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Early Administration of Insulin Glargine in Patients With Diabetic Ketoacidosis

Primary Purpose

DKA

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Insulin Glargine
Sponsored by
HealthPartners Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for DKA focused on measuring DKA, Hypoglycemia, Rebound Hyperglycemia, Type 1 Diabetes, Type 2 Diabetes

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Presented to Regions Hospital ED for chief complaint of DKA, nausea, vomiting, abdominal pain, hyperglycemia, or similar Meets all below diagnostic criteria for DKA per the American Diabetes Association: Arterial or venous pH </= 7.3 Serum Bicarbonate </= 18 mEq/L Ketonuria or ketonemia Anion Gap > 10 Blood sugar > 250 mg/dL Receiving IV insulin infusion It is feasible to provide insulin glargine within 2 hours (+/- 30 minutes) of IV infusion start Will be admitted to the ICU for DKA, or already admitted to the ICU for DKA Ability to provide informed consent Exclusion Criteria: Age < 18 End stage renal disease or hepatic disease Hypotension requiring IV vasopressors or inotropes at any point during admission (i.e. norepinephrine, dobutamine, vasopressin, etc.) Need for emergent surgery Pregnant patients Prisoners Indication for insulin therapy other than DKA (hypertriglyceridemia, beta-blocker overdose, hyperglycemia without DKA) Patients receiving prior to admission insulin pump therapy Patients receiving prior to admission combination insulin products (i.e. Novolin® 70/30, Novolog® 70/30, Humalog® 75/25, etc.) Did not consent to study

Sites / Locations

  • Regions HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

No Intervention

Active Comparator

Arm Label

Standard of Care

Intervention

Arm Description

Subjects presenting to ED with diagnosis of DKA and receiving intravenous short acting insulin will not have orders for subcutaneous insulin glargine placed for research purposes.

Subjects presenting to ED with diagnosis of DKA will receive study medication set to begin within 2 hours after initiation of the IV insulin infusion. The dose will come from IV pharmacy and dispensed in a 1 mL insulin syringe. If the patient was not taking basal insulin prior to admission, the patient will receive 0.2 units/kg insulin glargine. If the patient was taking basal insulin prior to admission, the patient will receive their home insulin glargine dose.

Outcomes

Primary Outcome Measures

Does early administration of insulin glargine result in a change in ICU length of stay when compared to usual care for the treatment of diabetic ketoacidosis?
Hypothesis: Early administration of insulin glargine will result in shorter ICU length of stay when compared to usual care in patients with DKA.

Secondary Outcome Measures

Does early administration of insulin glargine result in a change in hospital length of stay (defined as time between start of insulin infusion and discharge from hospital) when compared to usual care for the treatment of diabetic ketoacidosis?
Hypothesis: Early administration of insulin glargine will result in shorter hospital length of stay when compared to usual care in patients with DKA.
Does early administration of insulin glargine result in a change in recovery from DKA when compared to usual care for the treatment of diabetic ketoacidosis?
Recovery defined as blood glucose < 200 and two of: Anion Gap </= 12, Serum Bicarbonate ≥ 15 mEq/L, or pH > 7.3
Does early administration of insulin glargine result in a change in duration of time on IV insulin infusion when compared to usual care for the treatment of diabetic ketoacidosis?
Hypothesis: Early administration of insulin glargine will result in a shorter duration of time on IV insulin infusion when compared to usual care for the treatment of diabetic ketoacidosis.
Does early administration of insulin glargine result in a change in prevalence of rebound hyperglycemia when compared to usual care for the treatment of diabetic ketoacidosis?
Rebound hypoglycemia defined as blood glucose > 180 mg/dL in the 24 hours after IV insulin infusion discontinuation
The number of hypoglycemic (defined as blood glucose < 70mg/dL) events occurring while on IV insulin therapy or in the 24h hours after IV insulin infusion discontinuation with early insulin glargine administration compared to usual care
Hypothesis: The occurrence of a hypoglycemic event occurring while on IV insulin therapy or in the 24h hours after IV insulin infusion discontinuation with administration of insulin glargine is comparable to usual care.
The change in mean blood glucose values in the 24 hours and (separately) 48 hours after IV insulin infusion discontinuation
Hypothesis: Early administration of insulin glargine will result in a lower mean value of blood glucose in the 24 and 48 hours after IV insulin infusion discontinuation.
The change in duration of elevated anion gap when compared to usual care
Hypothesis: Early administration of insulin glargine will result in a shorter duration of elevated anion gap (defined as time with anion gap > 12) when compared to usual care for the treatment of diabetic ketoacidosis.

