Diabetes Mellitus, Type 2
Conditions
Brief summary
The primary objectives were: * To demonstrate the superiority of Lantus plus stepwise addition of mealtime Apidra® (Lantus/Apidra-3) versus twice-daily Premixed insulin based on the proportion of patients achieving target glycemic control (as measured by hemoglobin A1c \[HbA1c\] \<7.0%) at Week 60 * To demonstrate the noninferiority of Lantus plus addition of 1 mealtime Apidra injection (Lantus/Apidra-1) versus twice-daily Premixed insulin based on the reduction from Baseline to Week 60 in HbA1c
Interventions
DRUGInsulin Glulisine
Subcutaneous injection up to 1 injection per day
DRUGInsulin Glargine
Subcutaneous injection once-a-day
DRUGPremixed Insulin
Subcutaneous injection twice-a-day.
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
30 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Male or female patients * 30 to 80 years of age * Body Mass Index \<45 kg/m2 * With Type 2 diabetes mellitus for at least 2 years * With an HbA1c level at screening of \>7.5% and \>7.0% at randomization * On stable dual or triple oral therapy for at least 3 months * Oral agents in 2 or 3 of the following classes: SU or repaglinide, biguanide, or TZD, willing and able to perform self-monitoring of BG * Females of child-bearing potentially were required to be willing and able to use adequate contraception
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) < 7.0% at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30 - Intent To Treat (ITT) Population Without Good Clinical Practices (GCP) Noncompliant Sites) | At week 60 | Responders defined as patients who achieved an HbA1c value \<7.0% versus nonresponders. Patients who did not achieve an HbA1c value \<7.0% and patients with a missing HbA1c value at Week 60 were considered to be nonresponders. |
| Change From Baseline in Glycosylated Hemoglobin A1c (HbA1c) at Week 60 (Lantus/Apidra-1 Versus Novolog Mix 70/30)Per Protocol Population | At week 60 | Absolute Change in HbA1c from Baseline to Week 60. If the Week 60 HbA1c evaluation was missing, the patient was counted as having not completed per protocol. |
| Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) < 7.0% at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30 - ITT Population With All Sites) (Sensitivity Analysis) | At week 60 | Responders defined as patients who achieved an HbA1c value \<7.0% versus nonresponders. Patients who did not achieve an HbA1c value \<7.0% and patients with a missing HbA1c value at Week 60 were considered to be nonresponders. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Incidence Rate of Hypoglycemia | Week 60 | Adjusted incidence rate of hypoglycemia: estimated percent of patients having at least 1 event of a given type of hypoglycemia. A severe Hypoglycemic Event (HE) is one where patient requires assistance. It is confirmed either by a prompt response to certain countermeasures or by a blood Glucose (BG) \<36 mg/dL during or soon after the event. A serious HE is one where the patient has loss of consciousness, coma, seizure, or convulsion. Nocturnal = events occurring between 00:00 & 06:00 based on a 24-hour clock. An event is included if the HE start date is within the treatment period. |
| Absolute Change From Baseline in Glycosylated Hemoglobin A1c (HbA1c) at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30) | From baseline to week 60 | Absolute Change in HbA1c from Baseline to Week 60. |
| Adjusted Hypoglycemic Event Rates (Event/Patient-year) | Week 60 | Adjusted Hypoglycemic event rate: Total # of events for a given type of hypoglycemia divided by the total exposure to study drug (patient-years). Rates are estimated from a general linear model adjusted for baseline BMI and oral agent combination of antidiabetic medications on which the patient entered the study. An event is included if the hypoglycemic event start date is within the treatment period (i.e., from the Randomization date to & including 1 day after the date of last dose of study drug). |
| Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) <7.0% at Week 60 (Lantus/Apidra-1 Versus Novolog Mix 70/30) | At week 60 | Patients who achieved an HbA1c value \<7.0% were defined as responders. Patients who did not achieve HbA1c values \<7.0% and patients with missing HbA1c values were considered nonresponders. |
| Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) <7.0% at Week 60 Without a Severe Hypoglycemic Event or a Symptomatic Hypoglycemic Event With an Self Monitoring Blood Glucose (SMBG) <50 mg/dl | At week 60 | Severe hypoglycemia was defined as an event with clinical symptoms that are considered to result from hypoglycemia in which the patient required assistance of another person and one of the following: the event was associated with a measured blood glucose level below 36 mg/dL or the event was associated with prompt recovery after oral carbohydrate, iv glucose, or glucagon administration. A symptomatic hypoglycemic event was defined as a hypoglycemic episode with an associated SMBG value of \<50 mg/dL with reported symptoms. |
Countries
United States
Participant flow
Recruitment details
A total of 123 study sites were activated in the United States; 99 sites enrolled and randomized 588 patients from May 2006 to March 2010. 582 patients out of 588 patients were treated. Three sites (which included 26 patients) were found to be non Good Clinical Practices (GCP) compliant.
