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Thiamine as Adjunctive Therapy for Diabetic Ketoacidosis

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ClinicalTrials.gov Identifier: NCT03717896
Recruitment Status : Recruiting
First Posted : October 24, 2018
Last Update Posted : January 28, 2019
Sponsor:
Collaborator:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
Michael Donnino, Beth Israel Deaconess Medical Center

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.

Condition or disease Intervention/treatment Phase
Diabetic Ketoacidosis Drug: 200mg IV thiamine in 50mL 0.9% saline Drug: Placebo Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Thiamine as Adjunctive Therapy for Diabetic Ketoacidosis
Actual Study Start Date : November 21, 2018
Estimated Primary Completion Date : April 21, 2023
Estimated Study Completion Date : October 1, 2023

Resource links provided by the National Library of Medicine


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 Name: Vitamin B1

Placebo Comparator: Placebo
100mL 0.9% saline twice daily for two days
Drug: Placebo
50mL 0.9% saline




Primary Outcome Measures :
  1. plasma bicarbonate levels [ Time Frame: 24 hours ]
    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


Secondary Outcome Measures :
  1. anion gap [ Time Frame: 24 hours ]
    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

  2. lactate [ Time Frame: 24 hours ]
    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

  3. oxygen consumption by circulating mononuclear cells [ Time Frame: 24 hours ]
    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.

  4. ICU length of stay [ Time Frame: 24 hours ]
    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.

  5. hospital length of stay [ Time Frame: 24 hours ]
    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.

  6. hospital resource usage [ Time Frame: 24 hours ]
    The investigators will record this parameter from hospital records to determine if there is a difference between the two groups



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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., alcoholic)
  • Research-protected populations (pregnant women, prisoners, the intellectually disabled)
  • Patient enrolled previously in same study
  • Code status of Do Not Resuscitate/Do Not Intubate (DNR/DNI) or Comfort Measures Only (CMO)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03717896


Contacts
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Contact: Michael W Donnino, MD (617) 754-2341 mdonnino@bidmc.harvard.edu
Contact: Francesca Montillo, MS 617-754-2341 fmontill@bidmc.harvard.edu

Locations
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United States, Massachusetts
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 02215
Contact: Michael W Donnino, MD       mdonnino@bidmc.harvard.edu   
Contact: Jacob Boise    617-754-2881    jboise@bidmc.harvard.edu   
Principal Investigator: Michael W Donnino, MD         
Sub-Investigator: Chris Hansen, MD         
Sponsors and Collaborators
Beth Israel Deaconess Medical Center
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

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Responsible Party: Michael Donnino, Associate Professor of Medicine and Emergency Medicine, Beth Israel Deaconess Medical Center
ClinicalTrials.gov Identifier: NCT03717896     History of Changes
Other Study ID Numbers: 2018P000475
1R01DK112886-01A1 ( U.S. NIH Grant/Contract )
First Posted: October 24, 2018    Key Record Dates
Last Update Posted: January 28, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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

Keywords provided by Michael Donnino, Beth Israel Deaconess Medical Center:
diabetic ketoacidosis
DKA
thiamine
acidosis
oxygen consumption
lactate

Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Complications
Ketosis
Acidosis
Diabetic Ketoacidosis
Acid-Base Imbalance
Metabolic Diseases
Glucose Metabolism Disorders
Endocrine System Diseases
Thiamine
Vitamin B Complex
Vitamins
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs