Type 2 Diabetes Mellitus
Conditions
Keywords
diabetes, exenatide, Byetta, sitagliptin, Januvia, Amylin, Lilly
Brief summary
The purpose of this study is to determine whether ceasing sitagliptin and switching to exenatide and metformin is non-inferior to adding exenatide to sitagliptin and metformin, in those patients with type 2 diabetes who are experiencing inadequate glycemic control with a combination of sitagliptin and metformin.
Interventions
DRUGexenatide and sitagliptin
exenatide-subcutaneous injection, 5mcg (4 weeks) followed by 10mcg (16 weeks), twice a day; sitagliptin-100mg tablet orally once a day
exenatide-subcutaneous injection, 5mcg (4 weeks) followed by 10mcg (16 weeks), twice a day; placebo-tablet orally once a day
Sponsors
Eli Lilly and Company
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Present with type 2 diabetes * Patients have been treated with a stable dose of the following for at least 3 months prior to screening: * 100 mg/day sitagliptin and * ≥1500 mg/day metformin, or maximum tolerated dose (extended release or immediate-release). * Have inadequate glycemic control as evidenced by an HbA1c between 7.1% and 9%, inclusive. * Have a body mass index (BMI) ≥20 kg/m2 and \<45 kg/m2
Exclusion criteria
* Are currently enrolled in, or discontinued within the last 30 days (or longer, if local guidelines require) from, a clinical trial involving an off-label use of an investigational drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study. * Have previously completed or withdrawn from this study or any other study investigating exenatide. * Have a known allergy or hypersensitivity to exenatide, sitagliptin or excipients contained in exenatide or sitagliptin. * Used drugs for weight loss (for example, orlistat, sibutramine, phenylpropanolamine, or similar over-the-counter medications) within 1 month of screening. * Are currently treated with any of the following excluded medications: * Thiazolidinediones (TZD) within 3 months of screening. * Sulfonylurea (SU) within 3 months of screening. * Dipeptidyl peptidase-4 \[DPP-4\] inhibitors, with the exception of sitagliptin, within 3 months of screening. * Meglitinide derivatives (for example, repaglinide or nateglinide) within 3 months of screening. * Alpha-glucosidase inhibitors (for example, miglitol or acarbose) within 3 months of screening. * Exogenous insulin within the 3 months prior to screening. * Drugs that directly affect gastrointestinal motility, including, but not limited to: metoclopramide, cisapride, and chronic macrolide antibiotics. * Systemic corticosteroids (excluding topical and inhaled preparations) by oral, intravenous (IV), or intramuscular (IM) route used regularly (for longer than 1 month) or used within 1 month immediately prior to screening. * Any other oral antidiabetic (OAD) agent, other than sitagliptin or metformin, within 3 months prior to screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c (Percent) | Baseline to 20 Weeks | Change in HbA1c from baseline to endpoint (Week 20); difference of base percent values \[X% - Y%\] |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Achieving HbA1c <7.0% | Baseline to 20 Weeks | Percentage of patients whose baseline HbA1c was \>=7.0% achieving HbA1c \<7.0% at endpoint (Week 20) |
| Percentage of Patients Achieving HbA1c <=6.5% | Baseline to 20 Weeks | Percentage of patients whose baseline HbA1c was \> 6.5% achieving HbA1c \<=6.5% at endpoint (Week 20) |
| Change in FSG (mmol/L) | Baseline to 20 Weeks | Change in fasting serum glucose (FSG) from baseline to endpoint (Week 20) |
| Change in Body Weight (kg) | Baseline to 20 Weeks | Change in body weight from baseline to endpoint (Week 20) |
| Change in Waist Circumference (cm) | Baseline to 20 Weeks | Change in waist circumference from baseline to endpoint (Week 20) |
| Waist-to-Hip Ratio | Baseline to 20 Weeks | Change in waist-to-hip ratio from baseline to endpoint (Week20) |
| SMBG (mmol/L) | Baseline to 20 Weeks | 7 point Self Monitored Blood Glucose Profiles - daily mean value (Week 20) |
| Percentage of Patients Achieving HbA1c <=7.0% | Baseline to 20 Weeks | Percentage of patients whose baseline HbA1c was \> 7.0% achieving HbA1c \<=7.0% at endpoint (Week 20) |
| Change in HDL (mmol/L) | Baseline to 20 Weeks | Change in high-density lipoprotein (HDL) cholesterol from baseline to endpoint (Week 20) |