Pre-assignment details
Patient were considered enrolled after informed consent were obtained, and randomized after completion of the 4-week run-in phase and assessment of the randomization criteria.
Participants by arm
| Arm | Count |
|---|---|
| Lantus/Apidra-3 Insulin glargine (Lantus) plus up to 3 injections of insulin glulisine (Apidra) added to oral agents. | 195 |
| Lantus/Apidra-1 Insulin glargine (Lantus) plus up to 1 injection of insulin glulisine (Apidra) added to oral agents. | 196 |
| Novolog Mix 70/30 Premixed insulin (Novolog® Mix 70/30) added to oral agents. | 197 |
| Total | 588 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 5 | 4 |
| Overall Study | Lack of Efficacy | 0 | 3 | 2 |
| Overall Study | Loss of site personnel | 1 | 0 | 1 |
| Overall Study | Lost to Follow-up | 9 | 9 | 10 |
| Overall Study | No longer Requires Study Treatment | 1 | 0 | 1 |
| Overall Study | Patient moved | 1 | 0 | 1 |
| Overall Study | Patient non-compliant | 4 | 4 | 5 |
| Overall Study | Patient required surgery | 0 | 1 | 0 |
| Overall Study | Physician Decision | 1 | 0 | 0 |
| Overall Study | Progressive Disease | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 2 | 2 | 2 |
| Overall Study | Sponsor decision | 1 | 2 | 1 |
| Overall Study | Withdrawal by Subject | 14 | 19 | 29 |
Baseline characteristics
| Characteristic | Total | Lantus/Apidra-3 | Lantus/Apidra-1 | Novolog Mix 70/30 |
|---|---|---|---|---|
| Age at onset of diabetes | 45.3 years STANDARD_DEVIATION 10.05 | 46.0 years STANDARD_DEVIATION 10.74 | 45.1 years STANDARD_DEVIATION 9.36 | 44.8 years STANDARD_DEVIATION 10.01 |
| Age Continuous | 54.1 years STANDARD_DEVIATION 10.12 | 54.9 years STANDARD_DEVIATION 10.54 | 53.7 years STANDARD_DEVIATION 9.11 | 53.7 years STANDARD_DEVIATION 10.65 |
| Body Mass Index (BMI) | 33.1 Kilogram/m^2 STANDARD_DEVIATION 5.8 | 32.7 Kilogram/m^2 STANDARD_DEVIATION 5.79 | 33.4 Kilogram/m^2 STANDARD_DEVIATION 6 | 33.4 Kilogram/m^2 STANDARD_DEVIATION 5.62 |
| Duration of diabetes at study entry | 9.3 years STANDARD_DEVIATION 6.13 | 9.4 years STANDARD_DEVIATION 6.8 | 9.1 years STANDARD_DEVIATION 5.7 | 9.5 years STANDARD_DEVIATION 5.87 |
| Oral antidiabetic treatment combination at study entry sulfonylurea (SU) or meglitinide plus metformin | 293 participants | 97 participants | 99 participants | 97 participants |
| Oral antidiabetic treatment combination at study entry SU or meglitinide plus metformin plus TZD | 187 participants | 63 participants | 61 participants | 63 participants |
| Oral antidiabetic treatment combination at study entry SU or meglitinide plus thiazolinedione (TZD) | 28 participants | 9 participants | 9 participants | 10 participants |
| Oral antidiabetic treatment combination at study entry TZD plus metformin | 80 participants | 26 participants | 27 participants | 27 participants |
| Region of Enrollment United States | 588 participants | 195 participants | 196 participants | 197 participants |
| Sex: Female, Male Female | 252 Participants | 78 Participants | 88 Participants | 86 Participants |
| Sex: Female, Male Male | 336 Participants | 117 Participants | 108 Participants | 111 Participants |
| Weight | 96.8 kilograms (kg) STANDARD_DEVIATION 20.21 | 95.2 kilograms (kg) STANDARD_DEVIATION 19.21 | 97.2 kilograms (kg) STANDARD_DEVIATION 20.88 | 97.9 kilograms (kg) STANDARD_DEVIATION 20.49 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 140 / 194 | 150 / 194 | 152 / 194 |
| serious Total, serious adverse events | 22 / 194 | 23 / 194 | 21 / 194 |
Outcome results
Primary
Change From Baseline in Glycosylated Hemoglobin A1c (HbA1c) at Week 60 (Lantus/Apidra-1 Versus Novolog Mix 70/30)Per Protocol Population
Absolute Change in HbA1c from Baseline to Week 60. If the Week 60 HbA1c evaluation was missing, the patient was counted as having not completed per protocol.
