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

• Sponsor: Sanofi (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00993473
• Collaborator: (none)
• Enrollment: 125
• Locations: 61
• Arms: 2
• Duration (Months): 17
• Patients Per Site: 2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Type 1 Diabetes Mellitus	Drug: Insulin glargine (HOE901); Drug: Neutral Protamine Hagedorn (NPH) insulin; Drug: Insulin lispro	Phase 3

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 Design

• Study Type: Interventional
• Actual Enrollment: 125 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Oct 1, 2009
• Actual Primary Completion Date: Mar 1, 2011
• Actual Study Completion Date: Mar 1, 2011

Arms and Interventions

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: 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; 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®

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. Glycosylated Hemoglobin A1c (HbA1c): End of Treatment and Change From Baseline to End of Treatment [baseline, 6 months]

7. 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.

8. 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.

9. 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

1. 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.

2. 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.

3. 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.

4. 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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 6 Years
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sanofi-Aventis Investigational Site Number 840006	Sacramento	California	United States	95819
2	Sanofi-Aventis Investigational Site Number 840014	San Diego	California	United States	92123
3	Sanofi-Aventis Investigational Site Number 840005	Greenwood Village	Colorado	United States	80111
4	Sanofi-Aventis Investigational Site Number 840008	Baltimore	Maryland	United States	21229
5	Sanofi-Aventis Investigational Site Number 840007	Buffalo	New York	United States	14222
6	Sanofi-Aventis Investigational Site Number 840011	Philadelphia	Pennsylvania	United States	19104
7	Sanofi-Aventis Investigational Site Number 840010	Houston	Texas	United States	77030
8	Sanofi-Aventis Investigational Site Number 840002	San Antonio	Texas	United States	78229
9	Sanofi-Aventis Investigational Site Number 040001	Wien		Austria	1090
10	Sanofi-Aventis Investigational Site Number 076001	Brasilia		Brazil	71625-009
11	Sanofi-Aventis Investigational Site Number 076003	Curitiba		Brazil	80810-040
12	Sanofi-Aventis Investigational Site Number 076005	Fortaleza		Brazil	60135-170
13	Sanofi-Aventis Investigational Site Number 076004	Fortaleza		Brazil	60430-370
14	Sanofi-Aventis Investigational Site Number 076002	Porto Alegre		Brazil	91350-250
15	Sanofi-Aventis Investigational Site Number 076006	Rio De Janeiro		Brazil	20211-340
16	Sanofi-Aventis Investigational Site Number 152002	Santiago		Chile	7830489
17	Sanofi-Aventis Investigational Site Number 152003	Santiago		Chile	8207257
18	Sanofi-Aventis Investigational Site Number 152001	Santiago		Chile	8910095
19	Sanofi-Aventis Investigational Site Number 152004	Viña Del Mar		Chile	257-0017
