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A Multicenter, Randomized, Double-Blind, Active-Controlled, Phase 3 Trial to Evaluate the Efficacy and Safety of Saxagliptin in Combination with Metformin IR as Initial Therapy Compared to Saxagliptin Monotherapy and to Metformin IR Monotherapy in Subjects with Type 2 Diabetes who have Inadequate Glycaemic Control
Allocation: Randomized Endpoint Classification: Efficacy/Safety study Intervention Model: Parallel Assignment Masking: Double Blind Primary Purpose: Treatment
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Saxagliptin 5 mg + Metformin (500 mg with titration) | Experimental | Saxagliptin 5 mg once daily and metformin 500 mg once daily, then titrate. Acarbose will be used as rescue medication as needed. |
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| Saxagliptin 5 mg + Placebo | Active Comparator | Saxagliptin 5 mg once daily and Placebo 500 mg once daily, then titrate. Acarbose will be used as rescue medication as needed. |
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| Metformin (500 mg with titration) + Placebo | Active Comparator | Placebo 5 mg once daily and metformin 500 mg once daily, then titrate. Acarbose will be used as rescue medication as needed. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Saxagliptin 5 mg | Drug | Tablet, Oral, 5 mg, Once daily in the morning |
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| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in HbA1c From Baseline to Week 24 Provided That it is Prior to Rescue | To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to reduction in HbA1c (%) at the end of 24 weeks of double-blinded treatment. | Baseline to Week 24 (prior to rescue) |
| Measure | Description | Time Frame |
|---|---|---|
| Glycemic Response Defined as HbA1c < 7.0% at Week 24 | To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to the proportion of subjects achieving a therapeutic glycemic response defined as HbA1c < 7.0% at the end of 24 weeks of double-blinded treatment. | Week 24 (prior to rescue) |
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Inclusion Criteria:
1. Subjects with type 2 diabetes mellitus; 2. HbA1c ≥8% but ≤12%; 3.Fasting C-peptide ≥1.0 ng/ml; 4. Subject will be drug naïve; 5. Body mass index ≤40 kg/m2.
Exclusion Criteria:
1. Symptoms of poorly controlled diabetes; 2. Chronic or repeated intermittent corticosteroid treatment ; 3. Calculated creatinine clearance <60 ml/min or serum creatinine >132.6 μmol/L (>1.5 mg/dL) for men, >123.8 μmol/L (>1.4 mg/dL) for women; 4. Creatine Kinase ≥3x ULN; 5.Abnormal TSH value at screening will be further evaluated by free T4, subjects with an abnormal free T4 will be excluded; 6. History of administration of any antihyperglycaemic therapy for a total of 28 days or for more than three consecutive days or a total of seven non-consecutive days during the eight weeks prior to screening; 7. Current treatment with a strong CYP3A4/5 inhibitor; 8. Prior treatment with saxagliptin or any DPP-4 inhibitor; 9. Significant or history of cardiovascular disease, renal disease, psychiatric disorders, Immunocompromised individuals, hemoglobinopathies, liver disease, Pancreatitis.
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| Name | Affiliation | Role |
|---|---|---|
| Changyu Pan, Professor | The General Hospital of People's liberation Army | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Research Site | Beijing | China | ||||
| Research Site |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28926170 | Derived | Dou J, Ma J, Liu J, Wang C, Johnsson E, Yao H, Zhao J, Pan C. Efficacy and safety of saxagliptin in combination with metformin as initial therapy in Chinese patients with type 2 diabetes: Results from the START study, a multicentre, randomized, double-blind, active-controlled, phase 3 trial. Diabetes Obes Metab. 2018 Mar;20(3):590-598. doi: 10.1111/dom.13117. Epub 2017 Oct 26. |
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The study duration was up to 27 weeks, consisting of an initial screening period lasting up to 2 weeks, a 1-week lead-in period, and a 24-week treatment period. The number of subjects who signed the ICF is 1136, the number of subjects randomized is 640.
The study was conducted in 25 centers between 18 December 2014 and 03 August 2016.