Time frame: At week 60
Population: Analysis was performed on the Per Protocol (PP) population which included randomized patients who had no major protocol violation and who had HbA1c recorded for both Baseline \& Week 60. Patients from non-GCP compliant sites were, by population definition, excluded from this analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Lantus/Apidra-3 | Change From Baseline in Glycosylated Hemoglobin A1c (HbA1c) at Week 60 (Lantus/Apidra-1 Versus Novolog Mix 70/30)Per Protocol Population | baseline HbA1c | 9.30 percent HbA1c | Standard Error 0.176 |
| Lantus/Apidra-3 | Change From Baseline in Glycosylated Hemoglobin A1c (HbA1c) at Week 60 (Lantus/Apidra-1 Versus Novolog Mix 70/30)Per Protocol Population | Absolute change in HbA1c from baseline | -2.30 percent HbA1c | Standard Error 0.126 |
| Novolog Mix 70/30 | Change From Baseline in Glycosylated Hemoglobin A1c (HbA1c) at Week 60 (Lantus/Apidra-1 Versus Novolog Mix 70/30)Per Protocol Population | baseline HbA1c | 9.06 percent HbA1c | Standard Error 0.187 |
| Novolog Mix 70/30 | Change From Baseline in Glycosylated Hemoglobin A1c (HbA1c) at Week 60 (Lantus/Apidra-1 Versus Novolog Mix 70/30)Per Protocol Population | Absolute change in HbA1c from baseline | -1.97 percent HbA1c | Standard Error 0.132 |
p-value: 0.035995% CI: [-0.82, 0.15]Mixed Models Analysis
Primary
Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) < 7.0% at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30 - Intent To Treat (ITT) Population Without Good Clinical Practices (GCP) Noncompliant Sites)
Responders defined as patients who achieved an HbA1c value \<7.0% versus nonresponders. Patients who did not achieve an HbA1c value \<7.0% and patients with a missing HbA1c value at Week 60 were considered to be nonresponders.
Time frame: At week 60
Population: Analysis was performed on Intent-To-Treat population which consisted of all patients who were randomized and for whom there was any post-baseline follow-up information. Patients from nonGCP compliant sites were excluded from this analysis. Additional analysis including those patients were completed to ensure that study results were not compromised.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lantus/Apidra-3 | Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) < 7.0% at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30 - Intent To Treat (ITT) Population Without Good Clinical Practices (GCP) Noncompliant Sites) | HbA1c < 7.0% | 43.3 percentage of participants |
| Lantus/Apidra-3 | Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) < 7.0% at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30 - Intent To Treat (ITT) Population Without Good Clinical Practices (GCP) Noncompliant Sites) | HbA1c ≥ 7.0% | 35.3 percentage of participants |
| Lantus/Apidra-3 | Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) < 7.0% at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30 - Intent To Treat (ITT) Population Without Good Clinical Practices (GCP) Noncompliant Sites) | Missing data | 21.4 percentage of participants |
| Novolog Mix 70/30 | Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) < 7.0% at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30 - Intent To Treat (ITT) Population Without Good Clinical Practices (GCP) Noncompliant Sites) | HbA1c < 7.0% | 38.6 percentage of participants |
| Novolog Mix 70/30 | Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) < 7.0% at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30 - Intent To Treat (ITT) Population Without Good Clinical Practices (GCP) Noncompliant Sites) | HbA1c ≥ 7.0% | 32.3 percentage of participants |
| Novolog Mix 70/30 | Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) < 7.0% at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30 - Intent To Treat (ITT) Population Without Good Clinical Practices (GCP) Noncompliant Sites) | Missing data | 29.1 percentage of participants |
p-value: 0.062895% CI: [0.97, 2.52]Regression, Logistic
Primary
Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) < 7.0% at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30 - ITT Population With All Sites) (Sensitivity Analysis)
Responders defined as patients who achieved an HbA1c value \<7.0% versus nonresponders. Patients who did not achieve an HbA1c value \<7.0% and patients with a missing HbA1c value at Week 60 were considered to be nonresponders.