20	Sanofi-Aventis Investigational Site Number 203001	Olomouc		Czech Republic	77520
21	Sanofi-Aventis Investigational Site Number 203003	Pardubice		Czech Republic	53203
22	Sanofi-Aventis Investigational Site Number 203002	Usti Nad Labem		Czech Republic	40113
23	Sanofi-Aventis Investigational Site Number 276002	Düsseldorf		Germany	40225
24	Sanofi-Aventis Investigational Site Number 276003	Münster		Germany	48155
25	Sanofi-Aventis Investigational Site Number 348004	Budapest		Hungary	1023
26	Sanofi-Aventis Investigational Site Number 348005	Budapest		Hungary	1089
27	Sanofi-Aventis Investigational Site Number 348003	Miskolc		Hungary	3526
28	Sanofi-Aventis Investigational Site Number 348002	Szeged		Hungary	6701
29	Sanofi-Aventis Investigational Site Number 348001	Szombathely		Hungary	9700
30	Sanofi-Aventis Investigational Site Number 356003	Bangalore		India	560043
31	Sanofi-Aventis Investigational Site Number 356005	Bangalore		India	560052
32	Sanofi-Aventis Investigational Site Number 356001	Bangalore		India
33	Sanofi-Aventis Investigational Site Number 356002	Indore		India	452001
34	Sanofi-Aventis Investigational Site Number 356004	Karnal		India	132001
35	Sanofi-Aventis Investigational Site Number 484002	Guadalajara		Mexico	44620
36	Sanofi-Aventis Investigational Site Number 484003	Monterrey		Mexico	64640
37	Sanofi-Aventis Investigational Site Number 484001	Puebla		Mexico	72190
38	Sanofi-Aventis Investigational Site Number 604003	Lima		Peru	Lima 01
39	Sanofi-Aventis Investigational Site Number 604002	Lima		Peru	Lima 5
40	Sanofi-Aventis Investigational Site Number 604001	Lima		Peru
41	Sanofi-Aventis Investigational Site Number 616002	Gdansk		Poland
42	Sanofi-Aventis Investigational Site Number 616001	Warszawa		Poland	04-730
43	Sanofi-Aventis Investigational Site Number 642008	Bucharest		Romania	041451
44	Sanofi-Aventis Investigational Site Number 642001	Cluj Napoca		Romania	400370
45	Sanofi-Aventis Investigational Site Number 642011	Constanta		Romania	900591
46	Sanofi-Aventis Investigational Site Number 642006	Sibiu		Romania	550166
47	Sanofi-Aventis Investigational Site Number 643001	Moscow		Russian Federation	117036
48	Sanofi-Aventis Investigational Site Number 643002	Moscow		Russian Federation	119049
49	Sanofi-Aventis Investigational Site Number 643003	St-Petersburg		Russian Federation	193144
50	Sanofi-Aventis Investigational Site Number 643004	Ufa		Russian Federation	450000
51	Sanofi-Aventis Investigational Site Number 643005	Yaroslavl		Russian Federation	150042
52	Sanofi-Aventis Investigational Site Number 710004	Durban		South Africa
53	Sanofi-Aventis Investigational Site Number 710002	Johannesburg		South Africa	2193
54	Sanofi-Aventis Investigational Site Number 710001	Observatory		South Africa	7925
55	Sanofi-Aventis Investigational Site Number 710003	Pretoria		South Africa	0084
56	Sanofi-Aventis Investigational Site Number 724003	Santiago De Compostela		Spain	15706
57	Sanofi-Aventis Investigational Site Number 724001	Sevilla		Spain	41013
58	Sanofi-Aventis Investigational Site Number 724005	Valencia		Spain	46010
59	Sanofi-Aventis Investigational Site Number 724004	Zaragoza		Spain	50009
60	Sanofi-Aventis Investigational Site Number 792001	Ankara		Turkey	06100
61	Sanofi-Aventis Investigational Site Number 792003	Istanbul		Turkey	34000

