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

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

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

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes Mellitus
• Intervention / Treatment: Drug: Insulin glargine (HOE901); Drug: Insulin lispro; Drug: Neutral Protamine Hagedorn (NPH) insulin

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

• Study Type: Interventional
• Enrollment (Actual): 125
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Wien, Austria, 1090
    • Sanofi-Aventis Investigational Site Number 040001
• Brazil
  • Brasilia, Brazil, 71625-009
    • Sanofi-Aventis Investigational Site Number 076001
  • Curitiba, Brazil, 80810-040
    • Sanofi-Aventis Investigational Site Number 076003
  • Fortaleza, Brazil, 60135-170
    • Sanofi-Aventis Investigational Site Number 076005
  • Fortaleza, Brazil, 60430-370
    • Sanofi-Aventis Investigational Site Number 076004
  • Porto Alegre, Brazil, 91350-250
    • Sanofi-Aventis Investigational Site Number 076002
  • Rio De Janeiro, Brazil, 20211-340
    • Sanofi-Aventis Investigational Site Number 076006
• Chile
  • Santiago, Chile, 7830489
    • Sanofi-Aventis Investigational Site Number 152002
  • Santiago, Chile, 8207257
    • Sanofi-Aventis Investigational Site Number 152003
  • Santiago, Chile, 8910095
    • Sanofi-Aventis Investigational Site Number 152001
  • Viña Del Mar, Chile, 257-0017
    • Sanofi-Aventis Investigational Site Number 152004
• Czech Republic
  • Olomouc, Czech Republic, 77520
    • Sanofi-Aventis Investigational Site Number 203001
  • Pardubice, Czech Republic, 53203
    • Sanofi-Aventis Investigational Site Number 203003
  • Usti Nad Labem, Czech Republic, 40113
    • Sanofi-Aventis Investigational Site Number 203002
• Germany
  • Düsseldorf, Germany, 40225
    • Sanofi-Aventis Investigational Site Number 276002
  • Münster, Germany, 48155
    • Sanofi-Aventis Investigational Site Number 276003
• Hungary
  • Budapest, Hungary, 1023
    • Sanofi-Aventis Investigational Site Number 348004
  • Budapest, Hungary, 1089
    • Sanofi-Aventis Investigational Site Number 348005
  • Miskolc, Hungary, 3526
    • Sanofi-Aventis Investigational Site Number 348003
  • Szeged, Hungary, 6701
    • Sanofi-Aventis Investigational Site Number 348002
  • Szombathely, Hungary, 9700
    • Sanofi-Aventis Investigational Site Number 348001
• India
  • Bangalore, India, 560043
    • Sanofi-Aventis Investigational Site Number 356003
  • Bangalore, India, 560052
    • Sanofi-Aventis Investigational Site Number 356005
  • Bangalore, India
    • Sanofi-Aventis Investigational Site Number 356001
  • Indore, India, 452001
    • Sanofi-Aventis Investigational Site Number 356002
  • Karnal, India, 132001
    • Sanofi-Aventis Investigational Site Number 356004
• Mexico
  • Guadalajara, Mexico, 44620
    • Sanofi-Aventis Investigational Site Number 484002
  • Monterrey, Mexico, 64640
    • Sanofi-Aventis Investigational Site Number 484003
  • Puebla, Mexico, 72190
    • Sanofi-Aventis Investigational Site Number 484001
• Peru
  • Lima, Peru, Lima 01
    • Sanofi-Aventis Investigational Site Number 604003
  • Lima, Peru, Lima 5
    • Sanofi-Aventis Investigational Site Number 604002
  • Lima, Peru
    • Sanofi-Aventis Investigational Site Number 604001
• Poland
  • Gdansk, Poland
    • Sanofi-Aventis Investigational Site Number 616002
  • Warszawa, Poland, 04-730
    • Sanofi-Aventis Investigational Site Number 616001
• Romania
  • Bucharest, Romania, 041451
    • Sanofi-Aventis Investigational Site Number 642008
  • Cluj Napoca, Romania, 400370
    • Sanofi-Aventis Investigational Site Number 642001
  • Constanta, Romania, 900591
    • Sanofi-Aventis Investigational Site Number 642011
  • Sibiu, Romania, 550166
    • Sanofi-Aventis Investigational Site Number 642006
• Russian Federation
  • Moscow, Russian Federation, 117036
    • Sanofi-Aventis Investigational Site Number 643001
  • Moscow, Russian Federation, 119049
    • Sanofi-Aventis Investigational Site Number 643002
  • St-Petersburg, Russian Federation, 193144
    • Sanofi-Aventis Investigational Site Number 643003
  • Ufa, Russian Federation, 450000
    • Sanofi-Aventis Investigational Site Number 643004
  • Yaroslavl, Russian Federation, 150042
    • Sanofi-Aventis Investigational Site Number 643005
• South Africa
  • Durban, South Africa
    • Sanofi-Aventis Investigational Site Number 710004
  • Johannesburg, South Africa, 2193
    • Sanofi-Aventis Investigational Site Number 710002
  • Observatory, South Africa, 7925
    • Sanofi-Aventis Investigational Site Number 710001
  • Pretoria, South Africa, 0084
    • Sanofi-Aventis Investigational Site Number 710003
• Spain
  • Santiago De Compostela, Spain, 15706
    • Sanofi-Aventis Investigational Site Number 724003
  • Sevilla, Spain, 41013
    • Sanofi-Aventis Investigational Site Number 724001
  • Valencia, Spain, 46010
    • Sanofi-Aventis Investigational Site Number 724005
  • Zaragoza, Spain, 50009
    • Sanofi-Aventis Investigational Site Number 724004
• Turkey
  • Ankara, Turkey, 06100
    • Sanofi-Aventis Investigational Site Number 792001
  • Istanbul, Turkey, 34000
    • Sanofi-Aventis Investigational Site Number 792003
• United States
  • California
    • Sacramento, California, United States, 95819
      • Sanofi-Aventis Investigational Site Number 840006
    • San Diego, California, United States, 92123
      • Sanofi-Aventis Investigational Site Number 840014
  • Colorado
    • Greenwood Village, Colorado, United States, 80111
      • Sanofi-Aventis Investigational Site Number 840005
  • Maryland
    • Baltimore, Maryland, United States, 21229
      • Sanofi-Aventis Investigational Site Number 840008
  • New York
    • Buffalo, New York, United States, 14222
      • Sanofi-Aventis Investigational Site Number 840007
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Sanofi-Aventis Investigational Site Number 840011
  • Texas
    • Houston, Texas, United States, 77030
      • Sanofi-Aventis Investigational Site Number 840010
    • San Antonio, Texas, United States, 78229
      • Sanofi-Aventis Investigational Site Number 840002