Time frame: At week 60
Population: Analysis was performed on the Intent To Treat (ITT) population which consisted of all patients who were randomized, and for whom there was any post-baseline follow-up information. Patients from non-GCP compliant sites were included in this analysis. This analysis was performed to ensure that study results were not compromised.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lantus/Apidra-3 | Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) < 7.0% at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30 - ITT Population With All Sites) (Sensitivity Analysis) | HbA1c < 7.0% | 44.1 percentage of participants |
| Lantus/Apidra-3 | Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) < 7.0% at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30 - ITT Population With All Sites) (Sensitivity Analysis) | HbA1c ≥ 7.0% | 34.4 percentage of participants |
| Lantus/Apidra-3 | Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) < 7.0% at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30 - ITT Population With All Sites) (Sensitivity Analysis) | Missing data | 21.5 percentage of participants |
| Novolog Mix 70/30 | Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) < 7.0% at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30 - ITT Population With All Sites) (Sensitivity Analysis) | HbA1c < 7.0% | 38.1 percentage of participants |
| Novolog Mix 70/30 | Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) < 7.0% at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30 - ITT Population With All Sites) (Sensitivity Analysis) | HbA1c ≥ 7.0% | 32.0 percentage of participants |
| Novolog Mix 70/30 | Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) < 7.0% at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30 - ITT Population With All Sites) (Sensitivity Analysis) | Missing data | 29.9 percentage of participants |
p-value: 0.031395% CI: [1.04, 2.64]Regression, Logistic
Secondary
Absolute Change From Baseline in Glycosylated Hemoglobin A1c (HbA1c) at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30)
Absolute Change in HbA1c from Baseline to Week 60.
Time frame: From baseline to week 60
Population: Analysis was performed on the modified ITT (mITT) population which consisted of all patients who were randomized, and for whom there was a baseline observation and at least 1 postbaseline (on therapy) observation for HbA1c. Patients from non-GCP compliant sites (8 from Lantus/Apidra-3 \& 7 from Novolog Mix arms) were excluded from this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lantus/Apidra-3 | Absolute Change From Baseline in Glycosylated Hemoglobin A1c (HbA1c) at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30) | -2.45 percent HbA1c | Standard Error 0.134 |
| Novolog Mix 70/30 | Absolute Change From Baseline in Glycosylated Hemoglobin A1c (HbA1c) at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30) | -2.13 percent HbA1c | Standard Error 0.142 |
p-value: 0.056595% CI: [-0.63, 0.01]ANCOVA
Secondary
Adjusted Hypoglycemic Event Rates (Event/Patient-year)
Adjusted Hypoglycemic event rate: Total # of events for a given type of hypoglycemia divided by the total exposure to study drug (patient-years). Rates are estimated from a general linear model adjusted for baseline BMI and oral agent combination of antidiabetic medications on which the patient entered the study. An event is included if the hypoglycemic event start date is within the treatment period (i.e., from the Randomization date to & including 1 day after the date of last dose of study drug).
