Type 2 Diabetes Mellitus
Conditions
Keywords
Type 2 Diabetes Mellitus, Insulin, Dipeptidyl-Peptidase 4 Inhibitors, Metformin,saxagliptin,Endocrine System Diseases
Brief summary
A Multicenter, Randomized, Double-Blind, Phase 3b Trial to Evaluate the Efficacy and Safety of Saxagliptin Added to Insulin Monotherapy or to Insulin in Combination with Metformin in Chinese Subjects in China with Type 2 Diabetes Who Have Inadequate Glycaemic Control on Insulin Alone or on Insulin in Combination with Metformin
Detailed description
Study Design: Randomized, prospective, double-blind, two-arm, parallel group, multi-center trial. Target Subject Population: Subjects aged ≥18 who have type 2 diabetes (HbA1c of ≥7.5% and ≤11.0% and FPG\<270 mg/dL (15 mmol/L)) on stable baseline therapy (insulin alone or insulin combined with metformin, with insulin at doses of ≥20 and ≤150 units per day total) for at least eight weeks at the time of screening. Insulin may be long-acting, intermediate-acting, or pre-mixed. 444 patients are planned to be randomized. Investigational Product, Dosage and Mode of administration: Active treatment will comprise Saxagliptin 5 mg tablets once daily. Comparator, Dosage and Mode of administration: Matching placebo tablets will be used as comparator. Duration of Treatment: The study is divided to a single blind placebo lead in period of 8 weeks and a double-blind treatment phase of 24 weeks. Patients will be rescued based on high FPG values. Statistical Methods: The analysis of the primary endpoint of change from baseline to week 24 of treatment in HbA1c will consist of an analysis of covariance (ANCOVA) model with treatment group and metformin use at enrolment as fixed effects and baseline HbA1c value as a covariate. The analysis will be performed on the Full analysis Set (FAS) consisting of randomised subjects who received at least 1 randomised investigational product dose and had at least 1 non-missing baseline and 1 post-baseline efficacy assessment. Within the framework of the ANCOVA model, point estimates and two-sided 95% confidence intervals (CI) for the mean change within each treatment group as well as for the difference in mean change between treatment groups will be calculated. The Per Protocol (PP) analysis set is a subset of the full analysis set and will consist of subjects who do not deviate from the terms of the protocol which may affect the study outcome significantly as specified in the pre-defined protocol deviation list prior to unblinding the study. All decisions to exclude subjects from the primary data set will be made prior to the unblinding of the study. The primary efficacy endpoint of change from baseline in HbA1c, demographics, and baseline diabetes related characteristics and all secondary efficacy endpoints are to be analyzed using the PP Data Set. The analyses of PPG AUC, 120 minute PPG, FPG and mean total daily dose of insulin will also be done on the FAS and use a similar ANCOVA model as described above. Subjects achieving a therapeutic glycaemic response (A1C \<7%) will be analyzed using a Fisher's exact test and will include exact 95% confidence intervals. The FPG analyses will utilize the mean of the latest two FPG values prior to randomization as the baseline value. The endpoint for the FPG analysis will be the mean of the week 20 and week 24 FPG values. All analyses (except the analysis of mean total daily dose of insulin) will utilize only observations at visits prior to rescue or where the subject's mean total daily dose of insulin has not increased by \>10% from baseline. If an observation at week 24 is missing or does not meet these criteria, the latest post-baseline value that does will be carried forward (LOCF). The analysis of mean total daily dose of insulin will utilize the latest, non-missing, post-baseline value regardless of rescue. Multiplicity for the primary and secondary endpoints will be controlled via a hierarchical testing procedure that utilizes the full alpha (0.05) for each test. The sequence of testing will be: 1. Change from baseline in HbA1c at Week 24. 2. Change from baseline in PPG AUC at Week 24.3. Change from baseline in 120 minute PPG at Week 24. 4. Proportion of subjects achieving HbA1c \<7.0% at Week 24. 5. Change from baseline in FPG to the mean at Week 20 and Week 24. 6. Change from baseline in MTDDI at Week 24.
Interventions
DRUGSaxagliptin 5mg
Saxagliptin 5mg (plus stable insulin dose), given orally once daily (24 weeks); subjects stratified by use of stable metformin dose; flexible insulin dose (as needed for rescue).
Placebo tablets (plus stable insulin dose), given orally once daily (24 weeks); subjects stratified by use of stable metformin dose; flexible insulin dose (as needed for rescue).
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
1. Provision of informed consent before participating in the study. 2. Diagnosed with type 2 diabetes. 3. Inadequate glycemic control (screening: HbA1c ≥7.5% and ≤11.0% and FPG\<270 mg/dL (15mmol/L). At Day -4 visit, HbA1c ≥7.5% and ≤10.5%. and FPG\<270 mg/dL (15mmol/L)). 4. On a stable dose of insulin for 8 weeks or longer prior to screening. 5. If taking metformin, subjects should have been taking the same daily dose for 8 weeks or longer prior to screening. 6. Insulin type should be intermediate-acting or long-acting (basal) or premixed (premixed formulation may include short- or rapid-acting insulin as one component). 7. Body mass index ≤45 kg/m\^2.
