Thiamine as Adjunctive Therapy for Diabetic Ketoacidosis

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.

Study Overview

• Status: Completed
• Conditions: Diabetic Ketoacidosis
• Intervention / Treatment: Drug: 200mg IV thiamine in 50mL 0.9% saline; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 102
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Thiamine; 200mg IV thiamine in 50mL 0.9% saline twice daily for 2 days	Drug: 200mg IV thiamine in 50mL 0.9% saline; Thiamine 200mg IV every 12 hours for 2 days; Other Names: Vitamin B1
Placebo Comparator: Placebo; 100mL 0.9% saline twice daily for two days	Drug: Placebo; 50mL 0.9% saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Bicarbonate Levels	Primary outcome of plasma bicarbonate levels over 24 hours (6, 12, 18, 24 hours) following enrollment	6, 12, 18, and 24 hours after enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lactate	Secondary outcome of lactate over 24 hours (6, 12, 18, 24 hours) following enrollment	6, 12, 18, and 24 hours after enrollment
Anion Gap	Secondary outcome of anion gap over 24 hours (6, 12, 18, 24 hours) following enrollment	6, 12, 18, and 24 hours after enrollment
ICU Length of Stay	ICU length of stay reflects the number of ICU admission days.	45 days
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.	45 days
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
SOFA Score (Sequential Organ Failure Assessement Score)	The SOFA score is a validated measure of organ dysfunction commonly used in critically ill patients, particularly those with sepsis. It evaluates the function of six organ systems-respiratory, cardiovascular, neurologic, hepatic, renal, and coagulation-based on routinely collected clinical and laboratory data. Each organ system is assigned a score from 0 (normal function) to 4 (most severe dysfunction), resulting in a total score ranging from 0 to 24. Higher SOFA scores indicate greater severity of organ failure and a higher risk of adverse outcomes. SOFA score in this study uses 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
Oxygen Consumption by Circulating Mononuclear Cells	Oxygen consumption rate of circulating peripheral blood mononuclear cells measured using Seahorse. Basal respiration represents oxygen consumption under baseline conditions. ATP-linked respiration represents oxygen consumption coupled to ATP production, while proton leak represents oxygen consumption not linked to ATP synthesis. Maximal respiration represents the maximal capacity of the electron transport chain after uncoupling. Spare respiratory capacity represents the difference between maximal and basal respiration and indicates the ability to respond to increased energy demand. Non-mitochondrial respiration represents oxygen consumption independent of mitochondrial activity.	24 hours
Pyruvate Dehydrogenase Activity	Secondary outcome of change in PDH specific activity over 72 hours or at discharge if patient's hospital length of stay was less than 72 hours. PDH activity and total PDH protein quantity were measured in isolated peripheral blood mononuclear cells (PBMCs) following selective disruption of the mitochondrial membrane, using a previously validated immunocapture and microplate-based enzymatic assay protocol. PDH-specific activity was calculated as the ratio of measured PDH enzymatic activity to the natural logarithm of PDH protein quantity (PDH activity / ln[PDH quantity]), providing a normalized metric that reflects the functional efficiency of the enzyme independent of its expression level. Higher values suggest higher enzymatic efficiency.	24 hours and 72 hours (or at discharge if hostpial length of stay was less than 72 hours)
Neurocognitive: Hopkins Verbal Learning Test - Total Recall	The Hopkins Verbal Learning Test-Revised (HVLT-R) Total Recall score is a measure of verbal learning and immediate memory. Participants are read a list of 12 words (from three semantic categories) and asked to recall as many words as possible across three consecutive learning trials. The Total Recall score is calculated as the sum of correctly recalled words across the three trials, yielding a possible range of 0 to 36, with higher scores indicating better verbal learning and memory performance. This score reflects both initial acquisition and short-term retention of verbal information and is commonly used to assess cognitive function in clinical research.	At hospital discharge, median of 4 days
Neurocognitive: Hopkins Verbal Learning Test - Delayed Recall	The Hopkins Verbal Learning Test-Revised (HVLT-R) Delayed Recall score assesses retention of verbal information after a delay. Following completion of the three learning trials, participants are asked to recall the previously presented word list after a delay period (typically 20-25 minutes) without re-exposure to the words. The Delayed Recall score is calculated as the number of correctly recalled words, with a possible range of 0 to 12, where higher scores indicate better memory retention. This measure reflects the ability to consolidate and retrieve learned information over time and is commonly used to evaluate memory function in clinical and research settings.	At hospital discharge, median of 4 days
Neurocognitive: Hopkins Verbal Learning Test - Retention	The Hopkins Verbal Learning Test-Revised (HVLT-R) Retention (%) score reflects the proportion of learned information that is retained over a delay. It is calculated as the ratio of the Delayed Recall score to the highest number of words recalled on any of the three immediate recall trials, multiplied by 100, yielding a percentage value. Scores typically range from 0% to 100%, with higher values indicating better retention of previously learned material. This measure provides an index of memory retention independent of initial learning performance.	At hospital discharge, median of 4 days
Neurocognitive: Hopkins Verbal Learning Test - Recognition Discrimination Index	The Hopkins Verbal Learning Test-Revised (HVLT-R) Recognition Discrimination Index assesses recognition memory by evaluating the ability to distinguish previously learned words from novel distractors. During the recognition phase, participants are presented with a list of target words and distractor words and asked to identify those that were previously learned. The Recognition Discrimination Index is calculated as the number of true positives (correctly identified target words) minus the number of false positives (incorrectly identified distractor words), yielding a score typically ranging from -12 to 12. Higher scores indicate better recognition accuracy and discrimination ability, reflecting the integrity of memory retrieval processes.	At hospital discharge, median of 4 days
Neurocognitive: Brief Visuospatial Memory Test	The Brief Visuospatial Memory Test (BVMT) assesses visuospatial learning and memory. Participants are shown six geometric designs for a brief period and asked to reproduce them from memory across three learning trials. Performance is scored based on the accuracy and placement of each design, with a total recall score ranging from 0 to 36, where higher scores indicate better visuospatial memory. A delayed recall trial is administered after a delay to assess retention of visual information. This measure evaluates the ability to encode, store, and retrieve visuospatial material.	At hospital discharge, median of 4 days
Neurocognitive: Trail Making Test - Test Part A	The Trail Making Test Part A (TMT-A) assesses visual attention, processing speed, and psychomotor function. Participants are instructed to connect numbered circles in sequential order as quickly as possible. The primary outcome is the time to completion, measured in seconds, with lower times indicating better performance. There is no fixed maximum score, although testing is typically discontinued at a predefined time limit (commonly 300 seconds).	At hospital discharge, median of 4 days
Neurocognitive: Trail Making Test - Test Part B	The Trail Making Test Part B (TMT-B) assesses executive function, including cognitive flexibility and set-shifting, in addition to processing speed. Participants are required to alternate between numbers and letters in sequence (e.g., 1-A-2-B) as quickly as possible. The primary outcome is the time to completion, measured in seconds, with lower times indicating better performance. As with TMT-A, there is no fixed maximum score, and testing is typically discontinued at a predefined time limit (commonly 300 seconds).	At hospital discharge, median of 4 days
Neurocognitive: WAIS-IV Digit Span	The Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) Digit Span subtest assesses attention, working memory, and concentration. Participants are asked to repeat sequences of numbers in forward order (Digit Span Forward), reverse order (Digit Span Backward), and ascending order (Digit Span Sequencing). Scores are based on the total number of correctly recalled sequences, with higher scores indicating better attention and working memory capacity. The total score ranges from 0 to 48.	At hospital discharge, median of 4 days
Neurocognitive: Test of Verbal Fluency and Animal Naming	The Animal Naming test is a measure of semantic verbal fluency and executive function. Participants are asked to name as many animals as possible within a fixed time period. The score is the total number of unique, correct animal names generated, with higher scores indicating better semantic memory retrieval and executive functioning. Scores range from 0 with no fixed upper limit.	At hospital discharge, median of 4 days
Neurocognitive: Test of Premorbid Functioning	The Test of Premorbid Functioning (TOPF) estimates an individual's baseline cognitive ability prior to illness or injury. Participants are asked to read aloud a list of irregularly spelled words, and performance is scored based on correct pronunciation. Scores are used to estimate premorbid intellectual functioning. Scores range from 0 to 70, with higher scores indicating higher estimated premorbid functioning. This measure helps contextualize current cognitive performance relative to expected baseline levels.	At hospital discharge, median of 4 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
C-peptide Levels	C-peptide levels measured at time of study drug administration, 24 hours, and at 72 hours (or at discharge if hospital length of stay was less than 72 hours).	0, 24 hours, and 72 hours (or at discharge if hospital length of stay was less than 72 hours)