Time frame: Week 60
Population: The analysis was performed on the exposed population (i.e. safety population) regardless of enrollment in a non-GCP compliant site.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lantus/Apidra-3 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | SMBG< 50 mg/dl with symptoms, nocturnal | 0.10 event per patient year | Standard Error 0.04 |
| Lantus/Apidra-3 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | SMBG< 50 mg/dl | 1.38 event per patient year | Standard Error 0.21 |
| Lantus/Apidra-3 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | Severe hypoglycemias | 0.17 event per patient year | Standard Error 0.05 |
| Lantus/Apidra-3 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | SMBG< 50 mg/dl, nocturnal | 0.20 event per patient year | Standard Error 0.06 |
| Lantus/Apidra-3 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | SMBG< 50 mg/dl with symptoms | 0.89 event per patient year | Standard Error 0.15 |
| Lantus/Apidra-3 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | Self-Monitored Blood Glucose (SMBG) < 70 mg/dl | 14.50 event per patient year | Standard Error 1.72 |
| Lantus/Apidra-3 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | SMBG< 70 mg/dl, nocturnal | 1.90 event per patient year | Standard Error 0.32 |
| Lantus/Apidra-3 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | SMBG< 70 mg/dl with symptoms | 7.23 event per patient year | Standard Error 0.99 |
| Lantus/Apidra-3 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | SMBG< 36 mg/dl | 0.15 event per patient year | Standard Error 0.03 |
| Lantus/Apidra-3 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | SMBG< 70 mg/dl with symptoms, nocturnal | 1.16 event per patient year | Standard Error 0.21 |
| Lantus/Apidra-3 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | Serious hypoglycemias | NA event per patient year | — |
| Novolog Mix 70/30 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | SMBG< 50 mg/dl with symptoms | 0.83 event per patient year | Standard Error 0.15 |
| Novolog Mix 70/30 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | Self-Monitored Blood Glucose (SMBG) < 70 mg/dl | 12.85 event per patient year | Standard Error 1.5 |
| Novolog Mix 70/30 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | SMBG< 70 mg/dl with symptoms | 7.11 event per patient year | Standard Error 0.99 |
| Novolog Mix 70/30 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | SMBG< 70 mg/dl, nocturnal | 1.84 event per patient year | Standard Error 0.31 |
| Novolog Mix 70/30 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | SMBG< 70 mg/dl with symptoms, nocturnal | 1.10 event per patient year | Standard Error 0.21 |
| Novolog Mix 70/30 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | SMBG< 50 mg/dl | 1.17 event per patient year | Standard Error 0.19 |
| Novolog Mix 70/30 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | SMBG< 50 mg/dl, nocturnal | 0.18 event per patient year | Standard Error 0.06 |
| Novolog Mix 70/30 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | SMBG< 50 mg/dl with symptoms, nocturnal | 0.09 event per patient year | Standard Error 0.04 |
| Novolog Mix 70/30 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | SMBG< 36 mg/dl | 0.10 event per patient year | Standard Error 0.03 |
| Novolog Mix 70/30 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | Severe hypoglycemias | 0.10 event per patient year | Standard Error 0.03 |
| Novolog Mix 70/30 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | Serious hypoglycemias | NA event per patient year | — |
| Novolog Mix 70/30 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | Severe hypoglycemias | 0.17 event per patient year | Standard Error 0.05 |
| Novolog Mix 70/30 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | SMBG< 50 mg/dl with symptoms, nocturnal | 0.18 event per patient year | Standard Error 0.07 |
| Novolog Mix 70/30 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | SMBG< 70 mg/dl, nocturnal | 1.68 event per patient year | Standard Error 0.29 |
| Novolog Mix 70/30 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | Self-Monitored Blood Glucose (SMBG) < 70 mg/dl | 20.42 event per patient year | Standard Error 2.38 |
| Novolog Mix 70/30 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | SMBG< 36 mg/dl | 0.23 event per patient year | Standard Error 0.05 |
| Novolog Mix 70/30 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | SMBG< 70 mg/dl with symptoms | 12.23 event per patient year | Standard Error 1.68 |
| Novolog Mix 70/30 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | SMBG< 50 mg/dl with symptoms | 1.91 event per patient year | Standard Error 0.31 |
| Novolog Mix 70/30 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | SMBG< 50 mg/dl | 2.42 event per patient year | Standard Error 0.36 |
| Novolog Mix 70/30 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | Serious hypoglycemias | NA event per patient year | — |
| Novolog Mix 70/30 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | SMBG< 50 mg/dl, nocturnal | 0.27 event per patient year | Standard Error 0.09 |
| Novolog Mix 70/30 | Adjusted Hypoglycemic Event Rates (Event/Patient-year) | SMBG< 70 mg/dl with symptoms, nocturnal | 1.16 event per patient year | Standard Error 0.23 |
Secondary
Adjusted Incidence Rate of Hypoglycemia
Adjusted incidence rate of hypoglycemia: estimated percent of patients having at least 1 event of a given type of hypoglycemia. A severe Hypoglycemic Event (HE) is one where patient requires assistance. It is confirmed either by a prompt response to certain countermeasures or by a blood Glucose (BG) \<36 mg/dL during or soon after the event. A serious HE is one where the patient has loss of consciousness, coma, seizure, or convulsion. Nocturnal = events occurring between 00:00 & 06:00 based on a 24-hour clock. An event is included if the HE start date is within the treatment period.
