Effect of Saxagliptin in Addition to Dapagliflozin and Metformin on Insulin Resistance, Islet Cell Dysfunction, and Metabolic Control in Subjects With Type 2 Diabetes Mellitus on Previous Metformin Treatment
Trial Snapshot
- Phase
- Phase 4
- Status
- Completed
- Sponsor
- Enrollment
- 64
- Locations
- 1
- Primary Endpoint
- Glucagon / insulin ratio during hyperglycaemic clamp phase (AUCGluc270-390min / AUCIns270-390min)
Study Overview
Brief Summary
The purpose of this study is to evaluate alpha- and beta-cell function during combination treatment with saxagliptin in addition to dapagliflozin and metformin compared to placebo in addition to dapagliflozin and metformin in subjects with T2DM on stable metformin background therapy.
Detailed Description
List of Abbreviations AE Adverse event ALT Alanine aminotransferase ANOVA Analysis of variance APTT Activated partial thromboplastin time AST Aspartate aminotransferase AUCins Area under the serum insulin concentration time curve BMI Body mass index CRF Case report form CTA Clinical trial application ECG Electrocardiogram FSFV First subject first visit GCP Good clinical practice GIR Glucose infusion rate GIRmax Maximum glucose infusion rate HbA1C N-(1-deoxy)-fructosyl-haemoglobin HBsAg Hepatitis B surface antigen HIV Human immunodeficiency virus ICH International conference on harmonisation IEC Independent ethics committee INR International normalised ratio IRB Institutional review board IU International unit i.v. Intravenous(ly) LSFV Last subject first visit LSLV Last subject last visit MedDRA Medical Dictionary of Regulatory Activities OAD Oral antidiabetic drug q.d. daily SAE Serious adverse event SAP Statistical analysis plan s.c. Subcutaneous(ly) SMPG self-measured plasma glucose SOP Standard operating procedure WHO-DDE World Health Organization Drug Dictionary Enhanced
Under physiological conditions blood glucose is kept within a narrow range by complex interactions of several signalling pathways. In this context, fine-tuning of alpha- and beta cell activity is fundamental to avoid excessive metabolic excursions. The pathogenesis of type 2 diabetes mellitus (T2DM) is driven by insulin resistance, followed by an increasing imbalance between alpha and beta cell activity which is characterised by relative insulin deficiency and increased glucagon secretion especially in the postprandial state.
Individual arrangement of complementary antidiabetic drugs in the escalation of pharmacological intervention in T2DM is a major challenge. There is substantial need to provide a scientific rationale for the best effective combination of antidiabetic drugs with regard to their potency to address different aspects in the pathophysiology of T2DM. Therefore, studies evaluating potential synergistic and/or complementary effects of pharmacological interventions in T2DM deem imperative.
This study aims to evaluate the effect of the DPP-IV inhibitor saxagliptin (as compared to placebo) in addition to the SGLT-2 inhibitor dapagliflozin on insulin resistance, pancreatic alpha and beta cell function.
Triple therapy with metformin, SGLT-2 inhibitors, and DPP-IV inhibitors was shown to be efficacious and safe in several studies and has been approved for the treatment of T2DM by the European Medical Agency. Therefore, subjects with T2DM on a stable metformin background therapy will be enrolled in this trial.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 30 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Diabetes mellitus type 2 for at least three months prior to Screening
- •HbA1c 7.0%-9.9%, both inclusive
- •Treatment with metformin (daily dose 1500 - 3000 mg)
- •Age 30-75 years, both inclusive
- •BMI 25-35 kg/m^2, both inclusive
Exclusion Criteria
- •Use of any oral antidiabetic treatment except for metformin (i.e., sulphonylureas, DPP-IV inhibitors, thiazolidinediones, SGLT-2 inhibitors) within the last three months prior to Screening
- •Use of insulin or GLP-1 analogues within three months prior to Screening
- •Treatment with any other investigational drug within three months before screening
- •History of diabetes mellitus type 1
- •Acute infections within the last two weeks prior to Screening
- •Anamnestic history of hypersensitivity to the study drugs or to drugs with similar chemical structures
- •History of severe or multiple allergies
- •GFR (as calculated by the Cockroft-Gault equation) < 60 ml/min at Screening
- •State after kidney transplantation
- •Laboratory safety value(s) outside the reference range and deemed clinically relevant by the Investigator
- •Sexually active woman of childbearing age not practicing a highly effective method of birth control as defined as those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, hormonal IUDs, sexual abstinence or vasectomised partner
- •Pregnancy or breast feeding
- •Systolic blood pressure outside the range of 100-160 mmHg or diastolic blood pressure above 90 mmHg at Screening