Full Information

First Posted
December 15, 2022
Last Updated
August 21, 2023
Sponsor
HealthPartners Institute
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1. Study Identification

Unique Protocol Identification Number
NCT06007508
Brief Title
Early Administration of Insulin Glargine in Patients With Diabetic Ketoacidosis
Official Title
Early Administration of Insulin Glargine in Patients With Diabetic Ketoacidosis
Study Type
Interventional

2. Study Status

Record Verification Date
December 2022
Overall Recruitment Status
Recruiting
Study Start Date
May 31, 2022 (Actual)
Primary Completion Date
December 31, 2023 (Anticipated)
Study Completion Date
February 29, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
HealthPartners Institute

4. Oversight

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.
Yes
Data Monitoring Committee
No

5. Study Description

Brief Summary
Diabetic ketoacidosis (DKA) is a medical emergency that is associated with significant morbidity and mortality for both patients with type I and type II diabetes. By correcting hyperglycemia and inhibiting the release of free fatty acids, insulin administration leads to decreased ketone formation and resolution of acidosis. Short-acting intravenous insulin is often preferred to subcutaneous administration for initial management due to its short half-life and ease of titration, but patients will eventually need to transition to subcutaneous insulin prior to discharge. The timing of initiation or resumption of home long-acting subcutaneous insulin is controversial in the treatment of DKA. It is currently unknown if resuming a portion or all of the patient's home basal regimen during the initial treatment phase of DKA will provide an impact on patient care. The purpose of this study is to evaluate the impact of early glargine administration if the patient was not previously on basal insulin or resuming the patient's home basal insulin regimen within two hours after the start of the intravenous insulin infusion in addition to usual care will improve patient outcomes.
Detailed Description
In 2014, there were 168,000 hospitalizations for DKA, and the average length of stay was 3.4 days in 2009. The estimated annual direct medical expense and indirect cost is 2.4 billion dollars per year. DKA is a potentially life-threatening condition due to its ability to cause metabolic acidosis, electrolyte imbalances, and dehydration. While DKA treatment protocols differ from institution to institution, the goals of treatment remain the same --- resolution of acidosis, dehydration, and hyperglycemia. Following fluid resuscitation, correction of hyperglycemia with insulin therapy is the mainstay of treatment. Intravenous (IV) insulin infusions with regular insulin are commonly used due to its short half-life of 30 to 60 minutes and resulting titratability. Treatment is then continued with subcutaneous (SC) insulin once the acidosis and anion gaps have cleared and the patient's hemodynamics and electrolytes abnormalities have resolved. Traditionally, when SC insulin is initiated, the IV insulin infusion is stopped two hours later. However, the timing of SC initiation has becoming more controversial in recent years. The 2019 American Diabetes Association Standards of Care recommend transition of patients from IV to SC insulin requires administration of basal insulin 2-4 h prior to the intravenous insulin being stopped to prevent recurrence of ketoacidosis and rebound hyperglycemia. However, the 2014 Joint British Diabetes Societies Inpatient Care Group recommend continuing a patient's home basal insulin during the initial management of DKA to prevent rebound hyperglycemia and to avoid extending length of stay. Several recent papers have examined early basal insulin administration as adjunct therapies with IV insulin infusions for the treatment of hyperglycemia and DKA. In 2012, a single-center prospective, randomized controlled trial by Hsia et al. compared IV insulin infusion with or without early administration of insulin glargine (dose = 0.25 U/kg) in 61 hyperglycemic patients