Time frame: Week 60
Population: The analysis was performed on the exposed population (i.e. safety population) regardless of enrollment in a non-GCP compliant site.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lantus/Apidra-3 | Adjusted Incidence Rate of Hypoglycemia | SMBG< 50 mg/dl with symptoms, nocturnal | 6.93 estimated percentage per patient | Standard Error 2.28 |
| Lantus/Apidra-3 | Adjusted Incidence Rate of Hypoglycemia | SMBG< 50 mg/dl | 39.77 estimated percentage per patient | Standard Error 4.27 |
| Lantus/Apidra-3 | Adjusted Incidence Rate of Hypoglycemia | Severe hypoglycemias | 10.10 estimated percentage per patient | Standard Error 2.17 |
| Lantus/Apidra-3 | Adjusted Incidence Rate of Hypoglycemia | SMBG< 50 mg/dl, nocturnal | 12.05 estimated percentage per patient | Standard Error 2.88 |
| Lantus/Apidra-3 | Adjusted Incidence Rate of Hypoglycemia | SMBG< 50 mg/dl with symptoms | 31.51 estimated percentage per patient | Standard Error 3.95 |
| Lantus/Apidra-3 | Adjusted Incidence Rate of Hypoglycemia | Self-Monitored Blood Glucose (SMBG) < 70 mg/dl | 74.40 estimated percentage per patient | Standard Error 3.83 |
| Lantus/Apidra-3 | Adjusted Incidence Rate of Hypoglycemia | SMBG< 70 mg/dl, nocturnal | 46.30 estimated percentage per patient | Standard Error 4.28 |
| Lantus/Apidra-3 | Adjusted Incidence Rate of Hypoglycemia | SMBG< 70 mg/dl with symptoms | 60.14 estimated percentage per patient | Standard Error 4.24 |
| Lantus/Apidra-3 | Adjusted Incidence Rate of Hypoglycemia | SMBG< 36 mg/dl | 10.89 estimated percentage per patient | Standard Error 2.23 |
| Lantus/Apidra-3 | Adjusted Incidence Rate of Hypoglycemia | SMBG< 70 mg/dl with symptoms, nocturnal | 37.03 estimated percentage per patient | Standard Error 4.1 |
| Lantus/Apidra-3 | Adjusted Incidence Rate of Hypoglycemia | Serious hypoglycemias | 0.41 estimated percentage per patient | Standard Error 0.43 |
| Novolog Mix 70/30 | Adjusted Incidence Rate of Hypoglycemia | SMBG< 50 mg/dl with symptoms | 32.56 estimated percentage per patient | Standard Error 4 |
| Novolog Mix 70/30 | Adjusted Incidence Rate of Hypoglycemia | Self-Monitored Blood Glucose (SMBG) < 70 mg/dl | 74.78 estimated percentage per patient | Standard Error 3.8 |
| Novolog Mix 70/30 | Adjusted Incidence Rate of Hypoglycemia | SMBG< 70 mg/dl with symptoms | 62.50 estimated percentage per patient | Standard Error 4.18 |
| Novolog Mix 70/30 | Adjusted Incidence Rate of Hypoglycemia | SMBG< 70 mg/dl, nocturnal | 40.31 estimated percentage per patient | Standard Error 4.18 |
| Novolog Mix 70/30 | Adjusted Incidence Rate of Hypoglycemia | SMBG< 70 mg/dl with symptoms, nocturnal | 33.55 estimated percentage per patient | Standard Error 3.98 |
| Novolog Mix 70/30 | Adjusted Incidence Rate of Hypoglycemia | SMBG< 50 mg/dl | 39.55 estimated percentage per patient | Standard Error 4.25 |
