Insulin Therapy for Post-transplant Glucocorticoid Induced Hyperglycemia (PTHG)

No consensus guidelines exist for management of post-transplant glucocorticoid induced hyperglycemia, but most published reviews recommend insulin as first line therapy. A variety of insulin regimens have been proposed, including mealtime short-acting regular or analog insulin, once daily neutral protamine hagedorn (NPH) insulin, pre-mixed insulin, or basal insulin alone such as glargine or detemir. However, no randomized trial has ever examined different insulin regimens to determine which most effectively controls post-transplant steroid-induced hyperglycemia. Consequently, the proposed study intends to examine three commonly used insulin regimens used for managing post-transplant once-daily glucocorticoid-induced hyperglycemia to determine which is most effective:

• Group 1: Intermediate-acting (NPH) insulin at breakfast
• Group 2: Short-acting insulin (regular or aspart) before meals
• Group 3: Insulin glargine at breakfast

Question/Hypothesis:

Among three commonly used insulin regimens, which is most effective for managing post-transplant once-daily glucocorticoid-induced hyperglycemia?

Study Overview

• Status: Terminated
• Conditions: Post-Transplant Glucocorticoid Induced Diabetes
• Intervention / Treatment: Drug: Insulin glargine; Drug: Neutral protamine hagedorn (NPH) insulin; Drug: Regular human insulin or Insulin Aspart

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Vancouver General Hospital - Jim Pattison Pavilion

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Have undergone bone marrow, liver, lung, or renal transplant.
2. Be using once daily oral glucocorticoid therapy (total daily dose of Prednisone ≥10 mg, Hydrocortisone ≥40 mg, Dexamethasone ≥1.5 mg) administered in the morning and expected to continue for at least 2 weeks.

3. Have pre-existing or newly diagnosed diabetes mellitus established by any of the criteria listed below:

   1. Fasting plasma glucose ≥7.0 mmol/L (repeated x 1)
   2. Any plasma glucose ≥11.0 mmol/L
4. Have at least three pre-meal inpatient capillary blood glucose (CBG) readings ≥ 7.8 mmol/L
5. Be eating meals by mouth

Exclusion Criteria:

1. Heart, Pancreas, Islet cell transplant recipients
2. Previous use of Basal-Bolus or Pre-Mixed Insulin regimen
3. Diabetes mellitus type I
4. NPO (not eating meals by mouth)
5. Receiving enteral (tube feeds) or parenteral (TPN) nutrition

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Neutral protamine hagedorn (NPH) insulin; Drug: Neutral protamine hagedorn (NPH) insulin Other Names: Humulin N, Novolin N Route: Subcutaneous; Dosage: No fixed dose, varies between subjects; Frequency: daily before breakfast; Duration: 12 hours; for duration subjects are concurrently administered once-daily glucocorticoid.	Drug: Neutral protamine hagedorn (NPH) insulin; Other Names: Humulin N, Novolin N
Experimental: Regular or Aspart insulin; Drug: Regular human insulin or Insulin Aspart Other Names: Humulin R, Novolin R, Novolog, NovoRapid Route: Subcutaneous; Dosage: No fixed dose, varies between subjects; Frequency: daily before meals; Duration: 2 hours (Aspart) or 6 hours (Regular); for duration subjects are concurrently administered once-daily glucocorticoid.	Drug: Regular human insulin or Insulin Aspart; Other Names: Novolin R; Novolog; Humulin R; NovoRapid
Experimental: Insulin glargine; Drug: Insulin glargine Other Names: Lantus Route: Subcutaneous; Dosage: No fixed dose, varies between subjects; Frequency: daily before breakfast; Duration: 24 hours; for duration subjects are concurrently administered once-daily glucocorticoid.	Drug: Insulin glargine; Other Names: Lantus

