Insulin Therapy for Post-transplant Glucocorticoid Induced Hyperglycemia

Study Overview
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Brief Summary
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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?

Official Title
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Insulin Therapy for Post-transplant Glucocorticoid Induced Hyperglycemia

Conditions
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Post-Transplant Glucocorticoid Induced Diabetes

Intervention / Treatment
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* Drug: Neutral protamine hagedorn (NPH) insulin
* Drug: Regular human insulin or Insulin Aspart
* Drug: Insulin glargine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have undergone bone marrow, liver, lung, or renal transplant. 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. Have pre-existing or newly diagnosed diabetes mellitus established by any of the criteria listed below: Fasting plasma glucose ≥7.0 mmol/L (repeated x 1) Any plasma glucose ≥11.0 mmol/L Have at least three pre-meal inpatient capillary blood glucose (CBG) readings ≥ 7.8 mmol/L Be eating meals by mouth Exclusion Criteria: Heart, Pancreas, Islet cell transplant recipients Previous use of Basal-Bolus or Pre-Mixed Insulin regimen Diabetes mellitus type I NPO (not eating meals by mouth) Receiving enteral (tube feeds) or parenteral (TPN) nutrition

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Neutral protamine hagedorn (NPH) insulin<br>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<br> <br> * Other names: Humulin N, Novolin N;|
| Experimental: Regular or Aspart insulin<br>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<br> <br> * Other names: NovoRapid;|
| Experimental: Insulin glargine<br>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<br> <br> * Other names: Lantus;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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glucocorticoid, diabetes mellitus, post-transplant, insulin