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

• ClinicalTrials.gov Identifier: NCT01648218
• Recruitment Status: Terminated
• First Posted: July 24, 2012
• Last Update Posted: December 9, 2015
• Sponsor: Vancouver General Hospital
• Information provided by (Responsible Party): David E. Harris, MD, Vancouver General Hospital

Study Description

Brief Summary:

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?

Condition or disease	Intervention/treatment	Phase
Post-Transplant Glucocorticoid Induced Diabetes	Drug: Neutral protamine hagedorn (NPH) insulin; Drug: Regular human insulin or Insulin Aspart; Drug: Insulin glargine	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 5 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Insulin Therapy for Post-transplant Glucocorticoid Induced Hyperglycemia
• Study Start Date: August 2012
• Actual Primary Completion Date: April 2013
• Actual Study Completion Date: June 2013

Arms and Interventions

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 Name: 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: Humulin R; Novolin R; Novolog; 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 Name: Lantus

Outcome Measures

Primary Outcome Measures :

1. Blood glucose - inpatient [ Time Frame: Time (days) from enrollment to described treatment range, an expected average of 7 days ]
   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

Secondary Outcome Measures :

1. Blood glucose - inpatient [ Time Frame: Subjects will be followed from enrollment for the remainder of hospital stay (days), an expected average of 21 days ]
   Mean inpatient capillary blood glucose (mmol/L) from enrollment to discharge from hospital
2. Post prandial blood glucose - inpatient [ Time Frame: Subjects will be followed from enrollment for the remainder of hospital stay (days), an expected average of 21 days ]
   Mean inpatient two-hour post-lunch capillary blood glucose (mmol/L) from enrollment to discharge from hospital
3. Length of inpatient hospital stay [ Time Frame: Subjects will be followed from enrollment for the remainder of hospital stay (days), an expected average of 21 days ]
   Length of stay in hospital (days) from enrollment to discharge from hospital
4. Blood glucose [ Time Frame: Enrollment to 3 months ]
   Mean fasting blood glucose (mmol/L) from enrollment to 3 months
5. Hemoglobin A1C [ Time Frame: Enrollment to 3 months ]
   Mean hemoglobin A1C (%) from enrollment to 3 months
6. Post prandial blood glucose [ Time Frame: Enrollment to 3 months ]
   Mean two-hour post-lunch capillary blood glucose (mmol/L) from enrollment to 3 months
7. Hypoglycemic episodes [ Time Frame: Enrollment to 3 months ]

   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)

8. Glycemic treatment failure [ Time Frame: Enrollment to 3 months ]

   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.

9. Cardiovascular events [ Time Frame: Enrollment to 3 months ]
   New cardiovascular events defined as: myocardial infarction, new or worsened congestive heart failure, stroke, and cardiac arrhythmia.
10. Post-transplant infections or new antibiotic use [ Time Frame: Enrollment to 3 months ]
    Post-transplant infections or new antibiotic use from enrollment to 3 months.
11. Transplant graft failure [ Time Frame: Enrollment to 3 months ]
    Transplant graft failure (as specified by subject's medical transplant physician) from enrollment to 3 months.
12. New acute renal failure [ Time Frame: Enrollment to 3 months ]
    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
13. Mortality [ Time Frame: Enrollment to 3 months ]
    Overall subject mortality from baseline to 3 months.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

Canada, British Columbia

Vancouver General Hospital - Jim Pattison Pavilion

Vancouver, British Columbia, Canada, V5Z 1M9

Sponsors and Collaborators

Vancouver General Hospital

Investigators

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

More Information

Additional Information:

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

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.

• Responsible Party: David E. Harris, MD, MD, FRCPC, Clinical Endocrinology Fellow, University of British Columbia, Vancouver General Hospital
• ClinicalTrials.gov Identifier: NCT01648218
• Other Study ID Numbers: PTHG.VGH.UBC
• First Posted: July 24, 2012
• Last Update Posted: December 9, 2015
• Last Verified: December 2015

Keywords provided by David E. Harris, MD, Vancouver General Hospital:

glucocorticoid; diabetes mellitus; post-transplant; insulin

Additional relevant MeSH terms:

Hyperglycemia; Glucose Metabolism Disorders; Metabolic Diseases; Insulin; Insulin, Globin Zinc; Insulin Glargine; Insulin Aspart; Insulin, Isophane; Isophane Insulin, Human; Protamines; Hypoglycemic Agents; Physiological Effects of Drugs; Heparin Antagonists; Molecular Mechanisms of Pharmacological Action; Coagulants