Diabetes Mellitus, Type 2
Conditions
Brief summary
This study was the extension of the LANTU\_C\_02761 study named EASIE and identified as NCT00751114 (core study comparing insulin glargine versus sitagliptin in insulin-naïve patients treated with metformin and not adequately controlled). All patients with Glycosylated Hemoglobin A1c (HbA1c) ≥ 7% at the end of the core study had the possibility to enter this extension study if they met the other inclusion criteria and did not present with any exclusion criteria. The visit 14 of the core study (week 24) was the visit 1 (baseline, week 0) of the extension study which consisted of a 12-week treatment period. The objectives of this extension study were: * To assess the glycemic control (HbA1c \<7%) of a 3-month combination therapy with metformin, insulin glargine and sitagliptin in patients not adequately controlled by a previous treatment with metformin plus either insulin glargine or sitagliptin. * To assess the effect of insulin glargine in combination with sitagliptin on HbA1c level, fasting plasma glucose, 7-point glucose profile, hypoglycemia occurrence, body weight and overall safety.
Interventions
DRUGInsulin Glargine
Subcutaneous injection. 100 Units/mL solution for injection in a prefilled SoloStar® pen (3 mL).
DRUGSitagliptin
Oral administration. 100mg film-coated tablets.
DRUGMetformin
Patients continued with metformin as usual oral anti-diabetic treatment.
Sponsors
Sanofi
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
35 Years to 71 Years
Healthy volunteers
No
Inclusion criteria
* Patients who completed the core study LANTU\_C\_02761 (NCT00751114) i.e. went through the visit 14 investigation, * HbA1c \>= 7 %, * Dose of metformin compliant with the inclusion criteria of the core study (i.e. at least 1 g/day), and maintained stable for the duration of the core study * Ability and willingness to perform plasma blood glucose monitoring using the sponsor-provided plasma glucose meter and to complete the patient dairy, * Signed informed consent obtained prior any study procedure, * Willingness and ability to comply with the study protocol.
Exclusion criteria
* Treatment with oral antidiabetic drugs other than metformin and sitagliptin in the core study, * Treatment with insulin other than Insulin Glargine in the core study (except in case of an emergency, for a period of time less than 7 days), * Treatment with a non-permitted drug during the core study, * Pregnant or lactating women, * In-patient care, * Active proliferative retinopathy, as defined by a photocoagulation or vitrectomy occurrence in the 6 months prior to visit 1, or any other unstable (rapidly progressing) retinopathy that may require photocoagulation or surgical treatment during the study (an optic fundus examination should have been performed within the 2 years prior to study entry in the core study), * Impaired renal function: serum creatinine \>= 1.5 mg/dL (\>= 133µmol/L) or \>= 1.4 mg/dL (\>=124 µmol/L) in men and women, respectively, * History of sensitivity to the study drugs or to drugs with a similar chemical structure, * Impaired hepatic function: alanine aminotransferase (ALT), aspartate aminotransferase (AST) \> 3 x upper limit of normal range, * Alcohol or drug abuse within the last year, * Night shift worker, * Presence of any condition (medical, psychological, social or geographical), current or anticipated that the investigator feels would compromise the patient's safety or limit the patient successful participation in the study, * Treatment with weight loss medications (e.g. sibutramine, orlistat, rimonabant), * History of pancreatitis.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| HbA1c Response Rate: Percentage of Patients Achieving Glycosylated Haemoglobin A1c (HbA1c) < 7% at Study Endpoint (End of Treatment Period) | study endpoint: week 12 or earlier in case of premature discontinuation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Self-Monitored Fasting Plasma Glucose (SMFPG) Mean : Change From Baseline to Study Endpoint | baseline, study endpoint: week 12 or week 8 if value not available at week 12 | SMFPG mean = mean of the fasting plasma glucose values recorded on the 6 consecutive days before the visit (at least 3 values needed). Change = study endpoint - baseline. |
| 7-point Plasma Glucose Profile: Change From Baseline to Study Endpoint | baseline, study endpoint: week 12 or week 8 if value not available at week 12 | 7-point plasma glucose recorded before and after breakfast, before and after lunch, before and after dinner and at bedtime. Change = study endpoint - baseline. |
| HbA1c: Change From Baseline to Study Endpoint | baseline, study endpoint: week 12 or earlier in case of premature discontinuation | Change = study endpoint - baseline |
| Number of Patients With at Least One Episode of Symptomatic Hypoglycemia | During the treatment period (12 weeks) plus 7 days after last dose | Symptomatic hypoglycemia was defined as an event with clinical symptoms that were considered to result from hypoglycemia confirmed or not by a plasma glucose measurement \<= 70mg/dL \[3.9 mmol/L\] |
| Change in Body Weight From Baseline to Study Endpoint | baseline, study endpoint: week 12 or week 8 or week 4 depending on last available value | Change = study endpoint - baseline |
| Insulin Dose | baseline, week 4, week 8, week 12 | Daily dose at the face-to-face visits |
Countries
Austria, Brazil, Colombia, Egypt, Greece, Hong Kong, India, Israel, Lebanon, Mexico, Netherlands, Portugal, South Korea, Spain, United Kingdom, United States
Participant flow
Recruitment details
Among the 445 patients who completed the EASIE study, 194 had an endpoint Glycosylated Hemoglobin A1c (HbA1c) ≥ 7%. A total of 112 patients were included in the extension study: 37 uncontrolled on previous treatment with metformin and insulin glargine and 75 uncontrolled on previous treatment with metformin and sitagliptin in the EASIE study.