Sponsors and Collaborators

• Sanofi

Investigators

• Study Director: Clinical Sciences & Operations, Sanofi

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT00993473
• Other Study ID Numbers: EFC11202; 2009-011231-12
• First Posted: Oct 12, 2009
• Last Update Posted: Jun 27, 2012
• Last Verified: Jun 1, 2012

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Insulin; Insulin, Globin Zinc; Insulin Glargine; Insulin Lispro; Protamines

Study Results

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 Detail	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.

Arm/Group Title	Lantus (Insulin Glargine)	NPH Insulin
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	61	64
COMPLETED	57	54
NOT COMPLETED	4	10

Baseline Characteristics

Arm/Group Title	Lantus (Insulin Glargine)	NPH Insulin	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	61	64	125
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	4.3 (0.9)	4.1 (1.0)	4.2 (1.0)
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	5.0	4.0	4.0
Age, Customized (participants) [Number]
<= 3 years	10 16.4%	17 26.6%	27 21.6%
> 3 years	51 83.6%	47 73.4%	98 78.4%
Sex/Gender, Customized (participants) [Number]
Male	32 52.5%	30 46.9%	62 49.6%
Female	29 47.5%	34 53.1%	63 50.4%
Race/Ethnicity, Customized (participants) [Number]
Caucasian/White	53 86.9%	48 75%	101 80.8%
Black	2 3.3%	2 3.1%	4 3.2%
Asian/Oriental	4 6.6%	11 17.2%	15 12%
Other	2 3.3%	3 4.7%	5 4%
Race/Ethnicity, Customized (participants) [Number]
Hispanic	17 27.9%	13 20.3%	30 24%
Non Hispanic	44 72.1%	51 79.7%	95 76%
Duration of diabetes (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	2.12 (1.16)	2.12 (1.01)	2.12 (1.08)
Duration of diabetes (years) [Median (Full Range) ]
Median (Full Range) [years]	1.63	2.05	1.81
Treated by bolus insulin at baseline (participants) [Number]
Yes	54 88.5%	58 90.6%	112 89.6%
No	7 11.5%	6 9.4%	13 10.4%
Treated by basal insulin at baseline (participants) [Number]
Yes	58 95.1%	57 89.1%	115 92%
No	3 4.9%	7 10.9%	10 8%
Treated by mixed (bolus & basal) insulin at baseline (participants) [Number]
Yes	5 8.2%	8 12.5%	13 10.4%
No	56 91.8%	56 87.5%	112 89.6%
Number of daily basal insulin injections at baseline (participants) [Number]
1	32 52.5%	41 64.1%	73 58.4%
2	21 34.4%	15 23.4%	36 28.8%
>=3	5 8.2%	1 1.6%	6 4.8%
Not treated with basal insulin at baseline	3 4.9%	7 10.9%	10 8%
Total daily dose of basal insulin injection at baseline (participants) [Number]
Analyzed	57 93.4%	57 89.1%	114 91.2%
Not treated by basal insulin or missing	4 6.6%	7 10.9%	11 8.8%
Total daily dose of basal insulin injection at baseline (International Units) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [International Units]	7.29 (4.11)	7.61 (4.77)	7.45 (4.43)
Total daily dose of basal insulin injection at baseline (International Units) [Median (Full Range) ]
Median (Full Range) [International Units]	6.00	6.00	6.00
Total daily dose of bolus insulin injection at baseline (participants) [Number]
Analyzed	52 85.2%	57 89.1%	109 87.2%
Not treated by bolus insulin or missing	9 14.8%	7 10.9%	16 12.8%
Total daily dose of bolus insulin injection at baseline (International Units) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [International Units]	7.14 (3.64)	7.98 (7.20)	7.58 (5.77)
Total daily dose of bolus insulin injection at baseline (International Units) [Median (Full Range) ]
Median (Full Range) [International Units]	7.75	7.00	7.00

Outcome Measures

1. Primary Outcome

Title	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)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Lantus (Insulin Glargine)	NPH Insulin
Arm/Group Description	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.	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.
Measure Participants	61	64
Mean (Standard Deviation) [number of events per patient-year]	192.75 (119.28)	168.91 (101.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lantus (Insulin Glargine), NPH Insulin
	Comments	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.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Noninferiority would be demonstrated if the upper bound of the 95% confidence interval (CI) for the ratio of the rate of "all hypoglycemia" in the Lantus group to the rate in the NPH group was <1.15. Superiority would be demonstrated if the upper bound of the 95% CI was <1. The margin for noninferiority corresponded to one-half of the 30% difference in hypoglycemia event rate considered as a clinically significant difference by American Diabetes Association 2005 Working Group on Hypoglycemia.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.18
	Confidence Interval	(2-Sided) 95%; 0.97 to 1.44
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments	Risk ratio between treatment groups (Lantus/NPH) estimated by Generalized Linear Model with fixed effect terms for randomization strata and treatment.

2. Secondary Outcome

Title	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)
Description	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

Outcome Measure Data

Analysis Population Description

Same as for primary endpoint: mITT population.

Arm/Group Title	Lantus (Insulin Glargine)	NPH Insulin
Arm/Group Description	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.	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.
Measure Participants	61	64
Mean (Standard Deviation) [events per patient-year]	25.54 (37.25)	33.02 (47.95)

3. Secondary Outcome

Title	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
Description	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

Outcome Measure Data

Analysis Population Description

Same as for primary endpoint: mITT population.

Arm/Group Title	Lantus (Insulin Glargine)	NPH Insulin
Arm/Group Description	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.	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.
Measure Participants	61	64
Measure Episodes	4	2
Mean (Standard Deviation) [number of events per patient-year]	0.14 (0.55)	0.07 (0.38)

4. Secondary Outcome

Title	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
Description	Nocturnal hypoglycemia: any event from the "all hypoglycemia" total that occurred between 23:00 and 07:00 hours.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Same as for primary endpoint: mITT population.