| Change in LDL (mmol/L) | Baseline to 20 Weeks | Change in low-density lipoprotein (LDL) cholesterol from baseline to endpoint (Week 20) |
| Change in Total Cholesterol (mmol/L) | Baseline to 20 Weeks | Change in total cholesterol from baseline to endpoint (Week 20) |
| Incidence of Hypoglycemia (Overall) | Baseline to 20 Weeks | Incidence of hypoglycemic episodes experienced overall during the study |
| Incidence of Severe Hypoglycemia(Overall) | Baseline to 20 Weeks | Incidence of severe hypoglycemia experienced overall during the study |
| Incidence of Nocturnal Hypoglycemia (Overall) | Baseline to 20 Weeks | Incidence of nocturnal hypoglycemia experienced overall during the study |
| Incidence of Confirmed Hypoglycemia(Overall) | Baseline to 20 Weeks | Incidence of confirmed hypoglycemia experienced overall during the study |
| Change in Triglycerides (mmol/L) | Baseline to 20 Weeks | Change in triglycerides from baseline to endpoint (Week 20) |
Countries
Argentina, Australia, Germany, Greece, India, Mexico, South Korea
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Exenatide + Placebo Exenatide-subcutaneous injection, 5mcg (4 weeks) followed by 10mcg (16 weeks), twice a day; Placebo-tablet orally once a day. | 97 |
| Exenatide + Sitagliptin Exenatide-subcutaneous injection, 5mcg (4 weeks) followed by 10mcg (16 weeks), twice a day; Sitagliptin-100mg tablet orally once a day. | 111 |
| Total | 208 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 10 | 5 |
| Overall Study | Entry Criteria Not Met | 1 | 2 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Physician Decision | 3 | 1 |
| Overall Study | Protocol Violation | 3 | 3 |
| Overall Study | Subject Decision | 7 | 2 |
Baseline characteristics
| Characteristic | Exenatide + Placebo | Exenatide + Sitagliptin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 16 Participants | 14 Participants | 30 Participants |
| Age, Categorical Between 18 and 65 years | 81 Participants | 97 Participants | 178 Participants |
| Age, Continuous | 54.8 years STANDARD_DEVIATION 10.97 | 54.6 years STANDARD_DEVIATION 9.66 | 54.7 years STANDARD_DEVIATION 10.27 |
| Sex: Female, Male Female | 46 Participants | 58 Participants | 104 Participants |
| Sex: Female, Male Male | 51 Participants | 53 Participants | 104 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 36 / 127 | 28 / 128 |
| serious Total, serious adverse events | 4 / 127 | 6 / 128 |
Outcome results
Primary
Change in HbA1c (Percent)
Change in HbA1c from baseline to endpoint (Week 20); difference of base percent values \[X% - Y%\]
Time frame: Baseline to 20 Weeks
Population: Per Protocol Set: the set of data generated by the subset of patients who sufficiently complied with the protocol to ensure that these data would be likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide + Placebo | Change in HbA1c (Percent) | -0.38 Percent HbA1c | Standard Error 0.09 |
| Exenatide + Sitagliptin | Change in HbA1c (Percent) | -0.68 Percent HbA1c | Standard Error 0.08 |
p-value: 0.012Mixed Model Repeated Measures
Comparison: Power calculation: 80% assuming 200 patients (100 in each arm), no true difference and 1.0% standard deviation.p-value: 0.01295% CI: [0.07, 0.53]Mixed Model Repeated Measures
Secondary
Change in Body Weight (kg)
Change in body weight from baseline to endpoint (Week 20)
Time frame: Baseline to 20 Weeks
Population: Per Protocol Set: the set of data generated by the subset of patients who sufficiently complied with the protocol to ensure that these data would be likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide + Placebo | Change in Body Weight (kg) | -2.58 kg | Standard Error 0.25 |
| Exenatide + Sitagliptin | Change in Body Weight (kg) | -2.20 kg | Standard Error 0.24 |
p-value: 0.266Mixed Model Repeated Measures
Secondary
Change in FSG (mmol/L)
Change in fasting serum glucose (FSG) from baseline to endpoint (Week 20)
Time frame: Baseline to 20 Weeks
Population: Per Protocol Set: the set of data generated by the subset of patients who sufficiently complied with the protocol to ensure that these data would be likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide + Placebo | Change in FSG (mmol/L) | 0.06 mmol/L | Standard Error 0.23 |