with diabetes. Forty-one percent (25/61) of the patients enrolled in the trial were admitted with DKA. Those patients that received early glargine had lower prevalence of rebound hyperglycemia when the insulin infusion was discontinued (experimental group: 33% vs control group: 93.5%; P < 0.001). The total length of IV insulin infusion was similar in the two groups (control group: 35 ± 13h vs experimental group: 42 ± 24h). The mean blood glucose levels within the 12-hour study period were significantly lower in the intervention group, while there were 3 asymptomatic hypoglycemic measurements in the control group and none in the intervention group. In 2015, Doshi et al. conducted a two-center prospective, randomized controlled trial of 40 patients admitted for DKA. Patients were randomized to receive early insulin glargine (dose = 0.3 U/kg) or no glargine in addition to regular care. Those in the early insulin glargine arm were to receive the glargine subcutaneous injection within 2 hours of diagnosis. Patients in the control group were given insulin glargine once the anion gap closed and the IV insulin infusion was continued for two additional hours. There was no difference in time to anion gap closure, hospital length of stay, ICU admissions, ICU length of stay, and hypoglycemic events. In 2015, Houshyar et al. conducted a single-center, prospective, randomized controlled trial of 40 patients admitted for DKA. Patients were randomized to receive early insulin glargine (dose = 0.4 U/kg) or no insulin glargine in addition to usual care. Patients in the control group were given insulin glargine once the anion gap closed. There was no difference in duration of acidosis, hospital length of stay or rates of hypoglycemia. There were higher rates of hyperglycemia following discontinuation of the insulin infusion in those that did not receive early glargine (51% vs. 35% of measurements in the experimental group showed a glucose >8.3 mM or >150 mg/dL; p = 0.046). Rappaport et al. (2019) conducted a single-center, retrospective cohort study of 106 admissions for DKA comparing early vs late initiation of basal insulin. Patients admitted to the MICU who were treated with home-dose basal insulin prior to DKA resolution and within 24 hours of IV insulin infusion initiation (n = 33) were compared to patients who were initiated on basal insulin within 6 hours before or any time after IV insulin infusion discontinuation (n = 73). There was no difference in transitional failure, rebound hyperglycemia, hypoglycemia events, time to anion gap closure, length of ICU stay, or hospital length of stay. There was a statistically significant decrease for time on IV insulin infusion (early: 13.8h vs late: 17.1h, p = 0.04). As previously outlined, randomized studies using weight based basal insulin doses have shown that the early initiation of basal insulin can prevent rebound hyperglycemia with no increase in hypoglycemia. One retrospective study demonstrated a decrease of time on IV insulin infusion in those that received early basal insulin when compared to those that did not. These studies have also shown trends toward shorter ICU and hospital length of stay, anion gap closure, and time to resolution of acidosis but none have demonstrated statistical significance. However, no prospective trials have examined resuming the patient's home basal insulin early in the course of DKA and it is currently unknown if resuming a portion or the entirety of the patient's home basal regimen will provide an impact on patient care. By conducting a prospective study comparing initiation of early glargine administration at the patient's home dose to current standards of care, early administration may lead to shorter ICU and hospital lengths of stay as well as shorter duration of acidosis. This could provide significant cost-savings to the institution and benefit patients in need of treatment for this serious complication of diabetes.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
DKA
Keywords
DKA, Hypoglycemia, Rebound Hyperglycemia, Type 1 Diabetes, Type 2 Diabetes