Arm/Group Title	Lantus (Insulin Glargine)	NPH Insulin
Arm/Group Description	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.	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.
Measure Participants	61	64
Mean (Standard Deviation) [number of events per patient-year]	33.50 (25.62)	30.92 (24.97)

5. Secondary Outcome

Title	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
Description	Nocturnal symptomatic hypoglycemia: any symptomatic hypoglycemic event that occurred between 23:00 and 07:00 hours.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Same as for primary endpoint: mITT population.

Arm/Group Title	Lantus (Insulin Glargine)	NPH Insulin
Arm/Group Description	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.	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.
Measure Participants	61	64
Mean (Standard Deviation) [number of events per patient-year]	2.38 (5.42)	3.65 (6.75)

6. Secondary Outcome

Title	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
Description	Severe nocturnal symptomatic hypoglycemia: any severe symptomatic hypoglycemic event that occurred between 23:00 and 07:00 hours.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Same as for primary endpoint: mITT population.

Arm/Group Title	Lantus (Insulin Glargine)	NPH Insulin
Arm/Group Description	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.	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.
Measure Participants	61	64
Measure Episodes	1	0
Mean (Standard Deviation) [number of events per patient-year]	0.04 (0.29)	0.00 (0.00)

7. Secondary Outcome

Title	Glycosylated Hemoglobin A1c (HbA1c): End of Treatment and Change From Baseline to End of Treatment
Time Frame	baseline, 6 months

Outcome Measure Data

Analysis Population Description

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/Group Title	Lantus (Insulin Glargine)	NPH Insulin
Arm/Group Description	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.	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.
Measure Participants	61	64
Baseline HbA1c	8.023 (1.049)	8.248 (1.429)
End of treatment HbA1c (N = 59 & 57)	8.071 (0.884)	8.344 (1.161)
Absolute change from baseline (N = 59 & 57)	0.036 (0.979)	0.000 (1.035)

8. Secondary Outcome

Title	Glycosylated Hemoglobin A1c (HbA1c): End of Treatment and Change From Baseline to End of Treatment (ANCOVA Estimates)
Description	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

Outcome Measure Data

Analysis Population Description

Same as for primary endpoint: mITT population.

Arm/Group Title	Lantus (Insulin Glargine)	NPH Insulin
Arm/Group Description	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.	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.
Measure Participants	61	64
End of treatment HbA1c (ANCOVA)	8.139 (0.1065)	8.232 (0.1134)
Absolute change from baseline HbA1c (ANCOVA)	-0.048 (0.1065)	0.045 (0.1134)

9. Secondary Outcome

Title	Percentage of Patients Reaching HbA1c Target of Less Than 7.5% at the End of Treatment Visit
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Lantus (Insulin Glargine)	NPH Insulin
Arm/Group Description	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.	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.
Measure Participants	59	57
Number [percentage of participants]	22.0 36.1%	22.8 35.6%

10. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Lantus (Insulin Glargine)	NPH Insulin
Arm/Group Description	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.	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.
Measure Participants	61	64
Baseline daily BG (N= 61 & 63)	11.263 (1.887)	11.170 (1.986)
End of treatment daily BG (N= 60 & 63)	11.085 (2.077)	11.712 (2.166)
Absolute change from baseline (N= 60 & 62)	-0.218 (2.399)	0.501 (1.906)

11. Other Pre-specified Outcome

Title	Number of Patients With Different Types of Hypoglycemia Events
Description	Definitions of the different types of hypoglycemia events provided in the outcome measure description of the corresponding event rates.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Same as for primary endpoint: mITT population.

Arm/Group Title	Lantus (Insulin Glargine)	NPH Insulin
Arm/Group Description	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.	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.
Measure Participants	61	64
Patients with "All hypoglycemia"	61 100%	63 98.4%
Patients with symptomatic hypoglycemia	40 65.6%	44 68.8%
Patients with severe symptomatic hypoglycemia	4 6.6%	2 3.1%
Patients with nocturnal hypoglycemia	59 96.7%	60 93.8%
Patients with nocturnal symptomatic hypoglycemia	17 27.9%	28 43.8%
Patients with severe noct. sympto. hypoglycemia	1 1.6%	0 0%
Patients with "All confirmed low CGMS excursions"	60 98.4%	61 95.3%
Patients with "All confirmed low FSBG"	61 100%	63 98.4%