- •Acute myocardial infarction or cerebral event (stroke/TIA) within six months prior to Screening
- •Uncontrolled unstable angina pectoris or history of pericarditis, myocarditis, endocarditis
- •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
- •Hemodynamic relevant aortic stenosis, Aortic aneurysm
- •Repeated episodes of severe hypoglycaemia within six months prior to Screening
- •History of diabetic ketoacidosis, praecoma diabeticum, or diabetic coma
- •Recurrent urogenital infections
- •History of pancreatitis
- •Progressive fatal disease
- •Elective surgery planned during study participation
- •Acute or scheduled investigation with iodine containing radiopaque material
- •History of drug or alcohol abuse in the past two years
- •Donation of blood, major blood loss (>=500 ml), or major surgery within the last three months prior to Screening
- •Active hepatitis B, measured by positive tests of surface antigen HBsAg and/or active hepatitis C, measured by positive hepatitis C virus antibody tests (HCV) at Screening
- •Positive human immunodeficiency virus (HIV) antibodies or HIV 1 Ag at Screening
Arms & Interventions
Saxagliptin
Metformin and Dapagliflozin background therapy
Intervention: Saxagliptin (Drug)
Placebo
Metformin and Dapagliflozin background therapy
Intervention: Placebo for Saxagliptin (Drug)
Outcomes
Primary Outcomes
Glucagon / insulin ratio during hyperglycaemic clamp phase (AUCGluc270-390min / AUCIns270-390min)
Time Frame: at baseline (Day 0) as well as after Treatment Phase 1 (after 30 days) and after Treatment Phase 2 (after 60 days)
Secondary Outcomes
- First phase glucagon release during hyperglycaemic clamp phase (AUCGluc270-290min; pg/ml*min)(at baseline (Day 0) as well as after Treatment Phase 1 (after 30 days) and after Treatment Phase 2 (after 60 days))
- Second phase insulin release during hyperglycaemic clamp phase (AUCIns290-390min; pmol/l*min)(at baseline (Day 0) as well as after Treatment Phase 1 (after 30 days) and after Treatment Phase 2 (after 60 days))
- First Phase glucagon / insulin ratio during hyperglycaemic clamp phase (AUCGluc270-290min / AUCIns270-290min)(at baseline (Day 0) as well as after Treatment Phase 1 (after 30 days) and after Treatment Phase 2 (after 60 days))
- Second Phase glucagon / insulin ratio during hyperglycaemic clamp phase (AUCGluc290-390min / AUCIns290-390min)(at baseline (Day 0) as well as after Treatment Phase 1 (after 30 days) and after Treatment Phase 2 (after 60 days))
- Intact proinsulin release during hyperglycaemic clamp (AUCIP270-390min ; pmol/l*min)(at baseline (Day 0) as well as after Treatment Phase 1 (after 30 days) and after Treatment Phase 2 (after 60 days))
- Insulin / proinsulin ratio during hyperglycaemic clamp (AUCIns270-390min / AUCIP270-390min)(at baseline (Day 0) as well as after Treatment Phase 1 (after 30 days) and after Treatment Phase 2 (after 60 days))
- C-Peptide release during hyperglycaemic clamp (AUCC-Pep270-390min ; pmol/l*min)(at baseline (Day 0) as well as after Treatment Phase 1 (after 30 days) and after Treatment Phase 2 (after 60 days))
- C-Peptide/Insulin ratio during hyperglycaemic clamp (AUCC-Pep270-390min / AUCIP270-390min)(at baseline (Day 0) as well as after Treatment Phase 1 (after 30 days) and after Treatment Phase 2 (after 60 days))
- M-Value during euglycaemic-hyperinsulinaemic clamp phase (mg/kg*min)(at baseline (Day 0) as well as after Treatment Phase 1 (after 30 days) and after Treatment Phase 2 (after 60 days))
- HOMAIR Index(at baseline (Day 0) as well as after Treatment Phase 1 (after 30 days) and after Treatment Phase 2 (after 60 days))
- Body Weight (kg)(at baseline (Day 0) as well as after Treatment Phase 1 (after 30 days) and after Treatment Phase 2 (after 60 days))
- Fasting Adiponectin (µg/ml)(at baseline (Day 0) as well as after Treatment Phase 1 (after 30 days) and after Treatment Phase 2 (after 60 days))
- Fasting Plasma Glucose (mg/dl)(at baseline (Day 0) as well as after Treatment Phase 1 (after 30 days) and after Treatment Phase 2 (after 60 days))
- HbA1C (mmol/mol; %)(at baseline (Day 0) as well as after Treatment Phase 1 (after 30 days) and after Treatment Phase 2 (after 60 days))
- QuantoseTM Score(at baseline (Day 0) as well as after Treatment Phase 1 (after 30 days) and after Treatment Phase 2 (after 60 days))
- Blood Lipids (Triglycerides [mg/dl]; total, HDL, LDL cholesterol [mg/dl])(at baseline (Day 0) as well as after Treatment Phase 1 (after 30 days) and after Treatment Phase 2 (after 60 days))
- Glucagon release during hyperglycaemic clamp phase (AUCGluc270-390min; pg/ml*min)(at baseline (Day 0) as well as after Treatment Phase 1 (after 30 days) and after Treatment Phase 2 (after 60 days))
- First phase insulin release during hyperglycaemic clamp phase (AUCIns270-290min; pmol/l*min)(at baseline (Day 0) as well as after Treatment Phase 1 (after 30 days) and after Treatment Phase 2 (after 60 days))
Investigators
Prof. Dr. Thomas Forst
Chief Executive Officer (Prof. Dr.)
Profil Mainz GmbH & Co KG