| Novolog Mix 70/30 | Adjusted Incidence Rate of Hypoglycemia | SMBG< 50 mg/dl, nocturnal | 11.29 estimated percentage per patient | Standard Error 2.78 |
| Novolog Mix 70/30 | Adjusted Incidence Rate of Hypoglycemia | SMBG< 50 mg/dl with symptoms, nocturnal | 7.49 estimated percentage per patient | Standard Error 2.43 |
| Novolog Mix 70/30 | Adjusted Incidence Rate of Hypoglycemia | SMBG< 36 mg/dl | 8.63 estimated percentage per patient | Standard Error 2.02 |
| Novolog Mix 70/30 | Adjusted Incidence Rate of Hypoglycemia | Severe hypoglycemias | 7.19 estimated percentage per patient | Standard Error 1.85 |
| Novolog Mix 70/30 | Adjusted Incidence Rate of Hypoglycemia | Serious hypoglycemias | 0.00 estimated percentage per patient | Standard Error 0 |
| Novolog Mix 70/30 | Adjusted Incidence Rate of Hypoglycemia | Severe hypoglycemias | 8.23 estimated percentage per patient | Standard Error 1.97 |
| Novolog Mix 70/30 | Adjusted Incidence Rate of Hypoglycemia | SMBG< 50 mg/dl with symptoms, nocturnal | 8.88 estimated percentage per patient | Standard Error 2.76 |
| Novolog Mix 70/30 | Adjusted Incidence Rate of Hypoglycemia | SMBG< 70 mg/dl, nocturnal | 42.53 estimated percentage per patient | Standard Error 4.19 |
| Novolog Mix 70/30 | Adjusted Incidence Rate of Hypoglycemia | Self-Monitored Blood Glucose (SMBG) < 70 mg/dl | 83.15 estimated percentage per patient | Standard Error 3.11 |
| Novolog Mix 70/30 | Adjusted Incidence Rate of Hypoglycemia | SMBG< 36 mg/dl | 14.32 estimated percentage per patient | Standard Error 2.52 |
| Novolog Mix 70/30 | Adjusted Incidence Rate of Hypoglycemia | SMBG< 70 mg/dl with symptoms | 71.98 estimated percentage per patient | Standard Error 3.76 |
| Novolog Mix 70/30 | Adjusted Incidence Rate of Hypoglycemia | SMBG< 50 mg/dl with symptoms | 45.92 estimated percentage per patient | Standard Error 4.3 |
| Novolog Mix 70/30 | Adjusted Incidence Rate of Hypoglycemia | SMBG< 50 mg/dl | 53.14 estimated percentage per patient | Standard Error 4.33 |
| Novolog Mix 70/30 | Adjusted Incidence Rate of Hypoglycemia | Serious hypoglycemias | 2.29 estimated percentage per patient | Standard Error 1.12 |
| Novolog Mix 70/30 | Adjusted Incidence Rate of Hypoglycemia | SMBG< 50 mg/dl, nocturnal | 12.58 estimated percentage per patient | Standard Error 2.96 |
| Novolog Mix 70/30 | Adjusted Incidence Rate of Hypoglycemia | SMBG< 70 mg/dl with symptoms, nocturnal | 35.68 estimated percentage per patient | Standard Error 4.03 |
Secondary
Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) <7.0% at Week 60 (Lantus/Apidra-1 Versus Novolog Mix 70/30)
Patients who achieved an HbA1c value \<7.0% were defined as responders. Patients who did not achieve HbA1c values \<7.0% and patients with missing HbA1c values were considered nonresponders.
