Comparison of the Safety and Efficacy of HOE901-U300 With Lantus in Children and Adolescents With Type 1 Diabetes Mellitus (EDITION JUNIOR)

6-Month, Multicenter, Randomized, Open-label, 2-Arm, Parallel-group Study Comparing the Efficacy and Safety of a New Formulation of Insulin Glargine and Lantus® Injected Once Daily in Children and Adolescents Age 6 - 17 Years With Type 1 Diabetes Mellitus With a 6-month Safety Extension Period

Primary Objective:

To compare the efficacy of a new formulation of insulin glargine (HOE901-U300) to Lantus in terms of change of HbA1c from baseline to endpoint (month 6) in children and adolescents with type 1 diabetes mellitus.

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Secondary Objectives:

To compare HOE901-U300 and Lantus in terms of:

• Percentage of participants reaching target HbA1c and fasting plasma glucose (FPG).
• To assess the safety of HOE901-U300 including analysis of events of hypoglycemia, events of hyperglycemia with ketosis, and development of anti-insulin-antibodies.

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes Mellitus
• Intervention / Treatment: Drug: Insulin glargine,300 U/mL; Drug: Background therapy; Drug: Insulin glargine (100 units /mL)

Detailed Description

The study duration per participant was approximately 58 weeks that consisted of a 2 week screening period, a main 6-month comparative efficacy and safety treatment period, a 6-month comparative safety extension period, and a 4-week post treatment follow up period.