Collaborators and Investigators

• Sponsor: Beth Israel Deaconess Medical Center
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Michael Donnino, MD, Beth Israel Deaconess Medical Center

Publications and helpful links

General Publications

• Vine J, Mehta S, Balaji L, Berg KM, Berlin N, Liu X, Ngo L, Shea M, Moskowitz A, Donnino MW, Grossestreuer AV. Thiamine as adjunctive therapy for diabetic ketoacidosis (DKAT) trial protocol and statistical analysis plan: a prospective, single-centre, double-blind, randomised, placebo-controlled clinical trial in the USA. BMJ Open. 2024 Feb 29;14(2):e077586. doi: 10.1136/bmjopen-2023-077586.

Study record dates

Study Major Dates

• Study Start (Actual): November 21, 2018
• Primary Completion (Actual): September 30, 2024
• Study Completion (Actual): October 1, 2024

Study Registration Dates

• First Submitted: October 22, 2018
• First Submitted That Met QC Criteria: October 22, 2018
• First Posted (Actual): October 24, 2018

Study Record Updates

• Last Update Posted (Actual): June 23, 2026
• Last Update Submitted That Met QC Criteria: May 26, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: diabetic ketoacidosis; lactate; thiamine; oxygen consumption; DKA; acidosis
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Diabetes Mellitus; Diabetes Complications; Acid-Base Imbalance; Nutritional and Metabolic Diseases; Ketosis; Acidosis; Diabetic Ketoacidosis; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Thiazoles; Azoles; Inorganic Chemicals; Chlorine Compounds; Pyrimidines; Sodium Compounds; Chlorides; Hydrochloric Acid; Thiamine; Sodium Chloride
• Other Study ID Numbers: 2018P000475; 1R01DK112886-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No