| Exenatide + Sitagliptin | Change in FSG (mmol/L) | -0.55 mmol/L | Standard Error 0.21 |
p-value: 0.038ANCOVA
Secondary
Change in HDL (mmol/L)
Change in high-density lipoprotein (HDL) cholesterol from baseline to endpoint (Week 20)
Time frame: Baseline to 20 Weeks
Population: Per Protocol Set: the set of data generated by the subset of patients who sufficiently complied with the protocol to ensure that these data would be likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide + Placebo | Change in HDL (mmol/L) | -0.03 mmol/L | Standard Error 0.02 |
| Exenatide + Sitagliptin | Change in HDL (mmol/L) | -0.01 mmol/L | Standard Error 0.02 |
p-value: 0.269ANCOVA
Secondary
Change in LDL (mmol/L)
Change in low-density lipoprotein (LDL) cholesterol from baseline to endpoint (Week 20)
Time frame: Baseline to 20 Weeks
Population: Per Protocol Set: the set of data generated by the subset of patients who sufficiently complied with the protocol to ensure that these data would be likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide + Placebo | Change in LDL (mmol/L) | 0.06 mmol/L | Standard Error 0.06 |
| Exenatide + Sitagliptin | Change in LDL (mmol/L) | 0.10 mmol/L | Standard Error 0.06 |
p-value: 0.622ANCOVA
Secondary
Change in Total Cholesterol (mmol/L)
Change in total cholesterol from baseline to endpoint (Week 20)
Time frame: Baseline to 20 Weeks
Population: Per Protocol Set: the set of data generated by the subset of patients who sufficiently complied with the protocol to ensure that these data would be likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide + Placebo | Change in Total Cholesterol (mmol/L) | 0.09 mmol/L | Standard Error 0.07 |
| Exenatide + Sitagliptin | Change in Total Cholesterol (mmol/L) | 0.08 mmol/L | Standard Error 0.07 |
p-value: 0.888ANCOVA
Secondary
Change in Triglycerides (mmol/L)
Change in triglycerides from baseline to endpoint (Week 20)
Time frame: Baseline to 20 Weeks
Population: Per Protocol Set: the set of data generated by the subset of patients who sufficiently complied with the protocol to ensure that these data would be likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide + Placebo | Change in Triglycerides (mmol/L) | 0.17 mmol/L | Standard Error 0.1 |
| Exenatide + Sitagliptin | Change in Triglycerides (mmol/L) | -0.07 mmol/L | Standard Error 0.09 |
p-value: 0.055ANCOVA
Secondary
Change in Waist Circumference (cm)
Change in waist circumference from baseline to endpoint (Week 20)
Time frame: Baseline to 20 Weeks
Population: Per Protocol Set: the set of data generated by the subset of patients who sufficiently complied with the protocol to ensure that these data would be likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide + Placebo | Change in Waist Circumference (cm) | -3.25 cm | Standard Error 0.4 |
| Exenatide + Sitagliptin | Change in Waist Circumference (cm) | -2.36 cm | Standard Error 0.37 |
p-value: 0.095Mixed Model Repeated Measures
Secondary
Incidence of Confirmed Hypoglycemia(Overall)
Incidence of confirmed hypoglycemia experienced overall during the study
Time frame: Baseline to 20 Weeks
Population: As Treated Patients; Hypoglycemia defined as: patient experiencing a sign or symptom associated with hypoglycemia that is either self-treated or resolves on its own; has a concurrent fingerstick blood glucose \<3.0 mmol/L (54 mg/dL).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide + Placebo | Incidence of Confirmed Hypoglycemia(Overall) | 1 Participants |
| Exenatide + Sitagliptin | Incidence of Confirmed Hypoglycemia(Overall) | 2 Participants |
p-value: 1Fisher's Exact Test
Secondary
Incidence of Hypoglycemia (Overall)
Incidence of hypoglycemic episodes experienced overall during the study
Time frame: Baseline to 20 Weeks
Population: As Treated Patients; Hypoglycemia defined as: patient experiencing a sign or symptom associated with hypoglycemia that is either self-treated or resolves on its own; not confirmed with blood glucose values.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide + Placebo | Incidence of Hypoglycemia (Overall) | 5 Participants |
| Exenatide + Sitagliptin | Incidence of Hypoglycemia (Overall) | 10 Participants |
p-value: 0.287Fisher's Exact Test
Secondary
Incidence of Nocturnal Hypoglycemia (Overall)
Incidence of nocturnal hypoglycemia experienced overall during the study