12. Other Pre-specified Outcome

Title	Percent of Blood Glucose (BG) Within the Range of 70 - 180 mg/dL (3.9-10 mmol/L)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Lantus (Insulin Glargine)	NPH Insulin
Arm/Group Description	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.	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.
Measure Participants	60	63
Mean (Standard Deviation) [percent of CGMS values within the range]	41.667 (12.048)	38.158 (10.908)

13. Other Pre-specified Outcome

Title	Blood Glucose Variability Based on All On-treatment CGMS Values
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Lantus (Insulin Glargine)	NPH Insulin
Arm/Group Description	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.	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.
Measure Participants	60	63
Mean (Standard Deviation) [mmol/L]	4.954 (0.826)	5.089 (0.731)

14. Post-Hoc Outcome

Title	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)
Description	"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

Outcome Measure Data

Analysis Population Description

Same as for primary endpoint: mITT population.

Arm/Group Title	Lantus (Insulin Glargine)	NPH Insulin
Arm/Group Description	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.	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.
Measure Participants	61	64
Mean (Standard Deviation) [events per patient-year]	74.61 (74.09)	71.60 (53.20)

15. Post-Hoc Outcome

Title	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)
Description	"All confirmed low FSBG" consisted of all low FSBG readings (values <70 mg/dL) performed at other times.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Same as for primary endpoint: mITT population.

Arm/Group Title	Lantus (Insulin Glargine)	NPH Insulin
Arm/Group Description	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.	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.
Measure Participants	61	64
Mean (Standard Deviation) [events per patient-year]	192.69 (121.78)	168.24 (101.21)

16. Other Pre-specified Outcome

Title	Nocturnal Blood Glucose Variability Based on All On-treatment CGMS Values
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Lantus (Insulin Glargine)	NPH Insulin
Arm/Group Description	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.	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.
Measure Participants	60	63
Mean (Standard Deviation) [mmol/L]	4.747 (0.973)	4.837 (0.825)

Adverse Events

Time Frame	Adverse events were monitored from baseline to 7 days after last treatment visit.
Adverse Event Reporting Description	The safety analyses were conducted according to the treatment received rather than according to the randomization groups.
Arm/Group Title	Lantus		NPH Insulin
Arm/Group Description
All Cause Mortality
	Lantus		NPH Insulin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Lantus		NPH Insulin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/62 (12.9%)		2/63 (3.2%)
Gastrointestinal disorders
Gastritis	2/62 (3.2%)		0/63 (0%)
Abdominal pain	1/62 (1.6%)		0/63 (0%)
Infections and infestations
Viral infection	1/62 (1.6%)		0/63 (0%)
Lower respiratory tract infection	0/62 (0%)		1/63 (1.6%)
Metabolism and nutrition disorders
Hypoglycaemic seizure	2/62 (3.2%)		0/63 (0%)
Dehydration	1/62 (1.6%)		0/63 (0%)
Diabetic ketoacidosis	1/62 (1.6%)		1/63 (1.6%)
Other (Not Including Serious) Adverse Events
	Lantus		NPH Insulin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/62 (48.4%)		33/63 (52.4%)
Gastrointestinal disorders
Vomiting	5/62 (8.1%)		4/63 (6.3%)
General disorders
Device lead damage	5/62 (8.1%)		2/63 (3.2%)
Pyrexia	3/62 (4.8%)		7/63 (11.1%)
Infections and infestations
Gastroenteritis	6/62 (9.7%)		6/63 (9.5%)
Nasopharyngitis	6/62 (9.7%)		5/63 (7.9%)
Pharyngitis	6/62 (9.7%)		2/63 (3.2%)
Upper respiratory tract infection	4/62 (6.5%)		6/63 (9.5%)
Bronchitis	3/62 (4.8%)		5/63 (7.9%)
Otitis media	1/62 (1.6%)		4/63 (6.3%)
Tonsillitis	1/62 (1.6%)		4/63 (6.3%)
Respiratory, thoracic and mediastinal disorders
Cough	2/62 (3.2%)		4/63 (6.3%)

Limitations/Caveats

There are numerous potential biases that could affect the timing and frequency of performance of sporadic FSBG, such as mealtime dosing and choice of bolus insulin dose, stability and familiarity with insulin regimens, and parental anxiety levels.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.