Exenatide Inpatient Trial: A Randomized Controlled Pilot Trial on the Safety and Efficacy of Exenatide (Byetta®) Therapy for the Inpatient Management of Patients With Type 2 Diabetes

Study Overview
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Brief Summary
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The purpose of this study is to try and achieve similar glycemic control in general non-Intensive Care Unit (non-ICU) patients with Type 2 Diabetes with exenatide alone or in combination with basal insulin as compared to treatment with basal bolus insulin alone. The association between hyperglycemia and poor clinical outcomes in patients with diabetes is well established. Previous studies have shown that basal bolus insulin regimens improve glycemic control and reduce the rate of hospital complications compared to sliding scale regular insulin (SSRI) therapy, but has a significant risk of hypoglycemia. The investigators will compare the efficacy and safety of exenatide alone or in combination with basal insulin to control high blood glucose levels resulting in a lower risk of hypoglycemia.

Detailed Description
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The association between hyperglycemia and poor clinical outcomes in patients with diabetes is well established. Data from previous trials in hospitalized patients have shown a strong association between hyperglycemia and poor clinical outcomes, such as mortality, morbidity, length of stay (LOS), infections and overall complications. Basal bolus insulin regimens improve glycemic control and reduce the rate of hospital complications compared to sliding scale regular insulin (SSRI). However, the use of basal bolus is labor intensive, requiring multiple daily insulin injections, and has a significant risk of hypoglycemia. The investigators will study if treatment with exenatide alone or in combination with basal insulin will result in similar glycemic control and a lower frequency of hypoglycemia than treatment with basal bolus in general non-Intensive Care Unit (non-ICU) patients with Type 2 Diabetes.

Official Title
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Exenatide Inpatient Trial: A Randomized Controlled Pilot Trial on the Safety and Efficacy of Exenatide (Byetta®) Therapy for the Inpatient Management of General Medicine and Surgery Patients With Type 2 Diabetes

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Drug: Exenatide
* Drug: Glargine
* Drug: Rapid-acting insulin analogs


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A known history of Type 2 Diabetes receiving either diet alone or oral antidiabetic drugs (OAD) including insulin secretagogues, pioglitazone, DPP4 inhibitors, or metformin as monotherapy or in combination therapy, or low-dose insulin at <0.5 unit/kg/day. Males or females between the ages of 18 and 80 years discharged after hospital admission from general medicine and surgery services (non-Intensive Care Unit setting). Subjects with an admission / randomization BG < 400 mg/dL without laboratory evidence of diabetic ketoacidosis (serum bicarbonate < 18 mEq/L or positive serum or urinary ketones). Admission HbA1c between 7% and 10% BMI range: > 25 Kg/m^2 and < 45 Kg/m^2 Exclusion Criteria: Age < 18 or > 80 years Subjects with increased blood glucose (BG) concentration, but without a history of diabetes (stress hyperglycemia) Subjects with a history of type 1 diabetes (suggested by BMI < 25 Kg/m^2 requiring insulin therapy or with a history of diabetic ketoacidosis and hyperosmolar hyperglycemic state, or ketonuria). Treatment with high-dose (>0.5 unit/kg/day) insulin or with GLP-1 RA during the past 3 months prior to admission. Patients that required ICU care during the hospital admission. Recurrent severe hypoglycemia or hypoglycemic unawareness. Subjects with gastrointestinal obstruction, gastroparesis, history of pancreatitis or those expected to require gastrointestinal suction. Patients with clinically relevant pancreatic or gallbladder disease. Patients with unstable or rapidly progressing renal disease or severe renal impairment (creatinine clearance < 30 ml/min) Patients with clinically significant hepatic disease (cirrhosis, jaundice, end-stage liver disease), History of hypersensitivity to exenatide Treatment with oral or injectable corticosteroid (equal to a prednisone dose >5 mg/day), parenteral nutrition and immunosuppressive treatment. Patients with history of heavy alcohol use (female > 2 drinks per day, male > 3 drinks per day) or drug abuse within 3 months prior to admission. Mental condition rendering the subject unable to understand the nature, scope, and possible consequences of the