Type 1 Diabetes Mellitus
Conditions
Brief summary
The primary study objective was to compare the rate of all hypoglycemia (composite outcome of the following hypoglycemia events: symptomatic hypoglycemia episodes, low continuous glucose monitoring system (CGMS) excursions confirmed by fingerstick blood glucose (FSBG), low FSBG readings performed at other times) between children treated with Lantus (insulin glargine) and Neutral Protamine Hagedorn (NPH) insulin. Secondary objectives were to compare insulin glargine and NPH in terms of: * rates of specific types of hypoglycemia: symptomatic, severe, nocturnal, nocturnal symptomatic, and severe nocturnal symptomatic hypoglycemia * HbA1c change from baseline to end-of-treatment, and HbA1c at end-of-treatment * percentage of patients reaching HbA1c less than 7.5% (target value) at end of treatment * average blood glucose over whole trial and at end of trial, as estimated by continuous glucose monitoring (CGM), and blood glucose variability
Detailed description
Screening phase: 2 to 4 weeks Treatment phase: 24 weeks At randomization, patients were stratified with respect to their baseline HbA1c level (\<8.5% or ≥8.5%) and hypoglycemic event rate (number of CGMS hypoglycemic excursions \<0.5 or ≥0.5 events per 24 hours). Following randomization, trial basal insulin was initiated and up-titrated within the first 12 weeks to reach a stable dose. Follow-up phase: 2 weeks All Phases: 28 to 30 weeks
Interventions
100 U/mL commercial solution for injection available as both disposable pen devices Solostar® each containing 300 U and as 10 mL vials each containing 1000 U Dose: titrated to achieve the following glycemic targets without hypoglycemia: * Fasting blood glucose (BG) between 90 and 145 mg/dL (5.0 to 8.0 mmol/L), inclusive, * Bedtime BG between 120 and 180 mg/dL (6.7 to10.0 mmol/L), inclusive, * Nocturnal BG between 80 and 162 mg/dL (4.4 to 9.0 mmol/L), inclusive; and * HbA1c \<7.5%.
NPH insulin 100 U/mL commercial (Huminsulin Basal) solution for injection available as both disposable pen devices (Huminsulin Basal Pen) each containing 300 U and as 10 mL vials each containing 1000 U Dose: titrated to achieve glycemic targets as described above for insulin glargine
DRUGInsulin lispro
Insulin lispro used as the principal bolus insulin; regular human insulin permitted. Administration: multiple injection before meals and/or at bedtime at the discretion of the Investigator.
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 6 Years
Healthy volunteers
No
Inclusion criteria
* Pediatric patients with type 1 diabetes mellitus aged at least one year to less than 6 years at screening, for whom signed written informed consent has been obtained from parent or legal guardian to participate in the study
Exclusion criteria
* Diagnosis of type 1 diabetes for less than one year * HbA1c at screening \>12% or \<6% * Diabetes other than type 1 diabetes * Parents and patients not willing to undergo all study assessments and treatments, including home blood glucose monitoring, Continuous Glucose Monitoring System (CGMS) sensor placement and maintenance both at the site and at home, multiple daily insulin injections, and visits, as dictated by the protocol (if a telephone is not available patients may undergo all visits in person) * Patients and families for whom 6 days in total (not necessarily continuous) of useable CGMS data cannot be obtained (either by home sensor replacement, or by sensor replacement at the site at additional screening visits if needed) during the screening CGMS evaluations between Visit 2 and the randomization visit * Patients treated with insulin pump therapy during the two months prior to screening * History of primary seizure disorder * History of severe hypoglycemic episode accompanied by seizure and/or coma, or diabetic ketoacidosis leading to hospitalization or to care in the emergency ward, in the 2 months prior to the screening visit * Need for chronic treatment with acetaminophen (paracetamol)-containing medications * Serum creatinine \> 2.0mg/dL at screening * Serum ALT or AST greater than 3x upper limit of normal for the patient's age and gender, at screening * Hemoglobin \< 10g/dL, or platelet count less than 100,000/cu mm, at screening * Treatment with any pharmacologic anti-hyperglycemic oral agent for more than 3 months at any time * Treatment with any non-insulin antihyperglycemic medication (eg, Symlin®) for the 3 months prior to screening * Treatment with systemic glucocorticoids within the month prior to screening Above information not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event Rate of All Hypoglycemia Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years (Events Per Patient-year) | 6 months | The rate of all hypoglycemia was calculated from all hypoglycemia episodes which occurred during the 24-week on-treatment period and consisted of: - symptomatic hypoglycemia episodes validated by the study investigator based on entries in patients' diaries, - low continuous glucose monitoring system (CGMS) excursions (interstitial glucose \<70 mg/dL \[3.9 mmol/L\]) confirmed by fingerstick blood glucose (FSBG) \<70 mg/dL, - low FSBG readings (values \<70 mg/dL) performed at other times. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event Rate of Nocturnal Symptomatic Hypoglycemia Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years | 6 months | Nocturnal symptomatic hypoglycemia: any symptomatic hypoglycemic event that occurred between 23:00 and 07:00 hours. |
| Glycosylated Hemoglobin A1c (HbA1c): End of Treatment and Change From Baseline to End of Treatment | baseline, 6 months | — |
| Glycosylated Hemoglobin A1c (HbA1c): End of Treatment and Change From Baseline to End of Treatment (ANCOVA Estimates) | baseline, 6 months | Assessed using an analysis of covariance (ANCOVA) model with treatment, and randomization strata (baseline number of CGM hypoglycemic excursions \<0.5 events/24hours or ≥0.5 events/24 hours, and baseline HbA1c \<8.5% or ≥8.5%) as fixed effects, and using the baseline value as covariate. |
| Percentage of Patients Reaching HbA1c Target of Less Than 7.5% at the End of Treatment Visit | 6 months | Percentage of patients reaching International Society for Pediatric and Adolescent Diabetes (ISPAD)-recommended goals of Glycosylated Hemoglobin A1c \<7.5% at the end of treatment visit. |
| Average Daily Blood Glucose (BG) Based on CGMS Values: End of Treatment and Change From Baseline to End of Treatment | baseline, 6 months | — |
| Event Rate of Symptomatic Hypoglycemia (Individual Component of Primary Endpoint) Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years (Events Per Patient-year) | 6 months | Symptomatic hypoglycemia: any event with clinical symptoms considered to result from hypoglycemia, validated by the study investigator based on data from patient diaries. |
| Event Rate of Severe Symptomatic Hypoglycemia Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years | 6 months | Severe symptomatic hypoglycemia: any event with clinical symptoms considered to result from a hypoglycemic episode for which the patients required the assistance of a third party (ie, other than the patient, or a parent/usual caregiver; eg, from emergency personnel), because the patients/parents could not treat the event with acute neurological impairment directly resulting from the hypoglycemic event. The occurrence of seizure, coma, unconsciousness, or the use of glucagon, were also to qualify a hypoglycemic episode as severe. |
| Event Rate of Nocturnal Hypoglycemia Defined as the Total Number of All Hypoglycemia Episodes Divided by the Total Duration of the On-treatment Period in Years | 6 months | Nocturnal hypoglycemia: any event from the all hypoglycemia total that occurred between 23:00 and 07:00 hours. |
| Event Rate of Severe Nocturnal Hypoglycemia Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years | 6 months | Severe nocturnal symptomatic hypoglycemia: any severe symptomatic hypoglycemic event that occurred between 23:00 and 07:00 hours. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Blood Glucose Variability Based on All On-treatment CGMS Values | 6 months | Calculated for any given patient as the standard deviation (SD) of all CGMS interstitial glucose values recorded over all CGMS placements. |
| Nocturnal Blood Glucose Variability Based on All On-treatment CGMS Values | 6 months | Calculated for any given patient as the standard deviation (SD) of all CGMS interstitial glucose values recorded during the nocturnal time period (between 23:00 and 07:00 hours). |
| Percent of Blood Glucose (BG) Within the Range of 70 - 180 mg/dL (3.9-10 mmol/L) | 6 months | Calculated for each patient as the percent of all on-treatment CGMS values falling within the range of 70 - 180 mg/dL (3.9 - 10 mmol/L) inclusive. |
| Number of Patients With Different Types of Hypoglycemia Events | 6 months | Definitions of the different types of hypoglycemia events provided in the outcome measure description of the corresponding event rates. |
Countries
Austria, Brazil, Chile, Czechia, Germany, Hungary, India, Mexico, Peru, Poland, Romania, Russia, South Africa, Spain, Turkey (Türkiye), United States
Participant flow
Recruitment details
The study was conducted in 61 centers (72 were initiated) in 16 countries between October 15, 2009 and March 30, 2011.