Pre-assignment details
Among the 112 included patients, two patients prematurely discontinued from the study. One of them had continued his sitagliptin treatment but never started the insulin glargine treatment.
Participants by arm
| Arm | Count |
|---|---|
| Combination Insulin Glargine and Sitagliptin Insulin glargine administered once a day, in the evening, at dinner or at bedtime. Starting dose: - last dose administered in the core study for patients previously treated with insulin glargine, - 0.2 U/Kg of body weight for patients previously treated with sitagliptin. Monitoring of blood glucose and titration: all patients, irrespective of their previous treatment group in the core study were empowered to adjust their insulin doses, under strict investigator's supervision. The goal was to achieve through a force titration 70 \<FPG ≤ 100 mg/dL (3.9 \<FPG ≤ 5.5 mmol/L).
Sitagliptin: stable dose of 100 mg once a day administered with or without food. | 111 |
| Total | 111 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Combination Insulin Glargine and Sitagliptin |
|---|---|
| Age Continuous | 52.4 years STANDARD_DEVIATION 9.3 |
| At least one diabetic late complication No | 88 participants |
| At least one diabetic late complication Yes | 23 participants |
| Body Mass Index | 31.3 kg/m² STANDARD_DEVIATION 5.2 |
| Body Weight | 84.6 kg STANDARD_DEVIATION 21 |
| Diastolic Blood Pressure | 80.1 mmHg STANDARD_DEVIATION 7.3 |
| Duration of diabetes | 4.1 years INTER_QUARTILE_RANGE 5.1 |
| Fasting Plasma Glucose | 151.5 mg/dL STANDARD_DEVIATION 46.9 |
| Glycosylated Hemoglobin A1c (HbA1c) | 8.0 percent STANDARD_DEVIATION 1 |
| Heart Rate | 76.9 beats/min STANDARD_DEVIATION 9.1 |
| Self-Monitored Fasting Plasma Glucose | 144.4 mg/dL STANDARD_DEVIATION 38.2 |
| Sex: Female, Male Female | 56 Participants |
| Sex: Female, Male Male | 55 Participants |
| Systolic Blood Pressure | 129.9 mmHg STANDARD_DEVIATION 15.5 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 112 |
| serious Total, serious adverse events | 2 / 112 |
Outcome results
Primary
HbA1c Response Rate: Percentage of Patients Achieving Glycosylated Haemoglobin A1c (HbA1c) < 7% at Study Endpoint (End of Treatment Period)
Time frame: study endpoint: week 12 or earlier in case of premature discontinuation
Population: The population analyzed consisted of the subset of mITT patients who had HbA1c value at study endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Insulin Glargine and Sitagliptin | HbA1c Response Rate: Percentage of Patients Achieving Glycosylated Haemoglobin A1c (HbA1c) < 7% at Study Endpoint (End of Treatment Period) | 51.9 percentage of participants |
Secondary
7-point Plasma Glucose Profile: Change From Baseline to Study Endpoint
7-point plasma glucose recorded before and after breakfast, before and after lunch, before and after dinner and at bedtime. Change = study endpoint - baseline.