study. Female subjects who are pregnant or breast feeding at time of enrollment into the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Exenatide inpatient<br>Patients with Type 2 Diabetes treated with diet, oral antidiabetic drugs, or with low-dose insulin will receive exenatide (Byetta®) twice daily. Supplemental (correction) doses of rapid-acting insulin analogs will be given for blood glucose levels > 140 mg/dL per the sliding scale. | Drug: Exenatide<br>* Exenatide is dispensed via a 1.2 mL prefilled pen with 250 mcg/mL solution for subcutaneous (s.c.) injection and will be administered twice daily starting at 5 mcg per dose, either in the abdomen, thigh or upper arm. Exenatide injections will be given within 60 minutes prior to morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart between doses). The exenatide dose will be increased to 10 mcg twice daily after 1 month based on clinical response.<br>* Other names: Byetta;|
| Active Comparator: Exenatide plus glargine insulin inpatient<br>Patients with Type 2 Diabetes treated with diet, oral antidiabetic drugs, or with low-dose insulin will receive exenatide twice daily and glargine once daily. Glargine insulin will be given once daily at the same time. Supplemental (correction) doses of rapid-acting insulin analogs will be given for blood glucose levels > 140 mg/dL per the sliding scale. | Drug: Exenatide<br>* Exenatide is dispensed via a 1.2 mL prefilled pen with 250 mcg/mL solution for subcutaneous (s.c.) injection and will be administered twice daily starting at 5 mcg per dose, either in the abdomen, thigh or upper arm. Exenatide injections will be given within 60 minutes prior to morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart between doses). The exenatide dose will be increased to 10 mcg twice daily after 1 month based on clinical response.<br>* Other names: Byetta;Drug: Glargine<br>* Glargine will be given once daily, at the same time of day. If the BG is between 140-200 mg/dL, the dose will be 0.2 units/kg/day; for BG levels 201-400 mg/dL, the dose will be 0.25 units/kg/day. The patients will be discharged on glargine once daily at 50% of the hospital dose.The total daily dose (TDD) of glargine is based on the patient's fasting BG levels for the last 2 days. FBG >180 mg/dL, no hypoglycemia; glargine increased by 4 IU. FBG >140 mg/dL, no hypoglycemia; glargine increased by 2 IU. FBG 100-140 mg/dL, no hypoglycemia; no change in dosage. FBG 70 - 99 mg/dl, decrease glargine by 4 IU or 10% of TDD. FBG or RBG < 70 mg/dl, decrease glargine by 8 IU or 20% of TDD. FBG or RBG < 40 mg/dl, decrease dose of glargine by 30%.<br>* Other names: Lantus;|
| Active Comparator: Basal bolus regimen inpatient<br>Patients with Type 2 Diabetes treated with diet, oral antidiabetic drugs, or with low-dose insulin will receive the Basal Bolus Regimen with Glargine and Rapid-Acting Insulin Analogs. Patients treated with insulin previously will receive 80% of total home daily insulin dose as the basal bolus. Half of the total daily dose will be given as glargine and half as rapid-acting insulin analogs. Supplemental (correction) doses of rapid-acting insulin analogs will be given for blood glucose levels > 140 mg/dL per the sliding scale. | Drug: Glargine<br>* Glargine will be given once daily, at the same time of day. If the BG is between 140-200 mg/dL, the dose will be 0.2 units/kg/day; for BG levels 201-400 mg/dL, the dose will be 0.25 units/kg/day. The patients will be discharged on glargine once daily at 50% of the hospital dose.The total daily dose (TDD) of glargine is based on the patient's fasting BG levels for the last 2 days. FBG >180 mg/dL, no hypoglycemia; glargine increased by 4 IU. FBG >140 mg/dL, no hypoglycemia; glargine increased by 2 IU. FBG 100-140 mg/dL, no hypoglycemia; no change in dosage. FBG 70 - 99 mg/dl, decrease glargine by 4 IU or 10% of TDD. FBG or RBG < 70 mg/dl, decrease glargine by 8 IU or 20% of TDD. FBG or RBG < 40 mg/dl, decrease dose of glargine by 30%.<br>* Other names: Lantus;Drug: Rapid-acting insulin analogs<br>* If the BG levels are >140 mg/dL, rapid acting insulin analogs will be administered following the supplemental/sliding scale protocol. If a patient is able and expected to eat all or most of his/her meals, supplemental insulin will be administered before each meal and at bedtime following the usual dose of the sliding scale protocol. If a patient is not able to eat, supplemental insulin will be administered every 6 hours following the sensitive dose of the sliding scale. If the BG is 141-180 mg/dL, then 2,3 or 4 units of insulin will be given; for BG 181 - 220 mg/dL; the units of insulin will be 3, 4 or 6; for BG 221 - 260 mg/dL, the units of insulin will be 4,5 or 8; for BG 261 - 300 mg/dL, the units of insulin will be 5, 6 or 10; for BG 301 - 350, the insulin will be 6, 8 or 12 units; for BG 351 - 400 mg/dL, the units of insulin will be 7,10 or 14; for BG> 400 mg/dL, the insulin will be 8,12 or 16 units.<br>|