Pre-assignment details
A total of 165 patients were screened and 125 were randomized. Forty patients (24.2%) failed the screening selection process, mainly due to noncompliance with the study required Continuous Glucose Monitoring (CGM) performance and other procedures.
Participants by arm
| Arm | Count |
|---|---|
| Lantus (Insulin Glargine) Lantus (insulin glargine) given as basal insulin once a day in the morning by subcutaneous injection.
Dose: titrated to achieve glycemic targets as described in protocol section. | 61 |
| NPH Insulin Neutral Protamine Hagedorn (NPH) human insulin given as basal insulin either once or twice per day by subcutaneous injection.
Dose: titrated to achieve glycemic targets as described in protocol section. | 64 |
| Total | 125 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Family event | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 2 |
| Overall Study | Technical problem with CGM device | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 5 |
Baseline characteristics
| Characteristic | Total | NPH Insulin | Lantus (Insulin Glargine) |
|---|---|---|---|
| Age Continuous | 4.0 years | 4.0 years | 5.0 years |
| Age, Customized <= 3 years | 27 participants | 17 participants | 10 participants |
| Age, Customized > 3 years | 98 participants | 47 participants | 51 participants |
| Duration of diabetes | 1.81 years | 2.05 years | 1.63 years |
| Number of daily basal insulin injections at baseline 1 | 73 participants | 41 participants | 32 participants |
| Number of daily basal insulin injections at baseline 2 | 36 participants | 15 participants | 21 participants |
| Number of daily basal insulin injections at baseline >=3 | 6 participants | 1 participants | 5 participants |
| Number of daily basal insulin injections at baseline Not treated with basal insulin at baseline | 10 participants | 7 participants | 3 participants |
| Race/Ethnicity, Customized Asian/Oriental | 15 participants | 11 participants | 4 participants |
| Race/Ethnicity, Customized Black | 4 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized Caucasian/White | 101 participants | 48 participants | 53 participants |
| Race/Ethnicity, Customized Hispanic | 30 participants | 13 participants | 17 participants |
| Race/Ethnicity, Customized Non Hispanic | 95 participants | 51 participants | 44 participants |
| Race/Ethnicity, Customized Other | 5 participants | 3 participants | 2 participants |
| Sex/Gender, Customized Female | 63 participants | 34 participants | 29 participants |
| Sex/Gender, Customized Male | 62 participants | 30 participants | 32 participants |
| Total daily dose of basal insulin injection at baseline Analyzed | 114 participants | 57 participants | 57 participants |
| Total daily dose of basal insulin injection at baseline Not treated by basal insulin or missing | 11 participants | 7 participants | 4 participants |
| Total daily dose of basal insulin injection at baseline | 7.45 International Units STANDARD_DEVIATION 4.43 | 7.61 International Units STANDARD_DEVIATION 4.77 | 6.00 International Units |
| Total daily dose of bolus insulin injection at baseline Analyzed | 109 participants | 57 participants | 52 participants |
| Total daily dose of bolus insulin injection at baseline Not treated by bolus insulin or missing | 16 participants | 7 participants | 9 participants |
| Total daily dose of bolus insulin injection at baseline | 7.58 International Units STANDARD_DEVIATION 5.77 | 7.98 International Units STANDARD_DEVIATION 7.2 | 7.75 International Units |
| Treated by basal insulin at baseline No | 10 participants | 7 participants | 3 participants |
| Treated by basal insulin at baseline Yes | 115 participants | 57 participants | 58 participants |
| Treated by bolus insulin at baseline No | 13 participants | 6 participants | 7 participants |
| Treated by bolus insulin at baseline Yes | 112 participants | 58 participants | 54 participants |
| Treated by mixed (bolus & basal) insulin at baseline No | 112 participants | 56 participants | 56 participants |
| Treated by mixed (bolus & basal) insulin at baseline Yes | 13 participants | 8 participants | 5 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 30 / 62 | 33 / 63 |
