Dapagliflozin + Saxagliptin in a Basal-bolus Insulin Treatment

Study Overview
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Brief Summary
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To perform a study that investigates the effectiveness of adding the SGLT2 inhibitor dapagliflozin + the dipeptidyl peptidase 4 (DPP-4) inhibitor saxagliptin vs placebo to revert from a BBIT regimen to a BOT regimen in patients with type 2 diabetes.

Detailed Description
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This will be a phase IV study investigating the efficacy and safety of adding the SGLT2 inhibitor dapagliflozin together wih the DPP-4 inhibitor saxagliptin to an intensified insulin treatment regimen. Because BOT is superior to BBIT in respect to the development of bodyweight, hypoglycaemia and patient satisfaction in type 2 diabetes, we hypothesize that the combined addition of the SGLT2 inhibitor dapagliflozin with the DPP-4 inhibitor saxagliptin is effective and safe to revert from a BBIT to a BOT treatment regimen.

Official Title
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Effectiveness of Dapagliflozin + Saxagliptin to Revert From a Basal-bolus Insulin Treatment (BBIT) Regimen to a Basal Supported Oral Therapy (BOT) in Patients With Type 2 Diabetes

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Drug: Dapagliflozin 10 mg + Saxagliptin 5 mg
* Drug: Placebo 1 10 mg + Placebo 2 5 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 diabetes Age 18 - 75 years Anti-GAD antibodies negative (Glutamic Acid Decarboxylase) C-peptide levels ≥ 1.5 ng/mL Fasting blood glucose > 126 mg/dl HbA1c 8.0 - 10.5 % BMI 25.0 - 45.0 kg/m2 Previous therapy with BBIT (basal insulin and at least once daily bolus insulin) Exclusion Criteria: Use of any oral antidiabetic treatment except for metformin (i.e., sulphonylureas, DPP-IV inhibitors, thiazolidinediones, SGLT-2 inhibitors (Sodium dependent glucose transporter) or GLP-1 analogues (glucagone like peptide) within the last three months prior to Screening Repeated episodes of severe hypoglycaemia within the last six months prior to Screening History of diabetic ketoacidosis, precoma diabetica, or diabetic coma Treatment with any other investigational drug within the last three months before Screening Acute infections within the last four weeks prior to Screening Recurrent urogenital infections History of pancreatitis Anamnestic history of hypersensitivity to the study drugs or to drugs with similar chemical structures History of severe or multiple allergies Concomitant participation in other clinical trials Type 1 diabetes Cardiovascular disease Clinically relevant ventricular tachycardia or ventricular fibrillation, 3rd degree AV block or Torsades de Pointes or treatment with antiarrhythmic drugs. Percutaneous coronary intervention within the past 6 months. Any of the following within the past 6 months: myocardial infarction (MI), coronary artery bypass surgery; unstable angina; or stroke. Uncontrolled unstable angina pectoris or history of pericarditis, myocarditis, endocarditis. Congestive heart failure NYHA (New York Heart Association) class III or IV. Increased risk of thromboembolism, e.g. subjects with a history of deep leg vein thrombosis or family history of deep leg vein thrombosis, as judged by the Investigator. Malignancy including leukemia and lymphoma within the last 5y. Liver disease such as cirrhosis or chronic active hepatitis. Significant renal dysfunction (see also exclusion criteria laboratory abnormalities). State after kidney transplantation Endocrine disease: Acromegaly or treatment with growth hormone or similar drugs. Chronic oral or parenteral corticosteroid treatment (>7 consecutive days of treatment) within 8 weeks; thyroid hormone replacement is allowed if the dosage has been stable for at least 3 months and the TSH is within normal limits •Any of the following significant laboratory abnormalities: eGFR (as calculated by the MDRD equation) < 60 ml/min at Screening Fasting triglycerides >700 mg/dl (>7.9 mmol/l) Systolic blood pressure outside the range of 100-160 mmHg or diastolic blood pressure above 95 mmHg at Screening History of active substance abuse (including alcohol > 40g/day) within the past 2 years. Pregnancy or childbearing potential without adequate contraception Present therapy with systemic steroids Presence of psychiatric disorder or intake of anti-depressive or anti-psychotic agents with the exception of benzodiazepines and SSRIs/SNRI´s (selective serotonin reuptake inhibitor) Potentially unreliable subjects, and those judged by the investigator to be unsuitable for the study. Contraindications for Magnetic resonance (MR) scanning such as persons with cardiac pacemaker and implants out of metal or claustrophobia

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Verum<br>Dapagliflozin 10 mg + Saxagliptin 5 mg, each once daily, for 24 weeks | Drug: Dapagliflozin 10 mg + Saxagliptin 5 mg<br>* 24 weeks intervention with Dapagliflozin 10 mg + Saxagliptin 5 mg<br>* Other names: Forxiga + Onglyza;|
| Placebo Comparator: Placebo<br>Placebo 1 10 mg + Placebo 2 5 mg, each once daily, for 24 weeks | Drug: Placebo 1 10 mg + Placebo 2 5 mg<br>* 24 weeks intervention with Placebo 1 10 mg + Placebo 2 5 mg<br>* Other names: Placebo 1 + Placebo 2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of subjects achieving a HbA1c ≤ 7.5% and having a reversal from a BBIT to a BOT regimen | Percentage of subjects achieving a HbA1c ≤ 7.5% and having a reversal from a BBIT to a BOT regimen with treatment of dapagliflozin/saxagliptin or placebo | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| changes in HbA1c between groups | treatment of dapagliflozin/saxagliptin or placebo | 24 weeks | 
| changes in hypoglycaemic events between groups | treatment of dapagliflozin/saxagliptin or placebo | 24 weeks | 
| changes in fasting blood glucose between groups | treatment of dapagliflozin/saxagliptin or placebo | 24 weeks | 
| changes in daily insulin dose between groups | treatment of dapagliflozin/saxagliptin or placebo | 24 weeks | 
| changes in bodyweight between groups | treatment of dapagliflozin/saxagliptin or placebo | 24 weeks | 
| changes in body fat content between groups | treatment of dapagliflozin/saxagliptin or placebo | 24 weeks | 
| changes in body fat distribution between groups | treatment of dapagliflozin/saxagliptin or placebo | 24 weeks | 
| changes in liver fat content between groups | treatment of dapagliflozin/saxagliptin or placebo | 24 weeks | 
| changes in intra-nasal insulin-induced brain fMR (functional magnetic resonance) imaging results between groups | treatment of dapagliflozin/saxagliptin or placebo | 24 weeks | 
| changes in blood pressure between groups | treatment of dapagliflozin/saxagliptin or placebo | 24 weeks | 
| changes in the blood lipid profile between groups | treatment of dapagliflozin/saxagliptin or placebo | 24 weeks | 
| changes in microalbuminuria between groups | treatment of dapagliflozin/saxagliptin or placebo | 24 weeks | 
| changes in well being and disease perception between groups | treatment of dapagliflozin/saxagliptin or placebo | 24 weeks | 
| changes in fear of hypoglycemia between groups | treatment of dapagliflozin/saxagliptin or placebo | 24 weeks |