Time frame: Baseline to 20 Weeks
Population: As Treated Patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide + Placebo | Incidence of Nocturnal Hypoglycemia (Overall) | 0 Participants |
| Exenatide + Sitagliptin | Incidence of Nocturnal Hypoglycemia (Overall) | 3 Participants |
p-value: 0.247Fisher's Exact Test
Secondary
Incidence of Severe Hypoglycemia(Overall)
Incidence of severe hypoglycemia experienced overall during the study
Time frame: Baseline to 20 Weeks
Population: As Treated Patients; Severe hypo:symptoms consistent with hypoglycemia resulting in loss of consciousness or seizure with prompt recovery in response to administration of glucagon or glucose;or documented hypoglycemia (BG\< 3.0 mmol/L \[54/mg/dL\]) requiring the assistance of another person because of severe impairment in consciousness or behavior
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide + Placebo | Incidence of Severe Hypoglycemia(Overall) | 1 Participants |
| Exenatide + Sitagliptin | Incidence of Severe Hypoglycemia(Overall) | 0 Participants |
p-value: 0.498Fisher's Exact Test
Secondary
Percentage of Patients Achieving HbA1c <=6.5%
Percentage of patients whose baseline HbA1c was \> 6.5% achieving HbA1c \<=6.5% at endpoint (Week 20)
Time frame: Baseline to 20 Weeks
Population: Patients in the Per Protocol Set whose baseline HbA1c was \> 6.5%; Last Observation Carried Forward. Per Protocol Set: the set of data generated by the subset of patients who sufficiently complied with the protocol to ensure that these data would be likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide + Placebo | Percentage of Patients Achieving HbA1c <=6.5% | 16.5 Percentage |
| Exenatide + Sitagliptin | Percentage of Patients Achieving HbA1c <=6.5% | 20.7 Percentage |
p-value: 0.48Fisher's Exact Test
Secondary
Percentage of Patients Achieving HbA1c <=7.0%
Percentage of patients whose baseline HbA1c was \> 7.0% achieving HbA1c \<=7.0% at endpoint (Week 20)
Time frame: Baseline to 20 Weeks
Population: Patients in the Per Protocol Set whose baseline HbA1c was \> 7.0%; Last Observation Carried Forward.Per Protocol Set: the set of data generated by the subset of patients who sufficiently complied with the protocol to ensure that these data would be likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide + Placebo | Percentage of Patients Achieving HbA1c <=7.0% | 29.5 Percentage |
| Exenatide + Sitagliptin | Percentage of Patients Achieving HbA1c <=7.0% | 44.3 Percentage |
p-value: 0.038Fisher's Exact Test
Secondary
Percentage of Patients Achieving HbA1c <7.0%
Percentage of patients whose baseline HbA1c was \>=7.0% achieving HbA1c \<7.0% at endpoint (Week 20)
Time frame: Baseline to 20 Weeks
Population: Patients in the Per Protocol Set whose baseline HbA1c was \>= 7.0%; Last Observation Carried Forward. Per Protocol Set: the set of data generated by the subset of patients who sufficiently complied with the protocol to ensure that these data would be likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide + Placebo | Percentage of Patients Achieving HbA1c <7.0% | 26.6 Percentage |
| Exenatide + Sitagliptin | Percentage of Patients Achieving HbA1c <7.0% | 41.7 Percentage |
p-value: 0.027Fisher's Exact Test
Secondary
SMBG (mmol/L)
7 point Self Monitored Blood Glucose Profiles - daily mean value (Week 20)
Time frame: Baseline to 20 Weeks
Population: Per Protocol Set: the set of data generated by the subset of patients who sufficiently complied with the protocol to ensure that these data would be likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide + Placebo | SMBG (mmol/L) | 8.57 mmol/L | Standard Error 0.26 |
| Exenatide + Sitagliptin | SMBG (mmol/L) | 8.16 mmol/L | Standard Error 0.22 |
p-value: 0.207Mixed Model Repeated Measures
Secondary
Waist-to-Hip Ratio
Change in waist-to-hip ratio from baseline to endpoint (Week20)
Time frame: Baseline to 20 Weeks
Population: Per Protocol Set: the set of data generated by the subset of patients who sufficiently complied with the protocol to ensure that these data would be likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide + Placebo | Waist-to-Hip Ratio | -0.01 Ratio | Standard Error 0 |
| Exenatide + Sitagliptin | Waist-to-Hip Ratio | -0.00 Ratio | Standard Error 0 |
p-value: 0.567Mixed Model Repeated Measures