| serious Total, serious adverse events | 8 / 62 | 2 / 63 |
Outcome results
Primary
Event Rate of All Hypoglycemia Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years (Events Per Patient-year)
The rate of all hypoglycemia was calculated from all hypoglycemia episodes which occurred during the 24-week on-treatment period and consisted of: - symptomatic hypoglycemia episodes validated by the study investigator based on entries in patients' diaries, - low continuous glucose monitoring system (CGMS) excursions (interstitial glucose \<70 mg/dL \[3.9 mmol/L\]) confirmed by fingerstick blood glucose (FSBG) \<70 mg/dL, - low FSBG readings (values \<70 mg/dL) performed at other times.
Time frame: 6 months
Population: The efficacy population consisted of all randomized patients who received at least one dose of the study medication (modified intent-to-treat \[mITT\] population). For efficacy analyses, patients were analyzed in the treatment group allocated by the Interactive Voice Response System (IVRS) at randomization (as randomized).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lantus (Insulin Glargine) | Event Rate of All Hypoglycemia Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years (Events Per Patient-year) | 192.75 number of events per patient-year | Standard Deviation 119.28 |
| NPH Insulin | Event Rate of All Hypoglycemia Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years (Events Per Patient-year) | 168.91 number of events per patient-year | Standard Deviation 101.04 |
Comparison: The sample size was calculated to ensure sufficient power so that the upper bound of the 2-sided 95% CI for the Lantus /NPH ratio would not exceed 1.15 based on an expected overall rate of all hypoglycemia of 80 events per patient-year of exposure to NPH insulin and to Lantus. It was planned to randomize at least 45 and up to approximately 60 patients in each of the 2 treatment groups so that at least 70 patients would complete the 24 weeks of treatment.95% CI: [0.97, 1.44]Generalized Linear Model
Secondary
Average Daily Blood Glucose (BG) Based on CGMS Values: End of Treatment and Change From Baseline to End of Treatment
Time frame: baseline, 6 months
Population: Same as for primary endpoint: mITT population. However 1 patient in the NPH group did not have baseline CGM value and 2 other patients (1 in the Lantus group and 1 in the NPH group) did not have on-treatment CGM values.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lantus (Insulin Glargine) | Average Daily Blood Glucose (BG) Based on CGMS Values: End of Treatment and Change From Baseline to End of Treatment | Baseline daily BG (N= 61 & 63) | 11.263 mmol/L | Standard Deviation 1.887 |
| Lantus (Insulin Glargine) | Average Daily Blood Glucose (BG) Based on CGMS Values: End of Treatment and Change From Baseline to End of Treatment | End of treatment daily BG (N= 60 & 63) | 11.085 mmol/L | Standard Deviation 2.077 |
| Lantus (Insulin Glargine) | Average Daily Blood Glucose (BG) Based on CGMS Values: End of Treatment and Change From Baseline to End of Treatment | Absolute change from baseline (N= 60 & 62) | -0.218 mmol/L | Standard Deviation 2.399 |
| NPH Insulin | Average Daily Blood Glucose (BG) Based on CGMS Values: End of Treatment and Change From Baseline to End of Treatment | Baseline daily BG (N= 61 & 63) | 11.170 mmol/L | Standard Deviation 1.986 |
| NPH Insulin | Average Daily Blood Glucose (BG) Based on CGMS Values: End of Treatment and Change From Baseline to End of Treatment | End of treatment daily BG (N= 60 & 63) | 11.712 mmol/L | Standard Deviation 2.166 |
| NPH Insulin | Average Daily Blood Glucose (BG) Based on CGMS Values: End of Treatment and Change From Baseline to End of Treatment | Absolute change from baseline (N= 60 & 62) | 0.501 mmol/L | Standard Deviation 1.906 |
Secondary
Event Rate of Nocturnal Hypoglycemia Defined as the Total Number of All Hypoglycemia Episodes Divided by the Total Duration of the On-treatment Period in Years
Nocturnal hypoglycemia: any event from the all hypoglycemia total that occurred between 23:00 and 07:00 hours.
