Recruitment Status
Completed
Study Start Date
November 30, 2017 (Actual)
Primary Completion Date
March 20, 2019 (Actual)
Study Completion Date
March 20, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Yale University
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hyperglycaemia (Diabetic)
7. Study Design
Primary Purpose
Treatment
Study Phase
Early Phase 1
Interventional Study Model
Crossover Assignment
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
Participant
Masking Description
Once stable hypoglycemia is reached, a cognitive testing battery will be administered by a study co-investigator who will be blinded to the treatment assignment.
Allocation
Randomized
Enrollment
21 (Actual)
8. Arms, Groups, and Interventions
Arm Title
DCA in T1DM with severe hypoglycemia
Arm Type
Active Comparator
Arm Description
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).
Arm Title
Placebo in T1DM with severe hypoglycemia
Arm Type
Placebo Comparator
Arm Description
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.
Arm Title
DCA in healthy control subjects
Arm Type
Active Comparator
Arm Description
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).
Arm Title
Placebo in healthy control subjects
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Dichloroacetate
Other Intervention Name(s)
DCA
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo oral capsule
Other Intervention Name(s)
Placebo
Intervention Description
A Placebo oral capsule identical in shape and color to those with active ingredient.
Primary Outcome Measure Information:
Title
• Measurement of hormone changes during hypoglycemia
Description
Plasma counterregulatory hormone concentrations will be collected during the controlled insulin-induced hypoglycemic portion of the study.
Time Frame
1 day
Secondary Outcome Measure Information:
Title
cognitive function
Description
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.
Time Frame
1 day
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Raimund Herzog, MD
Organizational Affiliation
Yale School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Yale New Haven Hospital
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06510
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Development of Agents to Diminish the Risk of Hypoglycemia-induced Brain Injury in Type 1 Diabetes
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