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
This will be a two arm, prospective, randomized, open label trial in patients presenting with DKA. Block randomization will be used to ensure equal group sizes.
Masking
None (Open Label)
Allocation
Randomized
Enrollment
150 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Standard of Care
Arm Type
No Intervention
Arm Description
Subjects presenting to ED with diagnosis of DKA and receiving intravenous short acting insulin will not have orders for subcutaneous insulin glargine placed for research purposes.
Arm Title
Intervention
Arm Type
Active Comparator
Arm Description
Subjects presenting to ED with diagnosis of DKA will receive study medication set to begin within 2 hours after initiation of the IV insulin infusion. The dose will come from IV pharmacy and dispensed in a 1 mL insulin syringe. If the patient was not taking basal insulin prior to admission, the patient will receive 0.2 units/kg insulin glargine. If the patient was taking basal insulin prior to admission, the patient will receive their home insulin glargine dose.
Intervention Type
Drug
Intervention Name(s)
Insulin Glargine
Other Intervention Name(s)
Lantus, Basaglar, Semglee
Intervention Description
Long-acting insulin
Primary Outcome Measure Information:
Title
Does early administration of insulin glargine result in a change in ICU length of stay when compared to usual care for the treatment of diabetic ketoacidosis?
Description
Hypothesis: Early administration of insulin glargine will result in shorter ICU length of stay when compared to usual care in patients with DKA.
Time Frame
Assessed from time of intervention until discharge from ICU to general medical unit or from hospital, up to 12 weeks
Secondary Outcome Measure Information:
Title
Does early administration of insulin glargine result in a change in hospital length of stay (defined as time between start of insulin infusion and discharge from hospital) when compared to usual care for the treatment of diabetic ketoacidosis?
Description
Hypothesis: Early administration of insulin glargine will result in shorter hospital length of stay when compared to usual care in patients with DKA.
Time Frame
Until discharge from ICU to general medical unit or from hospital, up to 12 weeks
Title
Does early administration of insulin glargine result in a change in recovery from DKA when compared to usual care for the treatment of diabetic ketoacidosis?
Description
Recovery defined as blood glucose < 200 and two of: Anion Gap </= 12, Serum Bicarbonate ≥ 15 mEq/L, or pH > 7.3
Time Frame
Until discharge from ICU to general medical unit or from hospital, up to 12 weeks
Title
Does early administration of insulin glargine result in a change in duration of time on IV insulin infusion when compared to usual care for the treatment of diabetic ketoacidosis?
Description
Hypothesis: Early administration of insulin glargine will result in a shorter duration of time on IV insulin infusion when compared to usual care for the treatment of diabetic ketoacidosis.
Time Frame
Until discharge from ICU to general medical unit or from hospital, up to 12 weeks
Title
Does early administration of insulin glargine result in a change in prevalence of rebound hyperglycemia when compared to usual care for the treatment of diabetic ketoacidosis?
Description
Rebound hypoglycemia defined as blood glucose > 180 mg/dL in the 24 hours after IV insulin infusion discontinuation
Time Frame
Through 24 hour mark after IV insulin discontinuation
Title
The number of hypoglycemic (defined as blood glucose < 70mg/dL) events occurring while on IV insulin therapy or in the 24h hours after IV insulin infusion discontinuation with early insulin glargine administration compared to usual care
Description
Hypothesis: The occurrence of a hypoglycemic event occurring while on IV insulin therapy or in the 24h hours after IV insulin infusion discontinuation with administration of insulin glargine is comparable to usual care.
Time Frame
Assessed from time of hospitalization until 24 hour mark after IV insulin discontinuation
Title
The change in mean blood glucose values in the 24 hours and (separately) 48 hours after IV insulin infusion discontinuation
Description
Hypothesis: Early administration of insulin glargine will result in a lower mean value of blood glucose in the 24 and 48 hours after IV insulin infusion discontinuation.
Time Frame
Assessed from time of hospitalization until 48 hour mark after IV insulin discontinuation
Title
The change in duration of elevated anion gap when compared to usual care
Description
Hypothesis: Early administration of insulin glargine will result in a shorter duration of elevated anion gap (defined as time with anion gap > 12) when compared to usual care for the treatment of diabetic ketoacidosis.
Time Frame
Until discharge from ICU to general medical unit or from hospital, up to 12 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Presented to Regions Hospital ED for chief complaint of DKA, nausea, vomiting, abdominal pain, hyperglycemia, or similar Meets all below diagnostic criteria for DKA per the American Diabetes Association: Arterial or venous pH </= 7.3 Serum Bicarbonate </= 18 mEq/L Ketonuria or ketonemia Anion Gap > 10 Blood sugar > 250 mg/dL Receiving IV insulin infusion It is feasible to provide insulin glargine within 2 hours (+/- 30 minutes) of IV infusion start Will be admitted to the ICU for DKA, or already admitted to the ICU for DKA Ability to provide informed consent Exclusion Criteria: Age < 18 End stage renal disease or hepatic disease Hypotension requiring IV vasopressors or inotropes at any point during admission (i.e. norepinephrine, dobutamine, vasopressin, etc.) Need for emergent surgery Pregnant patients Prisoners Indication for insulin therapy other than DKA (hypertriglyceridemia, beta-blocker overdose, hyperglycemia without DKA) Patients receiving prior to admission insulin pump therapy Patients receiving prior to admission combination insulin products (i.e. Novolin® 70/30, Novolog® 70/30, Humalog® 75/25, etc.) Did not consent to study
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Wiktoria Pasek
Phone
651-254-9900
Email
Wiktoria.X.Pasek@HealthPartners.Com
First Name & Middle Initial & Last Name or Official Title & Degree
Alan Denney
Phone
651-254-9900
Email
Alan.M.Denney@HealthPartners.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Adis Keric, PharmD
Organizational Affiliation
Regions Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Regions Hospital
City
Saint Paul
State/Province
Minnesota
ZIP/Postal Code
55101
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Wiktoria Pasek
Phone
651-254-9900
Email
Wiktoria.X.Pasek@HealthPartners.Com
First Name & Middle Initial & Last Name & Degree
Alan Denney
Phone
651-254-9900
Email
Alan.M.Denney@HealthPartners.com
First Name & Middle Initial & Last Name & Degree
Adis Keric, PharmD
First Name & Middle Initial & Last Name & Degree
Eric Berg, PharmD
First Name & Middle Initial & Last Name & Degree
Kathryn Sandgren, PharmD

