6-month Comparison of Morning Lantus Versus Neutral Protamine Hagedorn Insulin in Young Children With Type 1 Diabetes

Study Overview
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Brief Summary
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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
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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

Official Title
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A 24-week, Randomized, Open-label, Parallel Group Multinational Comparison of Lantus® (Insulin Glargine) Given in the Morning as Once-a-day Basal Insulin Versus Neutral Protamine Hagedorn (NPH) Insulin, in Children With Type 1 Diabetes Mellitus Aged at Least 1 Year to Less Than 6 Years

Conditions
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Type 1 Diabetes Mellitus

Intervention / Treatment
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* Drug: Insulin glargine (HOE901)
* Drug: Neutral Protamine Hagedorn (NPH) insulin
* Drug: Insulin lispro


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lantus (insulin glargine)<br>Lantus given as basal insulin once a day in the morning by subcutaneous injection | Drug: Insulin glargine (HOE901)<br>* 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%.<br>* Other names: Lantus®;Drug: Insulin lispro<br>* 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.<br>* Other names: Humalog®;|
| Active Comparator: NPH insulin<br>Neutral Protamine Hagedorn (NPH) human insulin given as basal insulin either once or twice per day generally in the morning and /or at bedtime by subcutaneous injection | Drug: Neutral Protamine Hagedorn (NPH) insulin<br>* 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<br>Drug: Insulin lispro<br>* 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.<br>* Other names: Humalog®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 6 months | 
| 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. | 6 months | 
| 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. | 6 months | 
| 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. | 6 months | 
| 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. | 6 months | 
| 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) | 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. | baseline, 6 months | 
| 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. | 6 months | 
| Average Daily Blood Glucose (BG) Based on CGMS Values: End of Treatment and Change From Baseline to End of Treatment |  | baseline, 6 months |