Time frame: 6 months
Population: Same as for primary endpoint: mITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lantus (Insulin Glargine) | Event Rate of Nocturnal Hypoglycemia Defined as the Total Number of All Hypoglycemia Episodes Divided by the Total Duration of the On-treatment Period in Years | 33.50 number of events per patient-year | Standard Deviation 25.62 |
| NPH Insulin | Event Rate of Nocturnal Hypoglycemia Defined as the Total Number of All Hypoglycemia Episodes Divided by the Total Duration of the On-treatment Period in Years | 30.92 number of events per patient-year | Standard Deviation 24.97 |
Secondary
Event Rate of Nocturnal Symptomatic Hypoglycemia Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years
Nocturnal symptomatic hypoglycemia: any symptomatic hypoglycemic event that occurred between 23:00 and 07:00 hours.
Time frame: 6 months
Population: Same as for primary endpoint: mITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lantus (Insulin Glargine) | Event Rate of Nocturnal Symptomatic Hypoglycemia Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years | 2.38 number of events per patient-year | Standard Deviation 5.42 |
| NPH Insulin | Event Rate of Nocturnal Symptomatic Hypoglycemia Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years | 3.65 number of events per patient-year | Standard Deviation 6.75 |
Secondary
Event Rate of Severe Nocturnal Hypoglycemia Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years
Severe nocturnal symptomatic hypoglycemia: any severe symptomatic hypoglycemic event that occurred between 23:00 and 07:00 hours.
Time frame: 6 months
Population: Same as for primary endpoint: mITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lantus (Insulin Glargine) | Event Rate of Severe Nocturnal Hypoglycemia Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years | 0.04 number of events per patient-year | Standard Deviation 0.29 |
| NPH Insulin | Event Rate of Severe Nocturnal Hypoglycemia Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years | 0.00 number of events per patient-year | Standard Deviation 0 |
Secondary
Event Rate of Severe Symptomatic Hypoglycemia Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years
Severe symptomatic hypoglycemia: any event with clinical symptoms considered to result from a hypoglycemic episode for which the patients required the assistance of a third party (ie, other than the patient, or a parent/usual caregiver; eg, from emergency personnel), because the patients/parents could not treat the event with acute neurological impairment directly resulting from the hypoglycemic event. The occurrence of seizure, coma, unconsciousness, or the use of glucagon, were also to qualify a hypoglycemic episode as severe.
Time frame: 6 months
Population: Same as for primary endpoint: mITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lantus (Insulin Glargine) | Event Rate of Severe Symptomatic Hypoglycemia Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years | 0.14 number of events per patient-year | Standard Deviation 0.55 |
| NPH Insulin | Event Rate of Severe Symptomatic Hypoglycemia Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years | 0.07 number of events per patient-year | Standard Deviation 0.38 |
Secondary
Event Rate of Symptomatic Hypoglycemia (Individual Component of Primary Endpoint) Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years (Events Per Patient-year)
Symptomatic hypoglycemia: any event with clinical symptoms considered to result from hypoglycemia, validated by the study investigator based on data from patient diaries.