| Active Comparator: Exenatide outpatient<br>Patients with Type 2 Diabetes treated with diet, oral antidiabetic drugs, or with low-dose insulin will receive exenatide (Byetta®) twice daily. Supplemental (correction) doses of rapid-acting insulin analogs will be given for blood glucose levels > 140 mg/dL per the sliding scale. | Drug: Exenatide<br>* Exenatide is dispensed via a 1.2 mL prefilled pen with 250 mcg/mL solution for subcutaneous (s.c.) injection and will be administered twice daily starting at 5 mcg per dose, either in the abdomen, thigh or upper arm. Exenatide injections will be given within 60 minutes prior to morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart between doses). The exenatide dose will be increased to 10 mcg twice daily after 1 month based on clinical response.<br>* Other names: Byetta;|
| Active Comparator: Insulin Only<br>Patients with Type 2 Diabetes will be treated with Insulin only | Drug: Glargine<br>* Glargine will be given once daily, at the same time of day. If the BG is between 140-200 mg/dL, the dose will be 0.2 units/kg/day; for BG levels 201-400 mg/dL, the dose will be 0.25 units/kg/day. The patients will be discharged on glargine once daily at 50% of the hospital dose.The total daily dose (TDD) of glargine is based on the patient's fasting BG levels for the last 2 days. FBG >180 mg/dL, no hypoglycemia; glargine increased by 4 IU. FBG >140 mg/dL, no hypoglycemia; glargine increased by 2 IU. FBG 100-140 mg/dL, no hypoglycemia; no change in dosage. FBG 70 - 99 mg/dl, decrease glargine by 4 IU or 10% of TDD. FBG or RBG < 70 mg/dl, decrease glargine by 8 IU or 20% of TDD. FBG or RBG < 40 mg/dl, decrease dose of glargine by 30%.<br>* Other names: Lantus;Drug: Rapid-acting insulin analogs<br>* If the BG levels are >140 mg/dL, rapid acting insulin analogs will be administered following the supplemental/sliding scale protocol. If a patient is able and expected to eat all or most of his/her meals, supplemental insulin will be administered before each meal and at bedtime following the usual dose of the sliding scale protocol. If a patient is not able to eat, supplemental insulin will be administered every 6 hours following the sensitive dose of the sliding scale. If the BG is 141-180 mg/dL, then 2,3 or 4 units of insulin will be given; for BG 181 - 220 mg/dL; the units of insulin will be 3, 4 or 6; for BG 221 - 260 mg/dL, the units of insulin will be 4,5 or 8; for BG 261 - 300 mg/dL, the units of insulin will be 5, 6 or 10; for BG 301 - 350, the insulin will be 6, 8 or 12 units; for BG 351 - 400 mg/dL, the units of insulin will be 7,10 or 14; for BG> 400 mg/dL, the insulin will be 8,12 or 16 units.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Daily Blood Glucose Concentration Inpatient | The levels of blood glucose (BG) will be measured before each meal and at bedtime using a glucose meter. Blood glucose will be measured at baseline and during the hospital stay (up to 10 days). | Duration of hospital stay, an expected average of 10 days. | 
| Change in HbA1c Concentration Inpatient | The difference in the levels of HbA1c at discharge and at 12 weeks from discharge will be measured. The A1C test result is reported as a percentage. The higher the percentage, the higher a person's blood glucose levels have been. A normal A1C level is below 5.7 percent. | 12 weeks from discharge. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Fasting Blood Glucose Levels Inpatient | The blood glucose levels prior to the patient's first meal of the day will be assessed using a glucose meter. | Duration of hospital stay, an expected average of 10 days. | 
| Mean Premeal Blood Glucose Levels Inpatient | The blood glucose levels prior to each meal will using a glucose meter. | Duration of hospital stay, an expected average of 10 days | 
| Incidence of Hypoglycemic Events Inpatient | The number of patients with hypoglycemia (blood glucose levels < 70 mg/dL) will be recorded. | Duration of hospital stay, an expected average of 10 days | 
| Incidence of Hyperglycemic Events Inpatient | Percent of readings with hyperglycemia (blood glucose levels > 240 mg/dL) | Duration of hospital stay, an expected average of 10 days | 
| Total Daily Dose of Insulin Inpatient | The total daily dose of insulin needed for glycemic control from baseline through the patient's hospital stay will be recorded. | Duration of hospital stay, an expected average of 10 days | 