Time frame: baseline, study endpoint: week 12 or week 8 if value not available at week 12
Population: The population analyzed consisted of the subset of mITT patients who had valid 7-point plasma glucose profiles (4 points needed for a valid profile) both at baseline and endpoint.~Depending on the time point, few values were missing.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Combination Insulin Glargine and Sitagliptin | 7-point Plasma Glucose Profile: Change From Baseline to Study Endpoint | Before breakfast (N=104) | -34.2 mg/dL | Standard Deviation 38.1 |
| Combination Insulin Glargine and Sitagliptin | 7-point Plasma Glucose Profile: Change From Baseline to Study Endpoint | After breakfast (N=103) | -34.1 mg/dL | Standard Deviation 48.1 |
| Combination Insulin Glargine and Sitagliptin | 7-point Plasma Glucose Profile: Change From Baseline to Study Endpoint | Before lunch (N=104) | -26.6 mg/dL | Standard Deviation 48.2 |
| Combination Insulin Glargine and Sitagliptin | 7-point Plasma Glucose Profile: Change From Baseline to Study Endpoint | After lunch (N=104) | -26.5 mg/dL | Standard Deviation 43.7 |
| Combination Insulin Glargine and Sitagliptin | 7-point Plasma Glucose Profile: Change From Baseline to Study Endpoint | Before dinner (N=103) | -25.1 mg/dL | Standard Deviation 43 |
| Combination Insulin Glargine and Sitagliptin | 7-point Plasma Glucose Profile: Change From Baseline to Study Endpoint | After dinner (N=100) | -24.9 mg/dL | Standard Deviation 46.7 |
| Combination Insulin Glargine and Sitagliptin | 7-point Plasma Glucose Profile: Change From Baseline to Study Endpoint | At bedtime (N=93) | -35.2 mg/dL | Standard Deviation 51.7 |
Secondary
Change in Body Weight From Baseline to Study Endpoint
Change = study endpoint - baseline
Time frame: baseline, study endpoint: week 12 or week 8 or week 4 depending on last available value
Population: The population analyzed was the safety population with both baseline and endpoint values available
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Insulin Glargine and Sitagliptin | Change in Body Weight From Baseline to Study Endpoint | 1.15 kg | Standard Deviation 2.24 |
Secondary
HbA1c: Change From Baseline to Study Endpoint
Change = study endpoint - baseline
Time frame: baseline, study endpoint: week 12 or earlier in case of premature discontinuation
Population: The population analyzed consisted of the subset of mITT patients who had both baseline and endpoint for this outcome measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Insulin Glargine and Sitagliptin | HbA1c: Change From Baseline to Study Endpoint | -0.80 percent | Standard Deviation 1.05 |
Secondary
Insulin Dose
Daily dose at the face-to-face visits
Time frame: baseline, week 4, week 8, week 12
Population: mITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Combination Insulin Glargine and Sitagliptin | Insulin Dose | Baseline | 0.28 unit per kg body weight | Standard Deviation 0.18 |
| Combination Insulin Glargine and Sitagliptin | Insulin Dose | Week 4 N=110 | 0.37 unit per kg body weight | Standard Deviation 0.16 |
| Combination Insulin Glargine and Sitagliptin | Insulin Dose | Week 8 N=110 | 0.42 unit per kg body weight | Standard Deviation 0.18 |
| Combination Insulin Glargine and Sitagliptin | Insulin Dose | Week 12 | 0.46 unit per kg body weight | Standard Deviation 0.2 |
Secondary
Number of Patients With at Least One Episode of Symptomatic Hypoglycemia
Symptomatic hypoglycemia was defined as an event with clinical symptoms that were considered to result from hypoglycemia confirmed or not by a plasma glucose measurement \<= 70mg/dL \[3.9 mmol/L\]
Time frame: During the treatment period (12 weeks) plus 7 days after last dose
Population: The population analyzed for this outcome measure was the safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Insulin Glargine and Sitagliptin | Number of Patients With at Least One Episode of Symptomatic Hypoglycemia | 40 participants |
Secondary
Self-Monitored Fasting Plasma Glucose (SMFPG) Mean : Change From Baseline to Study Endpoint
SMFPG mean = mean of the fasting plasma glucose values recorded on the 6 consecutive days before the visit (at least 3 values needed). Change = study endpoint - baseline.
Time frame: baseline, study endpoint: week 12 or week 8 if value not available at week 12
Population: The population analyzed consisted of the subset of mITT patients who had both baseline and endpoint for this outcome measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Insulin Glargine and Sitagliptin | Self-Monitored Fasting Plasma Glucose (SMFPG) Mean : Change From Baseline to Study Endpoint | -35.43 mg/dL | Standard Deviation 39.61 |