Time frame: At week 60
Population: Analysis was performed on the modified intent-to-treat population which consisted of all patients who were randomized \& for whom there was a baseline observation \& at least 1 postbaseline (on therapy) observation for HbA1c. Patients from non-GCP compliant sites (9 for Lantus/Apidra-1 \& 7 for Novolog Mix arms) were excluded from this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lantus/Apidra-3 | Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) <7.0% at Week 60 (Lantus/Apidra-1 Versus Novolog Mix 70/30) | 51.1 percentage of participants |
| Novolog Mix 70/30 | Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) <7.0% at Week 60 (Lantus/Apidra-1 Versus Novolog Mix 70/30) | 39.5 percentage of participants |
p-value: 0.01495% CI: [1.12, 2.85]Regression, Logistic
Secondary
Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) <7.0% at Week 60 Without a Severe Hypoglycemic Event or a Symptomatic Hypoglycemic Event With an Self Monitoring Blood Glucose (SMBG) <50 mg/dl
Severe hypoglycemia was defined as an event with clinical symptoms that are considered to result from hypoglycemia in which the patient required assistance of another person and one of the following: the event was associated with a measured blood glucose level below 36 mg/dL or the event was associated with prompt recovery after oral carbohydrate, iv glucose, or glucagon administration. A symptomatic hypoglycemic event was defined as a hypoglycemic episode with an associated SMBG value of \<50 mg/dL with reported symptoms.
Time frame: At week 60
Population: Analysis was performed on the mITT population. Patients from non-GCP compliant sites (8 from Lantus/Apidra-3, 9 from Lantus/Apidra-1 \& 7 from Novolog Mix arms) were excluded from this analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lantus/Apidra-3 | Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) <7.0% at Week 60 Without a Severe Hypoglycemic Event or a Symptomatic Hypoglycemic Event With an Self Monitoring Blood Glucose (SMBG) <50 mg/dl | Missing data | 21.3 percentage of participants |
| Lantus/Apidra-3 | Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) <7.0% at Week 60 Without a Severe Hypoglycemic Event or a Symptomatic Hypoglycemic Event With an Self Monitoring Blood Glucose (SMBG) <50 mg/dl | HbA1c ≥ 7.0% | 55.7 percentage of participants |
| Lantus/Apidra-3 | Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) <7.0% at Week 60 Without a Severe Hypoglycemic Event or a Symptomatic Hypoglycemic Event With an Self Monitoring Blood Glucose (SMBG) <50 mg/dl | HbA1c < 7.0% | 23.0 percentage of participants |
| Novolog Mix 70/30 | Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) <7.0% at Week 60 Without a Severe Hypoglycemic Event or a Symptomatic Hypoglycemic Event With an Self Monitoring Blood Glucose (SMBG) <50 mg/dl | HbA1c ≥ 7.0% | 52.2 percentage of participants |
| Novolog Mix 70/30 | Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) <7.0% at Week 60 Without a Severe Hypoglycemic Event or a Symptomatic Hypoglycemic Event With an Self Monitoring Blood Glucose (SMBG) <50 mg/dl | HbA1c < 7.0% | 25.0 percentage of participants |
| Novolog Mix 70/30 | Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) <7.0% at Week 60 Without a Severe Hypoglycemic Event or a Symptomatic Hypoglycemic Event With an Self Monitoring Blood Glucose (SMBG) <50 mg/dl | Missing data | 22.8 percentage of participants |
| Novolog Mix 70/30 | Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) <7.0% at Week 60 Without a Severe Hypoglycemic Event or a Symptomatic Hypoglycemic Event With an Self Monitoring Blood Glucose (SMBG) <50 mg/dl | HbA1c < 7.0% | 14.1 percentage of participants |
| Novolog Mix 70/30 | Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) <7.0% at Week 60 Without a Severe Hypoglycemic Event or a Symptomatic Hypoglycemic Event With an Self Monitoring Blood Glucose (SMBG) <50 mg/dl | Missing data | 27.6 percentage of participants |
| Novolog Mix 70/30 | Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) <7.0% at Week 60 Without a Severe Hypoglycemic Event or a Symptomatic Hypoglycemic Event With an Self Monitoring Blood Glucose (SMBG) <50 mg/dl | HbA1c ≥ 7.0% | 58.4 percentage of participants |
p-value: 0.926895% CI: [0.61, 1.71]Regression, Logistic
p-value: 0.010795% CI: [1.19, 3.73]Regression, Logistic
p-value: 0.012195% CI: [1.17, 3.61]Regression, Logistic