| Average Number of Days of Hospital Stay | The average number of days in the hospital for subjects will be calculated. | Duration of hospital stay, an expected average of 10 days | 
| Incidence of the Need for ICU Care Inpatient | The total number of patients who require transfer to the ICU will be recorded. | Duration of hospital stay, an expected average of 10 days | 
| Hospital Mortality | The total number of subject deaths during hospital stay will be recorded. | Duration of hospital stay, an expected average of 10 days | 
| Hospital Complications | The total number of subjects who experience hospital complications like nosocomial pneumonia, bacteremia, respiratory failure, acute renal failure, and wound infections (surgery patients) will be recorded. Nosocomial infections will be diagnosed based on standardized Centers for Disease Control (CDC) criteria. | Duration of hospital stay, an expected average of 10 days | 
| Incidence of Acute Kidney Injury Inpatient | The number of patients who experience acute kidney injury diagnosed by an increment in serum creatinine >0.5 mg/dL from admission value or 50% of baseline value will be recorded. | Duration of hospital stay, an expected average of 10 days | 
| Incidence of Gastrointestinal Adverse Events Inpatient | The number of subjects who experience gastrointestinal side effects including nausea, vomiting and diarrhea will be recorded. | Duration of hospital stay, an expected average of 10 days | 
| Number of Patients With Severe Hypoglycemic Events Inpatient | Occurrences of hypoglycemia (blood glucose levels < 40 mg/dL) will be recorded. | Duration of hospital stay, an expected average of 10 days | 
| Incidence of Hospital Readmissions | The number of patients who require readmission to the hospital from the time of discharge to 12 weeks after discharge will be recorded. | 12 weeks after discharge | 
| Mean Fasting Blood Glucose Levels During Outpatient Period | Fasting Blood Glucose Levels were measured using blood test | 12 weeks after discharge | 
| Mean Daily Blood Glucose Concentration During Outpatient Period | Mean Daily Blood Glucose Concentration will be calculated and recorded. | 12 weeks after discharge | 
| The Number of Patients With Hypoglycemia Outpatient | Occurrence of hypoglycemia (blood glucose levels < 70 mg) will be identified by blood test | 12 weeks after discharge | 
| Number of Patients With Severe Hypoglycemic Events | Occurrences of hypoglycemia (blood glucose levels < 40 mg/dL) will be detected by blood test | 12 weeks after discharge | 
| Change in Body Weight | The change in Body Weight from discharge to 12 weeks after discharge will be recorded | Time of discharge, 12 weeks after discharge | 
| Change in Body Mass Index | The change in BMI from discharge to 12 weeks after discharge will be calculated | Discharge (after day 10 or hospital stay), 12 weeks after discharge 12 weeks after discharge | 
| Number of Patients Who Had Emergency Room Visits | The number of patients who had emergency room visits from the time of discharge to 12 weeks after discharge will be recorded. | 12 weeks after discharge | 
| Number of Hospital Readmissions | Number of hospital readmissions during 12 weeks after discharge will be recorded | 12 weeks after discharge | 
| Number of Acute Kidney Injury Events | Number of Acute Kidney Injury events will be recorded | 12 weeks from discharge. | 
| Number of Severe Gastrointestinal Adverse Events | Number of Severe (require hospitalization) Gastrointestinal Adverse Events | 12 weeks from discharge. | 
| Change in Systolic Blood Pressure | Change in Systolic Blood Pressure from the time of discharge to 12 weeks after discharge will be recorded | Discharge (after day 10 or hospital stay), 12 weeks after discharge | 
| Change in Heart Rate | Change in heart rate from the time of discharge to 12 weeks after discharge will be recorded | Discharge (after day 10 or hospital stay), 12 weeks after discharge | 
| Efficacy, Measured by HbA1c Levels and no Weight Gain | Number of patients who have an HbA1c <7.0% and no weight gain at 12 weeks from discharge will be recorded. | 12 weeks from discharge. | 
| Efficacy, Measured by HbA1c Levels and no Hypoglycemia | Number of patients who have an HbA1c <7.0% and no hypoglycemia at 12 weeks from discharge will be recorded. | 12 weeks from discharge. | 
| Change in Diastolic Blood Pressure | Change in Diastolic Blood Pressure from the time of discharge to 12 weeks after discharge will be recorded | Discharge (after day 10 or hospital stay), 12 weeks after discharge | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypoglycemia