The Effect of Simple Basal Insulin Titration, Metformin Plus Liraglutide for Type 2 Diabetes With Very Elevated HbA1c - The SIMPLE Study

Study Overview
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Brief Summary
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The aim of this clinical trial is to assess and compare the effect of insulin detemir in combination with liraglutide and metformin versus insulin detemir in combination with insulin aspart and metformin in subjects with very uncontrolled Type 2 Diabetes (A1c > 10%).

Detailed Description
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The aim of this study is to compare a GLP-1 plus basal insulin and metformin treatment regimen to a basal-bolus plus metformin treatment regimen in patients with very uncontrolled (HbA1c>10%) type 2 diabetes. The investigators will compare the two regimens with respect to efficacy in improving glycemic control, rate of hypoglycemia, change in weight, effect on patient quality of life, treatment burden, physician time, as well as healthcare related cost. The investigators hypothesize that at 26 weeks from randomization the two treatment regimens will have similar percentage of patients reaching A1c levels <7.0%, while more patients on the GLP-1 plus basal insulin strategy will achieve the composite end point of A1c levels <7.0% without severe hypoglycemia or significant weight gain.

Official Title
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The Effect of Simple Insulin Detemir Titration, Metformin Plus Liraglutide Compared to Simple Insulin Detemir Titration Plus Insulin Aspart and Metformin for Type 2 Diabetes With Very Elevated HbA1c - The SIMPLE Study: A 26 Week, Randomized, Open Label, Parallel-group, Intention to Treat Study

Conditions
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Diabetes Mellitus, Type 2, Diabetes

Intervention / Treatment
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* Drug: Metformin
* Drug: Detemir
* Drug: Liraglutide
* Drug: Insulin Aspart


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Clinical diagnosis of type 2 diabetes with confirmed HbA1c level >10% at time of enrollment, regardless of prior or current treatment regimens, or time since diagnosis. Exclusion Criteria: Age <18 as the feasibility and safety of this treatment regimen should be first established in the adult population; if successful, a subsequent pediatric study will be proposed; Type 1 diabetes as purposefully withholding meal-time insulin is contraindicated; Clinical state requiring inpatient admission/treatment; Contraindication or strong cautions to any of the study medications: Creatinine above 1.4 mg/dl for women and 1.5 mg/dl for men (per metformin label) History of lactic acidosis (per metformin label) Advanced hepatic or cardiac disease (per metformin label) Age >80 years (per metformin label) Chronic alcohol use (>14 drinks/week) History of pancreatitis (per liraglutide label) Personal or family history of medullary thyroid cancer or MEN syndrome (per liraglutide label) Pregnancy and lactation (per liraglutide label) Any serious or unstable medical condition as it would interfere with treatment assignment as well as outcome measurement; Any scheduled elective procedures/surgeries; Active infections, including osteomyelitis; Not willing to participate, unable to keep projected appointments, unwillingness to receive injectable treatment; unwillingness to perform 7-point glucose profiles over 2 consecutive days the weeks prior to Randomization (visit 1)and the week prior to visit 6 Non English speaking.

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: Control: Metformin, Insulin Detemir, Insulin Aspart<br>Metformin titrated to max tolerated dose (at least 1000 mg/day); Insulin detemir titrated based on the study protocol; Insulin Aspart titrated by the physician | Drug: Metformin<br>* Metformin will be started at 500 mg daily (or continued at current dose)and weekly titrated to 2000 mg or maximum tolerated dose (at least 1000 mg/day)<br>* Other names: Metformin tablets;Drug: Detemir<br>* Insulin detemir will be started in both groups at 0.3 units/kg or conversion 1:1 from dose of basal insulin prior to randomization. The titration will be primarily patient-driven, based on our study protocol table. Additional physician driven titration will be allowed in both groups if patient fails to intensify basal insulin dose as directed.<br>* Other names: Insulin Detemir subcutaneous once or twice daily;Drug: Insulin Aspart<br>* Insulin aspart will be initiated at a dose of 0.3 units/kg/day divided among the number of meals taken daily and titrated based on physician clinical judgment with the goal of pre-prandial BG 70-130 mg/dL and post-prandial BG <180<br>* Other names: Insulin Aspart Subcutaneous injection one to three times daily;|
| Active Comparator: Metformin, insulin determir, Liraglutide<br>Metformin titrated to max tolerated dose (at least 1000mg/day); Insulin detemir titrated based on the study protocol; Liraglutide titrated to max tolerated dose (at least 1.2 mg/day) | Drug: Metformin<br>* Metformin will be started at 500 mg daily (or continued at current dose)and weekly titrated to 2000 mg or maximum tolerated dose (at least 1000 mg/day)<br>* Other names: Metformin tablets;Drug: Detemir<br>* Insulin detemir will be started in both groups at 0.3 units/kg or conversion 1:1 from dose of basal insulin prior to randomization. The titration will be primarily patient-driven, based on our study protocol table. Additional physician driven titration will be allowed in both groups if patient fails to intensify basal insulin dose as directed.<br>* Other names: Insulin Detemir subcutaneous once or twice daily;Drug: Liraglutide<br>* Initial dose of 0.6 mg/day with weekly increments of 0.6 mg until dose of 1.8 mg/day or maximal tolerated dose (at least 1.2 mg/day)is reached<br>* Other names: Liraglutide 6 mg/mL Subcutaneously;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Randomization in A1c at Week 26 | Change in glycosylated Hemoglobin A1c (A1c) from randomization to 26 weeks of therapy | Baseline and Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite End-point | Percentage of participants with glycosylated Hemoglobin A1c (A1c)<8% AND no documented severe hypoglycemia (<56 mg/dL) during the study AND no significant weight gain (>3% from baseline) | Week 0 (Randomization) , Week 26 | 
| Percentage of Participants Reaching Target A1c of <7% at Week 26 |  | Week 26 | 
| Percentage of Participants Reaching Pre-specified Treatment Failure Outcome | Treatment Failure defined as A1c>10% at week 13 (visit 5) | week 13 | 
| Mean Change From Randomization in Body Weight | Change in body weight from randomization to end of study. | Week 0 (Randomization) , Week 26 | 
| Hypoglycemic Episodes | Percentage of participants experiencing any episodes of documented hypoglycemia defined as CBG reading of <70 mg/dl | Week 0 (Randomization) , Week 2, week 4, week 13, Week 26 | 
| Change in Diabetes Quality of Life (DQOL)Questionnaire Score- Least Squares Means | Diabetes Quality of Life (DQOL) questionnaires will be completed by the patient at the randomization and end-of study visits. ALL D-QOL domains are scored on a 1-5 scale, with a lower number representing better quality of life or treatment satisfaction. Outcome reported is difference between mean baseline and mean Week 26 score. | Week 0 (Randomization) , Week 26 | 
| Change in Short Form-36 (SF-36) Questionnaire Score | Quality of life questionnaires will be completed by the patient at the randomization and end-of study visits. SF-36 is scored on a 1-100 scale; a higher score represents a better self-assessed health - for all domains. | Week 0 (Randomization) , Week 26 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Insulin, Diabetes Mellitus, Type 2, Insulin, Long-Acting, Insulin, Short Acting, Detemir, Liraglutide, GLP-1, Glucagon Like Peptide, Metformin, Uncontrolled Diabetes, Elevated A1c, Incretins