Time frame: 6 months
Population: Same as for primary endpoint: mITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lantus (Insulin Glargine) | Event Rate of Symptomatic Hypoglycemia (Individual Component of Primary Endpoint) Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years (Events Per Patient-year) | 25.54 events per patient-year | Standard Deviation 37.25 |
| NPH Insulin | Event Rate of Symptomatic Hypoglycemia (Individual Component of Primary Endpoint) Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years (Events Per Patient-year) | 33.02 events per patient-year | Standard Deviation 47.95 |
Secondary
Glycosylated Hemoglobin A1c (HbA1c): End of Treatment and Change From Baseline to End of Treatment
Time frame: baseline, 6 months
Population: Same as for primary endpoint: mITT population. However post-baseline HbA1c values were missing for 9 patients: 2 patients in the Lantus group and 7 in the NPH group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lantus (Insulin Glargine) | Glycosylated Hemoglobin A1c (HbA1c): End of Treatment and Change From Baseline to End of Treatment | Baseline HbA1c | 8.023 percent HbA1c | Standard Deviation 1.049 |
| Lantus (Insulin Glargine) | Glycosylated Hemoglobin A1c (HbA1c): End of Treatment and Change From Baseline to End of Treatment | End of treatment HbA1c (N = 59 & 57) | 8.071 percent HbA1c | Standard Deviation 0.884 |
| Lantus (Insulin Glargine) | Glycosylated Hemoglobin A1c (HbA1c): End of Treatment and Change From Baseline to End of Treatment | Absolute change from baseline (N = 59 & 57) | 0.036 percent HbA1c | Standard Deviation 0.979 |
| NPH Insulin | Glycosylated Hemoglobin A1c (HbA1c): End of Treatment and Change From Baseline to End of Treatment | Baseline HbA1c | 8.248 percent HbA1c | Standard Deviation 1.429 |
| NPH Insulin | Glycosylated Hemoglobin A1c (HbA1c): End of Treatment and Change From Baseline to End of Treatment | End of treatment HbA1c (N = 59 & 57) | 8.344 percent HbA1c | Standard Deviation 1.161 |
| NPH Insulin | Glycosylated Hemoglobin A1c (HbA1c): End of Treatment and Change From Baseline to End of Treatment | Absolute change from baseline (N = 59 & 57) | 0.000 percent HbA1c | Standard Deviation 1.035 |
Secondary
Glycosylated Hemoglobin A1c (HbA1c): End of Treatment and Change From Baseline to End of Treatment (ANCOVA Estimates)
Assessed using an analysis of covariance (ANCOVA) model with treatment, and randomization strata (baseline number of CGM hypoglycemic excursions \<0.5 events/24hours or ≥0.5 events/24 hours, and baseline HbA1c \<8.5% or ≥8.5%) as fixed effects, and using the baseline value as covariate.
Time frame: baseline, 6 months
Population: Same as for primary endpoint: mITT population.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Lantus (Insulin Glargine) | Glycosylated Hemoglobin A1c (HbA1c): End of Treatment and Change From Baseline to End of Treatment (ANCOVA Estimates) | End of treatment HbA1c (ANCOVA) | 8.139 percent HbA1c | Standard Error 0.1065 |
| Lantus (Insulin Glargine) | Glycosylated Hemoglobin A1c (HbA1c): End of Treatment and Change From Baseline to End of Treatment (ANCOVA Estimates) | Absolute change from baseline HbA1c (ANCOVA) | -0.048 percent HbA1c | Standard Error 0.1065 |
| NPH Insulin | Glycosylated Hemoglobin A1c (HbA1c): End of Treatment and Change From Baseline to End of Treatment (ANCOVA Estimates) | End of treatment HbA1c (ANCOVA) | 8.232 percent HbA1c | Standard Error 0.1134 |
| NPH Insulin | Glycosylated Hemoglobin A1c (HbA1c): End of Treatment and Change From Baseline to End of Treatment (ANCOVA Estimates) | Absolute change from baseline HbA1c (ANCOVA) | 0.045 percent HbA1c | Standard Error 0.1134 |
Secondary
Percentage of Patients Reaching HbA1c Target of Less Than 7.5% at the End of Treatment Visit
Percentage of patients reaching International Society for Pediatric and Adolescent Diabetes (ISPAD)-recommended goals of Glycosylated Hemoglobin A1c \<7.5% at the end of treatment visit.
