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

NCT03356457 | Completed Early Phase 1 FDA Drug

• 1 other identifier: 2000029203
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

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.

Conditions

Hyperglycaemia (Diabetic)

Outcome Measures

Primary Outcomes (1)

• • 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 Outcomes (1)

• cognitive function

  1 day

Study Arms (4)

DCA in T1DM with severe hypoglycemia

ACTIVE COMPARATOR

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

Placebo in T1DM with severe hypoglycemia

PLACEBO COMPARATOR

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

DCA in healthy control subjects

ACTIVE COMPARATOR

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

Placebo in healthy control subjects

PLACEBO COMPARATOR

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

Interventions

Dichloroacetate 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.

Also known as: DCA

DCA in T1DM with severe hypoglycemia; DCA in healthy control subjects

Placebo oral capsule DRUG

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

Also known as: Placebo

Placebo in T1DM with severe hypoglycemia; Placebo in healthy control subjects

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Yale University: lead

Study Sites (1)

Yale New Haven Hospital

New Haven, Connecticut, 06510, United States

Location

MeSH Terms

Conditions

Hyperglycemia

Interventions

Dichloroacetic Acid

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Chloroacetates; Acetates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Hydrocarbons, Chlorinated; Hydrocarbons, Halogenated; Hydrocarbons

Study Officials

• Raimund Herzog, MD

  Yale University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: November 9, 2017
• First Posted: November 29, 2017
• Study Start: November 30, 2017
• Primary Completion: March 20, 2019
• Study Completion: March 20, 2019
• Last Updated: January 22, 2021

Record last verified: 2021-01

Locations

US (1)