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood glucose - inpatient	Mean time from baseline to achieve at least 80% of pre-meal capillary blood glucose values within 5.0 - 7.8 mmol/L over a 48 hour period during hospitalization	Time (days) from enrollment to described treatment range, an expected average of 7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood glucose - inpatient	Mean inpatient capillary blood glucose (mmol/L) from enrollment to discharge from hospital	Subjects will be followed from enrollment for the remainder of hospital stay (days), an expected average of 21 days
Post prandial blood glucose - inpatient	Mean inpatient two-hour post-lunch capillary blood glucose (mmol/L) from enrollment to discharge from hospital	Subjects will be followed from enrollment for the remainder of hospital stay (days), an expected average of 21 days
Length of inpatient hospital stay	Length of stay in hospital (days) from enrollment to discharge from hospital	Subjects will be followed from enrollment for the remainder of hospital stay (days), an expected average of 21 days
Blood glucose	Mean fasting blood glucose (mmol/L) from enrollment to 3 months	Enrollment to 3 months
Hemoglobin A1C	Mean hemoglobin A1C (%) from enrollment to 3 months	Enrollment to 3 months
Post prandial blood glucose	Mean two-hour post-lunch capillary blood glucose (mmol/L) from enrollment to 3 months	Enrollment to 3 months
Hypoglycemic episodes	Hypoglycemic episodes defined as: (1) Mild - any measured CBG 3.0-4.0 mmol/L; (2) Severe - any episode of hypoglycemia with a measured CBG < 3.0 mmol/L, OR which the subject is not able to recognize and treat without the direct (substantial) intervention of a professional caregiver, nurse or physician (e.g. intravenous dextrose or intramuscular glucagon)	Enrollment to 3 months
Glycemic treatment failure	Hypoglycemic treatment failure: subject experiences ≥3 hypoglycemic episodes (≤ 4.0 mmol/L) over any 5 day period or a single severe hypoglycemic event (as previously defined), they will be withdrawn from study and managed at discretion of attending physician, or hospital endocrine consult service. Hyperglycemic treatment failure: Severe hyperglycemia defined as CBG >20 mmol/L. If subject experiences ≥3 severe hyperglycemic measures over the course of 48 hours they will be withdrawn from the study and managed at discretion of attending physician, or hospital endocrine consult service.	Enrollment to 3 months
Cardiovascular events	New cardiovascular events defined as: myocardial infarction, new or worsened congestive heart failure, stroke, and cardiac arrhythmia.	Enrollment to 3 months
Post-transplant infections or new antibiotic use	Post-transplant infections or new antibiotic use from enrollment to 3 months.	Enrollment to 3 months
Transplant graft failure	Transplant graft failure (as specified by subject's medical transplant physician) from enrollment to 3 months.	Enrollment to 3 months
New acute renal failure	New acute renal failure is defined according to Acute Kidney Network Guidelines: rapid time course and decreased kidney function according to an absolute Creatinine (Cr) rise greater than 26 μmol/L, greater than 2-fold increase in serum Cr from baseline, or urine output less than 0.5 mL/kg/hr for greater than 6 hours	Enrollment to 3 months
Mortality	Overall subject mortality from baseline to 3 months.	Enrollment to 3 months

Collaborators and Investigators

• Sponsor: Vancouver General Hospital
• Investigators: Principal Investigator: Breay W Paty, MD, FRCPC, Vancouver General Hospital, University of British Columbia

Publications and helpful links

General Publications

• Lane JT, Dagogo-Jack S. Approach to the patient with new-onset diabetes after transplant (NODAT). J Clin Endocrinol Metab. 2011 Nov;96(11):3289-97. doi: 10.1210/jc.2011-0657.
• Sarno G, Muscogiuri G, De Rosa P. New-onset diabetes after kidney transplantation: prevalence, risk factors, and management. Transplantation. 2012 Jun 27;93(12):1189-95. doi: 10.1097/TP.0b013e31824db97d.
• Griffith ML, Jagasia M, Jagasia SM. Diabetes mellitus after hematopoietic stem cell transplantation. Endocr Pract. 2010 Jul-Aug;16(4):699-706. doi: 10.4158/EP10027.RA.
• Lansang MC, Hustak LK. Glucocorticoid-induced diabetes and adrenal suppression: how to detect and manage them. Cleve Clin J Med. 2011 Nov;78(11):748-56. doi: 10.3949/ccjm.78a.10180.
• Umpierrez GE, Hellman R, Korytkowski MT, Kosiborod M, Maynard GA, Montori VM, Seley JJ, Van den Berghe G; Endocrine Society. Management of hyperglycemia in hospitalized patients in non-critical care setting: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2012 Jan;97(1):16-38. doi: 10.1210/jc.2011-2098.

Helpful Links

• Multilingual dietary instructions to be distributed to ALL subjects during study from the Canadian Diabetes Association

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (Actual): April 1, 2013
• Study Completion (Actual): June 1, 2013

Study Registration Dates

• First Submitted: July 12, 2012
• First Submitted That Met QC Criteria: July 19, 2012
• First Posted (Estimate): July 24, 2012

Study Record Updates

• Last Update Posted (Estimate): December 9, 2015
• Last Update Submitted That Met QC Criteria: December 8, 2015
• Last Verified: December 1, 2015

More Information

Terms related to this study

• Keywords: insulin; diabetes mellitus; glucocorticoid; post-transplant
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperglycemia; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Coagulants; Heparin Antagonists; Insulin; Insulin, Globin Zinc; Insulin Aspart; Insulin Glargine; Insulin, Isophane; Isophane Insulin, Human; Protamines
• Other Study ID Numbers: PTHG.VGH.UBC