Exclusion criteria
1. Women of childbearing potential unable or unwilling to use acceptable birth control. 2. Women who are pregnant or breastfeeding. 3. Symptoms of poorly controlled diabetes. including but not limited to, marked polyuria and polydipsia with greater than 10% weight loss during the last three months prior to screening or other signs and symptoms. 4. Significant cardiovascular history defined as: myocardial infarction, coronary angioplasty or bypass graft, valvular disease or repair, unstable clinical significant arrhythmia, unstable angina pectoris, transient ischemic attack, or cerebrovascular accident. 5. Congestive heart failure 6. Chronic or repeated intermittent corticosteroid treatment (subjects receiving stable doses of replacement corticosteroid (except dexamethasone) therapy may be enrolled). 7. History of unstable or rapidly progressing renal disease. 8. History of alcohol or drug abuse within the previous year. 9. Unstable major psychiatric disorders. 10. History of hemoglobinopathies 11. Immunocompromised status 12. Severe liver disease. 13. In subjects treated with insulin alone a calculated creatinine clearance \<50 ml/min. In patients treated with insulin in combination with metformin a calculated creatinine clearance \<60 ml/min or serum creatinine \> 1.5 mg/dL in males or \> 1.4mg/dL in females. 14. Anemia
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change in HbA1c From Baseline to Week 24 | Baseline to 24 weeks |
Secondary
| Measure | Time frame |
|---|---|
| Change in Postprandial Glucose AUC From Baseline to Week 24 During a Meal Tolerance Test | Baseline to 24 weeks |
| Analysis of Change in 120-minute PPG From Baseline to Week 24 During a Meal Tolerance Test | Baseline to 24 weeks |
| Percentage of Patients Achieving a Therapeutic Glycaemic Response of HbA1c <7% | At Week 24 |
| The Analysis of Change in Fasting Plasma Glucose From Baseline to Week 24 (This Was the Average of Weeks 20 and 24) | Baseline to Average of Weeks 20 and 24 |
| Analysis of Change in Mean Total Daily Dose of Insulin From Baseline to Week 24 | Baseline to 24 weeks |
Countries
China
Participant flow
Recruitment details
This study was performed at 22 sites in the People's Republic of China (PRC).The first patient was enrolled on 07 May 2014 and the last patient completed the study on 26 February 2016. The study was divided into a single-blind placebo lead-in period of 8 weeks, a treatment period of 24 weeks and a follow-up phase of 4 weeks.
Pre-assignment details
953 patients were enrolled, of which 641 patients took at least 1 dose of study drug and entered the lead-in period. A total of 312 patients did not enter the lead-in period (289 did not fulfill eligibility criteria, 21 due to subject decision, 1 each for severe non-compliance to protocol and other reasons) and 466 patients were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Saxagliptin Plus Insulin Saxagliptin 5 mg plus insulin | 232 |
| Vs. Placebo Plus Insulin Patients receiving placebo 5 mg plus insulin | 230 |
| Total | 462 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 3 |
| Overall Study | Did not take study medication | 0 | 1 |
| Overall Study | Other listed | 2 | 1 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Study specific discontinuation criteria | 6 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 12 |
Baseline characteristics
| Characteristic | Total | Vs. Placebo Plus Insulin | Saxagliptin Plus Insulin |
|---|---|---|---|
| 0-180 min Post Prandial Glucose AUC | 44661.5 mg*min/dL STANDARD_DEVIATION 8772.22 | 43851.4 mg*min/dL STANDARD_DEVIATION 9051.26 | 45457.6 mg*min/dL STANDARD_DEVIATION 8433.08 |
| 120-min Post Prandial Glucose | 274.0 mg/dL STANDARD_DEVIATION 60.76 | 270.0 mg/dL STANDARD_DEVIATION 63.3 | 278.0 mg/dL STANDARD_DEVIATION 58 |
| Age, Continuous | 59.1 Years STANDARD_DEVIATION 8.05 | 58.9 Years STANDARD_DEVIATION 8.17 | 59.3 Years STANDARD_DEVIATION 7.93 |
| Baseline HbA1C | 8.53 % STANDARD_DEVIATION 0.69 | 8.53 % STANDARD_DEVIATION 0.7 | 8.52 % STANDARD_DEVIATION 0.69 |
| Duration of diabetes | 13.4 Years STANDARD_DEVIATION 6.83 | 13.3 Years STANDARD_DEVIATION 6.35 | 13.4 Years STANDARD_DEVIATION 7.28 |
| Fasting C-peptide | 1.020 ng/dL STANDARD_DEVIATION 0.55 | 1.012 ng/dL STANDARD_DEVIATION 0.58 | 1.029 ng/dL STANDARD_DEVIATION 0.52 |
| Fasting Glucagon | 40.119 pg/dL STANDARD_DEVIATION 22.39 | 40.231 pg/dL STANDARD_DEVIATION 21.06 | 40.007 pg/dL STANDARD_DEVIATION 23.68 |
| Fasting Plasma Glucose (FPG) | 167.64 mg/dL STANDARD_DEVIATION 32.1 | 167.34 mg/dL STANDARD_DEVIATION 32.86 | 167.94 mg/dL STANDARD_DEVIATION 31.39 |
