Investigation of a Switch From Insulin Therapy to a Metformin & Saxagliptin Combination in Patients With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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The purpose of this study is to investigate the success rate of a switch from insulin therapy to a metformin & saxagliptin combination in patients with type 2 diabetes mellitus.

Detailed Description
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The following study is based on a previous clinical trial performed at ikfe GmbH in Mainz in 2006 and 2007 (PIOswitch). [2] The purpose of this trial was to demonstrate that type 2 diabetes patients treated with insulin can be effectively switched to a pioglitazone/glimepiride combination without loss of glycemic control. The study was performed with 100 patients, out of whom 76 were finally successfully switched, resulting in a cheaper and more convenient therapy with indications of an improved laboratory cardiovascular risk biomarker profile (Hohberg et al., Diabetes Obes. Metab. 11:464-471, 2009). [2] Glimeperide is an agent with unspecific stimulating effect on the ß-cell and is considered to accelerate the progression of the disease while still controlling blood glucose. In addition, it may cause hypoglycemia. The combination of pioglitazone with glimepiride was selected, because pioglitazone requires approx. 5-6 weeks for developing its full anti-diabetic efficacy and an immediate effect on glucose was required to avoid glycemic deterioration. It is tempting to speculate that the combination of a drug providing ß-cell protection (like saxagliptin) with a drug effectively and rapidly lowering blood glucose through a different mechanism of action (metformin) instead of unspecific ß-cell stimulation would result in an even improved outcome without risk of hypoglycemia. The purpose of this study is to investigate the success rate of a switch from insulin therapy to a metformin & saxagliptin combination in patients with type 2 diabetes mellitus.

Official Title
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Investigation of a Switch From Insulin Therapy to a Metformin & Saxagliptin Combination in Patients With Type 2 Diabetes Mellitus

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Metformin and Saxagliptin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Combination of OAD and basal insulin treatment (BOT) or intensified conventional therapy (ICT; > 2 injections of basal and prandial) or conventional insulin therapy (CIT; 1 or 2 injections of basal or biphasic) HbA1c < 7.5 % Age: 18-80 years inclusively Duration of insulin therapy > 1 year Insulin dose < 120 IU/day Fasting C-peptide > 0.6 ng/l Fasting glucose ≤ 210 mg/dl Full legal, mental and physical ability to give informed consent Patient consent that the general physician will be informed of trail participation Experience in self measurement of blood glucose > 1 year Exclusion Criteria: Type 1 Diabetes mellitus History of drug or alcohol abuse within the last five years prior to screening History of severe or multiple allergies Progressive fatal disease History of significant cardiovascular, respiratory, gastrointestinal, hepatic (ALAT and/or ASAT > 3 times the normal reference range), neurological, psychiatric and/or haematological disease as judged by the investigator Renal insufficiency or history of significant renal diseases (creatinine clearance lower than 60 ml/min determined using the Cockroft-Goult equation). Contra-indications for study drugs including contraindications for the rescue drugs Anamnestic history of hypersensitivity to the study drugs or to drugs with similar chemical structures Pregnancy or breast feeding Sexually active women of childbearing potential not consistently and correctly practicing birth control by implants, injectables, combined oral contraceptives, hormonal intrauterine devices (IUDs), sexual abstinence or vasectomised partner Treatment with any other investigational drug within 3 months prior to screening Lack of compliance or other similar reason, that according to investigator, precludes satisfactory participation in 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 |
| --- | --- |
| No Intervention: Control arm<br>The patients randomized to the control arm will continue their current therapy, as individually prescribed. Insulin will be administered via subcutaneous injection and OADs (if applicable) will be administered orally, as individually prescribed. | |
| Experimental: Saxagliptin & metformin<br>Saxagliptin and metformin tablets will be administered orally. Pioglitazione (Rescue medication) tablets will be administered orally. Insulin glargine (Rescue medication) will be administered via subcutaneous injection as individually prescribed. | Drug: Metformin and Saxagliptin<br>* Metformin 500mg/daily titrated to 2000mg/d in 4 Weeks (continued for 20 weeks) Saxagliptin 5 mg daily over complete trial<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| percentage of patients with stable HbA1c |  | 26 ± 2 weeks (baseline to postbaseline values) at 4 week intervals | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| impact of the switch on: | - Biomarkers of insulin resistance and ß-cell function | 26 ± 2 weeks (baseline to postbaseline values) | 
| impact of the switch on: | - Biomarkers of cardiovaskular risk | 26 ± 2 weeks (baseline to postbaseline values) | 
| impact of the switch on: | - Patient treatment satifaction | 26 ± 2 weeks (baseline to postbaseline values) | 
| impact of the switch on: | - Treatment costs | 26 ± 2 weeks (baseline to postbaseline values) | 
| impact of the switch on: | - Requirement of 3rd line OAD pioglitazone as rescue drug | 26 ± 2 weeks (baseline to postbaseline values) | 
| impact of the switch on: | - oral Glucose Tolerance Test (oGTT) | 26 ± 2 weeks (baseline to postbaseline values) | 
| impact of the switch on: | - Macrophagen activation (in a subpopulation at site 01 ikfe GmbH) | 26 ± 2 weeks (baseline to postbaseline values) |