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| ID | Title | Description |
|---|---|---|
| FG000 | METFORMIN + PLACEBO 5MG QD | |
| FG001 | SAXAGLIPTIN 5MG QD + METFORMIN | |
| FG002 | SAXAGLIPTIN 5MG QD + PLACEBO |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Placebo 5 mg for Saxagliptin | Drug | Tablet, Oral, 5 mg, Once daily in the morning |
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| Placebo 500 mg for metformin (with titration) | Drug | Tablet, 500 mg, Once daily in the evening the first two weeks and thereafter according to titration. |
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| Metformin 500 mg with titration | Drug | Tablet, 500 mg, Once daily in the evening the first two weeks and thereafter according to titration. |
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| Change From Baseline to Week 24 (Prior to Rescue) in Fasting Plasma Glucose | To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to reduction in fasting plasma glucose at the end of 24 weeks of double-blinded treatment. | Baseline to Week 24 prior to rescue |
| Change From Baseline to Week 24 (Prior to Rescue) in Area Under the Curve From 0-180 Minutes for Postprandial Glucose Response to a Meal Tolerance Test | To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to change in 180-minute postprandial glucose response to a meal tolerance test at the end of 24 weeks of double-blinded treatment. | Baseline to Week 24 prior to rescue |
| Glycemic Response Defined as HbA1c ≤ 6.5% at Week 24 | To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to the proportion of subjects achieving a therapeutic glycemic response defined as HbA1c ≤ 6.5% at the end of 24 weeks of double-blinded treatment. | Week 24 (prior to rescue) |
| Change From Baseline to Week 24 in 120-minute Postprandial Glucose Response to a Meal Tolerance Test | To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to change in 120-minute postprandial glucose response to a meal tolerance test at the end of 24 weeks of double-blinded treatment. | Baseline to Week 24 prior to rescue |
| Patients Rescued for Failing to Achieve Pre-specified Glycemic Targets or Discontinuation for Lack of Efficacy During the 24-week Double-blind Treatment Phase | To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to the proportion of subjects requiring rescue for failing to achieve pre-specified glycemic targets or discontinuing for lack of efficacy within the 24 weeks of double-blinded treatment. | Baseline to Week 24 |
| Changchun |
| China |
| Research Site | Chuangchun | China |
| Research Site | Fuzhou | China |
| Research Site | Guiyang | China |
| Research Site | Hangzhou | China |
| Research Site | Ha’erbin | China |
| Research Site | Hefei | China |
| Research Site | Jinan | China |
| Research Site | Nanchang | China |
| Research Site | Nanjing | China |
| Research Site | Shanghai | China |
| Research Site | Shijiazhuang | China |
| Research Site | Siping | China |
| Research Site | Tianjin | China |
| Research Site | Wuxi | China |
| Research Site | Yueyang | China |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | METFORMIN + PLACEBO 5MG QD | |
| BG001 | SAXAGLIPTIN 5MG QD + METFORMIN | |
| BG002 | SAXAGLIPTIN 5MG QD + PLACEBO | |
| BG003 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | Years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Number | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change From Baseline in HbA1c From Baseline to Week 24 Provided That it is Prior to Rescue | To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to reduction in HbA1c (%) at the end of 24 weeks of double-blinded treatment. | The full analysis set consisted of patients who were randomized, took at least 1 randomized study medication, and had both a baseline and at least 1 post-baseline efficacy assessment for the time point under consideration. | Posted | Least Squares Mean | Standard Error | % HbA1c | Baseline to Week 24 (prior to rescue) |
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| Secondary | Glycemic Response Defined as HbA1c < 7.0% at Week 24 | To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to the proportion of subjects achieving a therapeutic glycemic response defined as HbA1c < 7.0% at the end of 24 weeks of double-blinded treatment. | The full analysis set consisted of patients who were randomized, took at least 1 randomized study medication, and had both a baseline and at least 1 post-baseline efficacy assessment for the time point under consideration. | Posted | Number | Percentage of patients | Week 24 (prior to rescue) |
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| Secondary | Change From Baseline to Week 24 (Prior to Rescue) in Fasting Plasma Glucose | To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to reduction in fasting plasma glucose at the end of 24 weeks of double-blinded treatment. | The full analysis set consisted of patients who were randomized, took at least 1 randomized study medication, and had both a baseline and at least 1 post-baseline efficacy assessment for the time point under consideration. | Posted | Least Squares Mean | Standard Error | mmol/L | Baseline to Week 24 prior to rescue |
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| Secondary | Change From Baseline to Week 24 (Prior to Rescue) in Area Under the Curve From 0-180 Minutes for Postprandial Glucose Response to a Meal Tolerance Test | To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to change in 180-minute postprandial glucose response to a meal tolerance test at the end of 24 weeks of double-blinded treatment. | The full analysis set consisted of patients who were randomized, took at least 1 randomized study medication, had both a baseline and at least 1 post-baseline efficacy assessment for the time point under consideration, and participated in a meal tolerance test. | Posted | Least Squares Mean | Standard Error | mmol*min/L | Baseline to Week 24 prior to rescue |
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| Secondary | Glycemic Response Defined as HbA1c ≤ 6.5% at Week 24 | To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to the proportion of subjects achieving a therapeutic glycemic response defined as HbA1c ≤ 6.5% at the end of 24 weeks of double-blinded treatment. | The full analysis set consisted of patients who were randomized, took at least 1 randomized study medication, and had both a baseline and at least 1 post-baseline efficacy assessment for the time point under consideration. | Posted | Number | Percentage of patients | Week 24 (prior to rescue) |
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| Secondary | Change From Baseline to Week 24 in 120-minute Postprandial Glucose Response to a Meal Tolerance Test | To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to change in 120-minute postprandial glucose response to a meal tolerance test at the end of 24 weeks of double-blinded treatment. | The full analysis set consisted of patients who were randomized, took at least 1 randomized study medication, had both a baseline and at least 1 post-baseline efficacy assessment for the time point under consideration, and participated in a meal tolerance test. | Posted | Least Squares Mean | Standard Error | mmol/L | Baseline to Week 24 prior to rescue |
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| Secondary | Patients Rescued for Failing to Achieve Pre-specified Glycemic Targets or Discontinuation for Lack of Efficacy During the 24-week Double-blind Treatment Phase | To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to the proportion of subjects requiring rescue for failing to achieve pre-specified glycemic targets or discontinuing for lack of efficacy within the 24 weeks of double-blinded treatment. | The full analysis set consisted of patients who were randomized, took at least 1 randomized study medication, and had both a baseline and at least 1 post-baseline efficacy assessment for the time point under consideration. | Posted | Number | Percentage of patients | Baseline to Week 24 |
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Total number at risk is number of patients in safety analysis set (out of 640 randomized, 1 did not take study drug).
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | METFORMIN + PLACEBO 5MG QD | 11 | 210 | 30 | 210 | |||
| EG001 | SAXAGLIPTIN 5MG QD + METFORMIN | 4 | 215 | 37 | 215 | |||
| EG002 | SAXAGLIPTIN 5MG QD + PLACEBO | 12 | 214 | 21 | 214 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Acute myocardial infarction | Cardiac disorders | MedDRA 19.0 | Systematic Assessment |
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| Cataract | Eye disorders | MedDRA 19.0 | Systematic Assessment |
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| Diabetic retinopathy | Eye disorders | MedDRA 19.0 | Systematic Assessment |
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| Gastric ulcer | Gastrointestinal disorders | MedDRA 19.0 | Systematic Assessment |
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| Gastritis | Gastrointestinal disorders | MedDRA 19.0 | Systematic Assessment |
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| Large intestine polyp | Gastrointestinal disorders | MedDRA 19.0 | Systematic Assessment |
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| Pancreatic mass | Gastrointestinal disorders | MedDRA 19.0 | Systematic Assessment |
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| Bile duct obstruction | Hepatobiliary disorders | MedDRA 19.0 | Systematic Assessment |
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| Cholecystitis | Hepatobiliary disorders | MedDRA 19.0 | Systematic Assessment |
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| Cholecystitis acute | Hepatobiliary disorders | MedDRA 19.0 | Systematic Assessment |
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| Cholelithiasis | Hepatobiliary disorders | MedDRA 19.0 | Systematic Assessment |
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| Hepatitis alcoholic | Hepatobiliary disorders | MedDRA 19.0 | Systematic Assessment |
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| Chronic hepatitis B | Infections and infestations | MedDRA 19.0 | Systematic Assessment |
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| Localised infection | Infections and infestations | MedDRA 19.0 | Systematic Assessment |
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| Tuberculosis | Infections and infestations | MedDRA 19.0 | Systematic Assessment |
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| Humerus fracture | Injury, poisoning and procedural complications | MedDRA 19.0 | Systematic Assessment |
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| Injury | Injury, poisoning and procedural complications | MedDRA 19.0 | Systematic Assessment |
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| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA 19.0 | Systematic Assessment |
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| Adrenal adenoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 19.0 | Systematic Assessment |
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| Adrenal neoplasm | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 19.0 | Systematic Assessment |
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| Plasma cell myeloma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 19.0 | Systematic Assessment |
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| Cerebral infarction | Nervous system disorders | MedDRA 19.0 | Systematic Assessment |
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| Diabetic neuropathy | Nervous system disorders | MedDRA 19.0 | Systematic Assessment |
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| Diabetic nephropathy | Renal and urinary disorders | MedDRA 19.0 | Systematic Assessment |
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| Glomerulonephritis chronic | Renal and urinary disorders | MedDRA 19.0 | Systematic Assessment |
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| Ureterolithiasis | Renal and urinary disorders | MedDRA 19.0 | Systematic Assessment |
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| Pulmonary mass | Respiratory, thoracic and mediastinal disorders | MedDRA 19.0 | Systematic Assessment |
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| Hypertension | Vascular disorders | MedDRA 19.0 | Systematic Assessment |
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| Phlebitis | Vascular disorders | MedDRA 19.0 | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders | MedDRA 19.0 | Systematic Assessment |
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| Upper respiratory tract infection | Infections and infestations | MedDRA 19.0 | Systematic Assessment |
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| Hyperlipidaemia | Metabolism and nutrition disorders | MedDRA 19.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Eva Johnsson, MD, PhD | AstraZeneca | 46 31 7762484 | Eva.Johnsson@astrazeneca.com |
| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| D004700 | Endocrine System Diseases |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| C502994 | saxagliptin |
| D008687 | Metformin |
| ID | Term |
|---|---|
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
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| Male |
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| Mean Difference (Net) |
| -0.213 |
| Standard Error of the Mean |
| 0.1005 |
| 2-Sided |
| 95 |
| -0.410 |
| -0.016 |
| Superiority or Other |
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