| Mean Tolerated Daily Dose of Insulin | 38.7 Insulin Dose Units STANDARD_DEVIATION 15.6 | 38.9 Insulin Dose Units STANDARD_DEVIATION 14.68 | 38.6 Insulin Dose Units STANDARD_DEVIATION 16.49 |
| Metformin use at enrolment No | 153 Participants | 76 Participants | 77 Participants |
| Metformin use at enrolment Yes | 309 Participants | 154 Participants | 155 Participants |
| Sex: Female, Male Female | 253 Participants | 130 Participants | 123 Participants |
| Sex: Female, Male Male | 209 Participants | 100 Participants | 109 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 96 / 231 | 89 / 234 |
| serious Total, serious adverse events | 14 / 231 | 12 / 234 |
Outcome results
Primary
Change in HbA1c From Baseline to Week 24
Time frame: Baseline to 24 weeks
Population: 229 and 227 indicate the number of participants with non-missing baseline and Week 24 values in the Full Analysis Set of 232 and 230 respectively.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Saxagliptin Plus Insulin | Change in HbA1c From Baseline to Week 24 | -0.64 Percentage change |
| Vs. Placebo Plus Insulin | Change in HbA1c From Baseline to Week 24 | -0.06 Percentage change |
p-value: <0.00195% CI: [-0.72, -0.45]ANCOVA
Secondary
Analysis of Change in 120-minute PPG From Baseline to Week 24 During a Meal Tolerance Test
Time frame: Baseline to 24 weeks
Population: 215 and 211 indicate the number of participants with non-missing baseline and Week 24 values in the Full Analysis Set of 232 and 230 respectively.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Saxagliptin Plus Insulin | Analysis of Change in 120-minute PPG From Baseline to Week 24 During a Meal Tolerance Test | -30.28 mg/dL |
| Vs. Placebo Plus Insulin | Analysis of Change in 120-minute PPG From Baseline to Week 24 During a Meal Tolerance Test | 8.84 mg/dL |
p-value: <0.00195% CI: [-49.41, -28.82]ANCOVA
Secondary
Analysis of Change in Mean Total Daily Dose of Insulin From Baseline to Week 24
Time frame: Baseline to 24 weeks
Population: 232 and 230 indicate the number of participants with non-missing baseline and Week 24 values in the Full Analysis Set of 232 and 230 respectively.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Saxagliptin Plus Insulin | Analysis of Change in Mean Total Daily Dose of Insulin From Baseline to Week 24 | -0.09 IU |
| Vs. Placebo Plus Insulin | Analysis of Change in Mean Total Daily Dose of Insulin From Baseline to Week 24 | 0.04 IU |
p-value: 0.4395% CI: [-0.44, 0.19]ANCOVA
Secondary
Change in Postprandial Glucose AUC From Baseline to Week 24 During a Meal Tolerance Test
Time frame: Baseline to 24 weeks
Population: 213 and 206 indicate the number of participants with non-missing baseline and Week 24 values in the Full Analysis Set of 232 and 230 respectively.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Saxagliptin Plus Insulin | Change in Postprandial Glucose AUC From Baseline to Week 24 During a Meal Tolerance Test | -4702.2 mg*min/dL |
| Vs. Placebo Plus Insulin | Change in Postprandial Glucose AUC From Baseline to Week 24 During a Meal Tolerance Test | 1431.0 mg*min/dL |
p-value: <0.00195% CI: [-7668.5, -4597.9]ANCOVA
Secondary
Percentage of Patients Achieving a Therapeutic Glycaemic Response of HbA1c <7%
Time frame: At Week 24
Population: 229 and 227 indicate the number of participants with non-missing baseline and Week 24 values in the Full Analysis Set of 232 and 230 respectively.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Saxagliptin Plus Insulin | Percentage of Patients Achieving a Therapeutic Glycaemic Response of HbA1c <7% | 11.4 % of participants |
| Vs. Placebo Plus Insulin | Percentage of Patients Achieving a Therapeutic Glycaemic Response of HbA1c <7% | 3.5 % of participants |
p-value: 0.00295% CI: [3.1, 12.6]Difference in proportions
Secondary
The Analysis of Change in Fasting Plasma Glucose From Baseline to Week 24 (This Was the Average of Weeks 20 and 24)
Time frame: Baseline to Average of Weeks 20 and 24
Population: 232 and 229 indicate the number of participants with non-missing baseline and Week 24 values in the Full Analysis Set of 232 and 229 for this outcome measure respectively.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Saxagliptin Plus Insulin | The Analysis of Change in Fasting Plasma Glucose From Baseline to Week 24 (This Was the Average of Weeks 20 and 24) | -11.23 mg/dL |
| Vs. Placebo Plus Insulin | The Analysis of Change in Fasting Plasma Glucose From Baseline to Week 24 (This Was the Average of Weeks 20 and 24) | 4.65 mg/dL |
p-value: <0.00195% CI: [-21.53, -10.22]ANCOVA