Clinical trial NCT03717896: Thiamine As Adjunctive Therapy for Diabetic Ketoacidosis
Official title: Thiamine As Adjunctive Therapy for Diabetic Ketoacidosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diabetic Ketoacidosis
Keywords: diabetic ketoacidosis
DKA
thiamine
acidosis
oxygen consumption
lactate
Lead sponsor: Beth Israel Deaconess Medical Center
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2018-10-24
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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 (β-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)

Primary outcomes:
measure: plasma bicarbonate levels
timeFrame: 24 hours
Secondary outcomes:
measure: anion gap
timeFrame: 24 hours
measure: lactate
timeFrame: 24 hours
measure: oxygen consumption by circulating mononuclear cells
timeFrame: 24 hours
measure: ICU length of stay
timeFrame: 24 hours
measure: hospital length of stay
timeFrame: 24 hours
measure: hospital resource usage
timeFrame: 24 hours
Other outcomes:
measure: SOFA score (sequential organ failure assessement score)
timeFrame: 24 hours
measure: C-peptide levels
timeFrame: 0 and 72 hours
measure: Duration of insulin therapy
timeFrame: First 7 days after enrollment
measure: Cognitive function: Hopkins Verbal Learning Test
timeFrame: between 72 and 96 hours after enrollment or prior to discharge (whichever comes first)
measure: Cognitive function: Brief Visual Spatial Memory Test
timeFrame: between 72 and 96 hours after enrollment or prior to discharge (whichever comes first)
measure: Cognitive function: Trail Making Test A and B
timeFrame: between 72 and 96 hours after enrollment or prior to discharge (whichever comes first)
measure: Cognitive function: WAIS-IV Digit Span
timeFrame: between 72 and 96 hours after enrollment or prior to discharge (whichever comes first)
measure: Cognitive function: Test of Verbal Fluency and Animal Naming
timeFrame: between 72 and 96 hours after enrollment or prior to discharge (whichever comes first)
measure: Cognitive function: Test of Premorbid Functioning
timeFrame: between 72 and 96 hours after enrollment or prior to discharge (whichever comes first)
Locations:
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
Study officials:
affiliation: Beth Israel Deaconess Medical Center
name: Michael Donnino, MD
role: PRINCIPAL_INVESTIGATOR
References: