Thiamine as Adjunctive Therapy for Diabetic Ketoacidosis

Diabetic Ketoacidosis Clinical Trial

Official title:

Thiamine as Adjunctive Therapy for Diabetic Ketoacidosis

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03717896
• Other study ID #: 2018P000475
• Secondary ID: 1R01DK112886-01A
• Status: Recruiting
• Phase: Phase 2
• Start date: November 21, 2018
• Est. completion date: October 1, 2024

Study information

• Verified date: January 2024
• Source: Beth Israel Deaconess Medical Center
• Contact: Michael W Donnino, MD
• Phone: (617) 754-2341
• Email: mdonnino[@]bidmc.harvard.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a randomized, double-blind, placebo-controlled trial to determine if administration of intravenous thiamine will lead to quicker resolution of acidosis in patients admitted to the hospital with diabetic ketoacidosis. The investigators will secondarily investigate whether thiamine improves cellular oxygen consumption, shortens intensive care unit (ICU) and hospital stay or decreases hospital resource utilization.

Description:

Thiamine (vitamin B1) is a water-soluble vitamin that plays a key role in aerobic glucose metabolism. Thiamine is a cofactor of pyruvate dehydrogenase (PDH), an enzyme that must be activated for entry into the Krebs Cycle for aerobic metabolism. PDH activity is reduced in thiamine deficient states, resulting in a shift in pyruvate metabolism to the anaerobic pathway. This leads to increased lactate production and acidosis. Thiamine loss in the urine, with consequent thiamine deficiency, is not uncommon in diabetes. The investigators' preliminary studies have found that thiamine deficiency in occurs in as many as 39% of patients with DKA, and that thiamine levels are inversely associated with lactate and acidosis. The investigator hypothesizes that treating DKA patients with intravenous thiamine will lead to faster resolution of acidosis and improved aerobic metabolism. The investigator's secondary hypothesis is that thiamine treatment will shorten stays in the ICU and hospital and lead to utilization of fewer hospital resources. In this randomized, double-blind, placebo-controlled trial, patients admitted to the hospital with DKA who are enrolled in the study will be randomized to either intravenous thiamine (200mg in 0.9% saline) twice daily for two days or an identical volume of 0.9% saline on the same schedule. The investigator's primary outcome is change in bicarbonate over the 24 hours following enrollment, with measurements at 0, 6, 12, 18, 24 hours, using a linear mixed-effects model. Secondarily, patients will be stratified by Type I and Type II DM. Additionally, a pre-planned sub-analysis of thiamine deficient subjects will be performed.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: October 1, 2024
• Est. primary completion date: May 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Bicarbonate =15 mEq/L
• Anion gap > 12 mEq/L
• Blood pH= 7.24 (if already obtained by clinical team)
• Urine ketones (qualitative) or serum ketones (ß-hydroxybutyric acid) > 3 mmol/L
• Enrollment within 6 hours of presentation

Exclusion Criteria:

• Current thiamine supplementation = 6 milligrams per day (i.e., more than a multivitamin)
• Competing causes of severe acidosis including seizure, carbon monoxide poisoning, cyanide toxicity, cardiac arrest, liver dysfunction (specifically defined as known cirrhosis)
• Known allergy to thiamine
• Competing indication for thiamine administration as judged by the clinical team (e.g., significant alcohol use)
• Research-protected populations (pregnant women and prisoners)
• Patient enrolled previously in same study
• Code status of Do Not Resuscitate/Do Not Intubate (DNR/DNI) or Comfort Measures Only (CMO)

Related Conditions & MeSH terms

• Acidosis
• Diabetic Ketoacidosis
• Ketosis

Intervention

Drug:
• 200mg IV thiamine in 50mL 0.9% saline
Thiamine 200mg IV every 12 hours for 2 days
• Placebo
50mL 0.9% saline