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 months to 4 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lantus (insulin glargine); Lantus given as basal insulin once a day in the morning by subcutaneous injection	Drug: Insulin glargine (HOE901); 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%.; Other Names: Lantus®; Drug: Insulin 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.; Other Names: Humalog®
Active Comparator: NPH insulin; 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: Insulin 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.; Other Names: Humalog®; Drug: Neutral Protamine Hagedorn (NPH) insulin; 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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	6 months
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.	6 months
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.	6 months
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).	6 months

Collaborators and Investigators

• Sponsor: Sanofi

Publications and helpful links

General Publications

• Danne T, Becker RH, Ping L, Philotheou A. Insulin glargine metabolite 21(A) -Gly-human insulin (M1) is the principal component circulating in the plasma of young children with type 1 diabetes: results from the PRESCHOOL study. Pediatr Diabetes. 2015 Jun;16(4):299-304. doi: 10.1111/pedi.12161. Epub 2014 Jul 9.

Study record dates

Study Major Dates

• Study Start: October 1, 2009
• Primary Completion (Actual): March 1, 2011
• Study Completion (Actual): March 1, 2011

Study Registration Dates

• First Submitted: October 9, 2009
• First Submitted That Met QC Criteria: October 9, 2009
• First Posted (Estimate): October 12, 2009

Study Record Updates

• Last Update Posted (Estimate): June 27, 2012
• Last Update Submitted That Met QC Criteria: June 25, 2012
• Last Verified: June 1, 2012

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Coagulants; Heparin Antagonists; Insulin; Insulin, Globin Zinc; Insulin Glargine; Insulin Lispro; Protamines
• Other Study ID Numbers: EFC11202; 2009-011231-12 (EudraCT Number)