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

NCT ID: NCT03356457

Last Updated: 2021-01-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 21 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-11-30
• Study Completion Date: 2019-03-20

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.

Conditions

Hyperglycaemia (Diabetic)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

DCA in T1DM with severe hypoglycemia

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).

Group Type: ACTIVE_COMPARATOR

Dichloroacetate

Intervention Type: DRUG

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.

Placebo in T1DM with severe hypoglycemia

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.

Group Type: PLACEBO_COMPARATOR

Placebo oral capsule

Intervention Type: DRUG

A Placebo oral capsule identical in shape and color to those with active ingredient.

DCA in healthy control subjects

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).

Group Type: ACTIVE_COMPARATOR

Dichloroacetate

Intervention Type: DRUG

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.

Placebo in healthy control subjects

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.

Group Type: PLACEBO_COMPARATOR

Placebo oral capsule

Intervention Type: DRUG

A Placebo oral capsule identical in shape and color to those with active ingredient.

Interventions

Dichloroacetate

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

Placebo oral capsule

A Placebo oral capsule identical in shape and color to those with active ingredient.

Intervention Type: DRUG

Other Intervention Names

DCA; Placebo

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Yale University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Raimund Herzog, MD

Role: PRINCIPAL_INVESTIGATOR

Yale University

Locations

Yale New Haven Hospital

New Haven, Connecticut, United States

Countries

United States

Other Identifiers

2000029203

Identifier Type: -

Identifier Source: org_study_id