Locations

Country	Name	City	State
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Beth Israel Deaconess Medical Center	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	SOFA score (sequential organ failure assessement score)	Investigators will assess the difference between the thiamine and placebo groups in SOFA score.; The SOFA score will be defined using a modification in which the arterial oxygen saturation/fraction of inspired oxygen (SaO2 /FiO2) ratio is substituted for the partial pressure of arterial oxygen/fraction of inspired oxygen (PaO2 /FiO2 ratio).	24 hours
Other	C-peptide levels	Investigators will measure C-peptide levels at time of study drug administration and at 72 hours or before discharge. This outcome will be analyzed separately for patients with diabetes type 1 and type 2.	0 and 72 hours
Other	Duration of insulin therapy	The duration of insulin therapy is calculated by examining the hospital clinical information systems for all records of IV insulin infusion beginning at the time of enrollment. The start and the stop time-stamps of medication infusion are used to calculate a duration of infusion.	First 7 days after enrollment
Other	Cognitive function: Hopkins Verbal Learning Test	As an exploratory outcome, we will measure cognitive function using the Hopkins Verbal Learning Test (measures verbal learning and memory). The test will be administered by trained research assistants at the patient's bedside 72-96 hours after enrollment or prior to discharge (whichever comes first).	between 72 and 96 hours after enrollment or prior to discharge (whichever comes first)
Other	Cognitive function: Brief Visual Spatial Memory Test	As an exploratory outcome, we will measure cognitive function using the Brief Visual Spatial Memory Test (measures visuospatial memory). The test will be administered by trained research assistants at the patient's bedside 72-96 hours after enrollment or prior to discharge (whichever comes first).	between 72 and 96 hours after enrollment or prior to discharge (whichever comes first)
Other	Cognitive function: Trail Making Test A and B	As an exploratory outcome, we will measure cognitive function using the Trail Making Test A and B (measurement of cognitive function utilizing connection of dots by correct order). The test will be administered by trained research assistants at the patient's bedside 72-96 hours after enrollment or prior to discharge (whichever comes first).	between 72 and 96 hours after enrollment or prior to discharge (whichever comes first)
Other	Cognitive function: WAIS-IV Digit Span	As an exploratory outcome, we will measure cognitive function using the WAIS-IV Digit Span (measures working memory). The test will be administered by trained research assistants at the patient's bedside 72-96 hours after enrollment or prior to discharge (whichever comes first).	between 72 and 96 hours after enrollment or prior to discharge (whichever comes first)
Other	Cognitive function: Test of Verbal Fluency and Animal Naming	As an exploratory outcome, we will measure cognitive function using the Test of Verbal Fluency and Animal Naming (measures phonemic and semantic verbal fluency). The test will be administered by trained research assistants at the patient's bedside 72-96 hours after enrollment or prior to discharge (whichever comes first).	between 72 and 96 hours after enrollment or prior to discharge (whichever comes first)
Other	Cognitive function: Test of Premorbid Functioning	As an exploratory outcome, we will measure cognitive function using the Test of Premorbid Functioning (estimates premorbid intellectual function). The test will be administered by trained research assistants at the patient's bedside 72-96 hours after enrollment or prior to discharge (whichever comes first).	between 72 and 96 hours after enrollment or prior to discharge (whichever comes first)
Primary	plasma bicarbonate levels	Our primary outcome is change in bicarbonate over the 24 hours following enrollment with measurements at 0, 6, 12, 18, 24 hours using a linear-effects model	24 hours
Secondary	anion gap	Our secondary outcomes include change in anion gap over the 24 hours following enrollment with measurements at 0, 6, 12, 18, 24 hours using a linear-effects model	24 hours
Secondary	lactate	Another secondary outcome is change in lactate over the 24 hours following enrollment with measurements at 0, 6, 12, 18, 24 hours using a linear-effects model	24 hours
Secondary	oxygen consumption by circulating mononuclear cells	Oxygen consumption by circulating mononuclear cells is an index of whole body oxidative glucose metabolism. It also reflects whole body thiamine status due to the critical cofactor role of thiamine in oxidative metabolism. Mononuclear cell oxygen consumption will be assessed by the investigators when the patient is admitted into the study and again after 24 hours to determine if there is a difference between the two groups.	24 hours
Secondary	ICU length of stay	ICU length of stay reflects how rapidly the patient recovers from the most severe consequences of diabetic ketoacidosis. The investigators will record this parameter from hospital records.to determine if there is a difference between the two groups.	24 hours
Secondary	hospital length of stay	Hospital length of stay reflects how long it takes a diabetic ketoacidosis patient to recover to the point where he/she can be released from the hospital. The investigators will record this parameter from hospital records to determine if there is a difference between the two groups.	24 hours
Secondary	hospital resource usage	The investigators will record this parameter from hospital records to determine if there is a difference between the two groups	24 hours