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
There is no plan to share IPD with investigators not currently involved in the study.
Citations:
PubMed Identifier
19564476
Citation
Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009 Jul;32(7):1335-43. doi: 10.2337/dc09-9032. No abstract available.
Results Reference
background
PubMed Identifier
15647580
Citation
Hirsch IB. Insulin analogues. N Engl J Med. 2005 Jan 13;352(2):174-83. doi: 10.1056/NEJMra040832. No abstract available.
Results Reference
background
PubMed Identifier
30559235
Citation
American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019 Jan;42(Suppl 1):S90-S102. doi: 10.2337/dc19-S009.
Results Reference
background
PubMed Identifier
22685233
Citation
Hsia E, Seggelke S, Gibbs J, Hawkins RM, Cohlmia E, Rasouli N, Wang C, Kam I, Draznin B. Subcutaneous administration of glargine to diabetic patients receiving insulin infusion prevents rebound hyperglycemia. J Clin Endocrinol Metab. 2012 Sep;97(9):3132-7. doi: 10.1210/jc.2012-1244. Epub 2012 Jun 8.
Results Reference
background
PubMed Identifier
26013711
Citation
Doshi P, Potter AJ, De Los Santos D, Banuelos R, Darger BF, Chathampally Y. Prospective randomized trial of insulin glargine in acute management of diabetic ketoacidosis in the emergency department: a pilot study. Acad Emerg Med. 2015 Jun;22(6):657-62. doi: 10.1111/acem.12673. Epub 2015 May 25.
Results Reference
background
PubMed Identifier
26155506
Citation
Houshyar J, Bahrami A, Aliasgarzadeh A. Effectiveness of Insulin Glargine on Recovery of Patients with Diabetic Ketoacidosis: A Randomized Controlled Trial. J Clin Diagn Res. 2015 May;9(5):OC01-5. doi: 10.7860/JCDR/2015/12005.5883. Epub 2015 May 1.
Results Reference
background
PubMed Identifier
31069278
Citation
Rappaport SH, Endicott JA, Gilbert MP, Farkas JD, Clouser RD, McMillian WD. A Retrospective Study of Early vs Delayed Home Dose Basal Insulin in the Acute Management of Diabetic Ketoacidosis. J Endocr Soc. 2019 Apr 11;3(5):1079-1086. doi: 10.1210/js.2018-00400. eCollection 2019 May 1.
Results Reference
background
PubMed Identifier
25061324
Citation
Gosmanov AR, Gosmanova EO, Dillard-Cannon E. Management of adult diabetic ketoacidosis. Diabetes Metab Syndr Obes. 2014 Jun 30;7:255-64. doi: 10.2147/DMSO.S50516. eCollection 2014.
Results Reference
background
Links:
URL
https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf
Description
2017 National Diabetes Fact Sheet - Accessed August 6, 2019

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Early Administration of Insulin Glargine in Patients With Diabetic Ketoacidosis

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