Time frame: 6 months
Population: The population analyzed consisted of patients from the mITT population (as defined for primary outcome measure) with post-baseline HbA1c values. 2 patients from the Lantus group and 7 from the NPH group had no post-baseline HbA1c value.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lantus (Insulin Glargine) | Percentage of Patients Reaching HbA1c Target of Less Than 7.5% at the End of Treatment Visit | 22.0 percentage of participants |
| NPH Insulin | Percentage of Patients Reaching HbA1c Target of Less Than 7.5% at the End of Treatment Visit | 22.8 percentage of participants |
Other Pre-specified
Blood Glucose Variability Based on All On-treatment CGMS Values
Calculated for any given patient as the standard deviation (SD) of all CGMS interstitial glucose values recorded over all CGMS placements.
Time frame: 6 months
Population: The population analyzed consisted of patients from the mITT population (as defined for primary outcome measure) with on-treatment CGM values (1 patient from the Lantus group and 1 from the NPH group did not have on-treatment CGM).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lantus (Insulin Glargine) | Blood Glucose Variability Based on All On-treatment CGMS Values | 4.954 mmol/L | Standard Deviation 0.826 |
| NPH Insulin | Blood Glucose Variability Based on All On-treatment CGMS Values | 5.089 mmol/L | Standard Deviation 0.731 |
Post Hoc
Event Rate of All Confirmed Low CGMS Excursions (Individual Component of Primary Endpoint) Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years (Events Per Patient-year)
All confirmed low CGMS excursions consisted of all low continuous glucose monitoring system (CGMS) excursions (interstitial glucose \<70 mg/dL \[3.9 mmol/L\]) confirmed by fingerstick blood glucose (FSBG) \<70 mg/dL.
Time frame: 6 months
Population: Same as for primary endpoint: mITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lantus (Insulin Glargine) | Event Rate of All Confirmed Low CGMS Excursions (Individual Component of Primary Endpoint) Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years (Events Per Patient-year) | 74.61 events per patient-year | Standard Deviation 74.09 |
| NPH Insulin | Event Rate of All Confirmed Low CGMS Excursions (Individual Component of Primary Endpoint) Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years (Events Per Patient-year) | 71.60 events per patient-year | Standard Deviation 53.2 |
Post Hoc
Event Rate of All Confirmed Low FSBG (Individual Component of the Primary Endpoint) Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years (Events Per Patient-year)
All confirmed low FSBG consisted of all low FSBG readings (values \<70 mg/dL) performed at other times.
Time frame: 6 months
Population: Same as for primary endpoint: mITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lantus (Insulin Glargine) | Event Rate of All Confirmed Low FSBG (Individual Component of the Primary Endpoint) Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years (Events Per Patient-year) | 192.69 events per patient-year | Standard Deviation 121.78 |
| NPH Insulin | Event Rate of All Confirmed Low FSBG (Individual Component of the Primary Endpoint) Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years (Events Per Patient-year) | 168.24 events per patient-year | Standard Deviation 101.21 |
Other Pre-specified
Nocturnal Blood Glucose Variability Based on All On-treatment CGMS Values
Calculated for any given patient as the standard deviation (SD) of all CGMS interstitial glucose values recorded during the nocturnal time period (between 23:00 and 07:00 hours).
Time frame: 6 months
Population: The population analyzed consisted of patients from the mITT population (as defined for primary outcome measure) with on-treatment CGM values (1 patient from the Lantus group and 1 from the NPH group did not have on-treatment CGM).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lantus (Insulin Glargine) | Nocturnal Blood Glucose Variability Based on All On-treatment CGMS Values | 4.747 mmol/L | Standard Deviation 0.973 |
| NPH Insulin | Nocturnal Blood Glucose Variability Based on All On-treatment CGMS Values | 4.837 mmol/L | Standard Deviation 0.825 |
Other Pre-specified
Number of Patients With Different Types of Hypoglycemia Events
Definitions of the different types of hypoglycemia events provided in the outcome measure description of the corresponding event rates.
Time frame: 6 months
Population: Same as for primary endpoint: mITT population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lantus (Insulin Glargine) | Number of Patients With Different Types of Hypoglycemia Events | Patients with All hypoglycemia | 61 participants |
| Lantus (Insulin Glargine) | Number of Patients With Different Types of Hypoglycemia Events | Patients with symptomatic hypoglycemia | 40 participants |
| Lantus (Insulin Glargine) | Number of Patients With Different Types of Hypoglycemia Events | Patients with severe symptomatic hypoglycemia | 4 participants |
| Lantus (Insulin Glargine) | Number of Patients With Different Types of Hypoglycemia Events | Patients with nocturnal hypoglycemia | 59 participants |
| Lantus (Insulin Glargine) | Number of Patients With Different Types of Hypoglycemia Events | Patients with nocturnal symptomatic hypoglycemia | 17 participants |
| Lantus (Insulin Glargine) | Number of Patients With Different Types of Hypoglycemia Events | Patients with severe noct. sympto. hypoglycemia | 1 participants |
| Lantus (Insulin Glargine) | Number of Patients With Different Types of Hypoglycemia Events | Patients with All confirmed low CGMS excursions | 60 participants |
| Lantus (Insulin Glargine) | Number of Patients With Different Types of Hypoglycemia Events | Patients with All confirmed low FSBG | 61 participants |
| NPH Insulin | Number of Patients With Different Types of Hypoglycemia Events | Patients with All confirmed low FSBG | 63 participants |
| NPH Insulin | Number of Patients With Different Types of Hypoglycemia Events | Patients with All hypoglycemia | 63 participants |
| NPH Insulin | Number of Patients With Different Types of Hypoglycemia Events | Patients with nocturnal symptomatic hypoglycemia | 28 participants |
| NPH Insulin | Number of Patients With Different Types of Hypoglycemia Events | Patients with symptomatic hypoglycemia | 44 participants |
| NPH Insulin | Number of Patients With Different Types of Hypoglycemia Events | Patients with All confirmed low CGMS excursions | 61 participants |
| NPH Insulin | Number of Patients With Different Types of Hypoglycemia Events | Patients with severe symptomatic hypoglycemia | 2 participants |
| NPH Insulin | Number of Patients With Different Types of Hypoglycemia Events | Patients with severe noct. sympto. hypoglycemia | 0 participants |
| NPH Insulin | Number of Patients With Different Types of Hypoglycemia Events | Patients with nocturnal hypoglycemia | 60 participants |
Other Pre-specified
Percent of Blood Glucose (BG) Within the Range of 70 - 180 mg/dL (3.9-10 mmol/L)
Calculated for each patient as the percent of all on-treatment CGMS values falling within the range of 70 - 180 mg/dL (3.9 - 10 mmol/L) inclusive.
Time frame: 6 months
Population: The population analyzed consisted of patients from the mITT population (as defined for primary outcome measure) with on-treatment CGM values (1 patient from the Lantus group and 1 from the NPH group did not have on-treatment CGM).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lantus (Insulin Glargine) | Percent of Blood Glucose (BG) Within the Range of 70 - 180 mg/dL (3.9-10 mmol/L) | 41.667 percent of CGMS values within the range | Standard Deviation 12.048 |
| NPH Insulin | Percent of Blood Glucose (BG) Within the Range of 70 - 180 mg/dL (3.9-10 mmol/L) | 38.158 percent of CGMS values within the range | Standard Deviation 10.908 |