• Study Type: Interventional
• Enrollment (Actual): 463
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Caba, Argentina, C1180AAX
    • Investigational Site Number 0320003
  • Caba, Argentina, C1270AAN
    • Investigational Site Number 0320001
  • Capital Federal, Argentina, C1179AAB
    • Investigational Site Number 0320004
  • Capital Federal, Argentina, C1425DUC
    • Investigational Site Number 0320002
  • Mendoza, Argentina, 5500
    • Investigational Site Number 0320006
  • Salta, Argentina, 4400
    • Investigational Site Number 0320005
  • San Miguel De Tucuman, Argentina, 4107
    • Investigational Site Number 0320007
• Brazil
  • Curitiba, Brazil, 80810-040
    • Investigational Site Number 0760005
  • Fortaleza, Brazil, 60430-350
    • Investigational Site Number 0760004
  • Fortaleza, Brazil, 60115-282
    • Investigational Site Number 0760006
  • Porto Alegre, Brazil, 91350-250
    • Investigational Site Number 0760003
  • Sao Paulo, Brazil, 04022-001
    • Investigational Site Number 0760001
  • Sao Paulo, Brazil
    • Investigational Site Number 0760002
• Bulgaria
  • Plovdiv, Bulgaria, 4000
    • Investigational Site Number 1000001
  • Sofia, Bulgaria, 1784
    • Investigational Site Number 1000005
  • Varna, Bulgaria, 9000
    • Investigational Site Number 1000004
• Canada
  • Halifax, Canada, B3K6R8
    • Investigational Site Number 1240003
  • Montreal, Canada, H1T 2M4
    • Investigational Site Number 1240002
  • Montreal, Canada, H3T 1C5
    • Investigational Site Number 1240005
  • Sherbrooke, Canada, J1H 5N4
    • Investigational Site Number 1240006
• Chile
  • Santiago, Chile, 8207257
    • Investigational Site Number 1520002
  • Santiago, Chile, 8330074
    • Investigational Site Number 1520004
  • Santiago, Chile
    • Investigational Site Number 1520006
  • Temuco, Chile, 4813299
    • Investigational Site Number 1520007
  • Viña Del Mar, Chile
    • Investigational Site Number 1520003
• Czechia
  • Hradec Kralove, Czechia, 500 05
    • Investigational Site Number 2030003
  • Ostrava - Poruba, Czechia, 70852
    • Investigational Site Number 2030005
  • Praha 5 - Motol, Czechia, 15006
    • Investigational Site Number 2030001
• Denmark
  • Herlev, Denmark, 2730
    • Investigational Site Number 2080001
• France
  • Montpellier, France, 34295
    • Investigational Site Number 2500003
  • Toulouse, France, 31059
    • Investigational Site Number 2500002
• Germany
  • Hannover, Germany, 30173
    • Investigational Site Number 2760002
  • Heidelberg, Germany, 69120
    • Investigational Site Number 2760001
  • Leipzig, Germany, 04103
    • Investigational Site Number 2760004
  • Münster, Germany, 48155
    • Investigational Site Number 2760003
• Hungary
  • Budapest, Hungary, 1036
    • Investigational Site Number 3480001
  • Budapest, Hungary, 1083
    • Investigational Site Number 3480004
  • Budapest, Hungary, 1089
    • Investigational Site Number 3480003
  • Gyula, Hungary, 5700
    • Investigational Site Number 3480005
  • Miskolc, Hungary, 3529
    • Investigational Site Number 3480002
  • Pécs, Hungary, 7623
    • Investigational Site Number 3480006
  • Székesfehérvár, Hungary, 8000
    • Investigational Site Number 3480007
• Israel
  • Beer Sheva, Israel, 84101
    • Investigational Site Number 3760003
  • Haifa, Israel, 31096
    • Investigational Site Number 3760001
  • Holon, Israel, 58100
    • Investigational Site Number 3760006
  • Petach Tikva, Israel
    • Investigational Site Number 3760002
• Italy
  • Firenze, Italy, 50139
    • Investigational Site Number 3800001
  • Roma, Italy, 00165
    • Investigational Site Number 3800005
  • Torino, Italy, 10126
    • Investigational site number 3800004
  • Varese, Italy, 21100
    • Investigational Site Number 3800006
  • Verona, Italy, 37134
    • Investigational Site Number 3800003
• Japan
  • Chiyoda-Ku, Japan
    • Investigational Site Number 3920006
  • Fukuoka-Shi, Japan
    • Investigational Site Number 3920002
  • Hiroshima-Shi, Japan
    • Investigational Site Number 3920003
  • Kobe-Shi, Japan
    • Investigational Site Number 3920007
  • Osaka-Shi, Japan
    • Investigational Site Number 3920005
  • Shinjuku-Ku, Japan
    • Investigational Site Number 3920004
• Latvia
  • Daugavpils, Latvia, LV-5417
    • Investigational Site Number 4280002
  • Rīga, Latvia, LV-1004
    • Investigational Site Number 4280001
• Mexico
  • Durango, Mexico, 34000
    • Investigational Site Number 4840003
  • Monterrey, Mexico, 64460
    • Investigational Site Number 4840001
  • México, Mexico, 06700
    • Investigational Site Number 4840004
  • Puebla, Mexico, 72190
    • Investigational Site Number 4840002
  • Veracruz, Mexico, 91910
    • Investigational Site Number 4840005
• North Macedonia
  • Skopje, North Macedonia, 1000
    • Investigational Site Number 8070001
• Poland
  • Bielsko-Biala, Poland, 43-316
    • Investigational Site Number 6160005
  • Gdansk, Poland, 80-952
    • Investigational Site Number 6160001
  • Szczecin, Poland, 71-252
    • Investigational Site Number 6160006
  • Warszawa, Poland, 02-091
    • Investigational Site Number 6160007
  • Warszawa, Poland, 04-730
    • Investigational Site Number 6160004
  • Warszawa, Poland, 04-736
    • Investigational Site Number 6160003
• Romania
  • Bucharest, Romania, 041451
    • Investigational Site Number 6420005
  • Constanta, Romania, 900591
    • Investigational Site Number 6420007
  • Craiova, Romania, 200542
    • Investigational Site Number 6420004
  • Sibiu, Romania, 550166
    • Investigational Site Number 6420006
  • Timisoara, Romania, 300011
    • Investigational Site Number 6420003
• Russian Federation
  • Moscow, Russian Federation, 117036
    • Investigational Site Number 6430001
  • Smolensk, Russian Federation, 214018
    • Investigational Site Number 6430004
  • St-Petersburg, Russian Federation, 193144
    • Investigational Site Number 6430002
  • Ufa, Russian Federation, 450000
    • Investigational Site Number 6430003
• Serbia
  • Belgrade, Serbia, 11000
    • Investigational Site Number 6880002
  • Belgrade, Serbia, 11000
    • Investigational Site Number 6880003
  • Nis, Serbia, 18000
    • Investigational Site Number 6880004
• Spain
  • Barcelona, Spain, 08035
    • Investigational Site Number 7240005
  • Barcelona, Spain, 08041
    • Investigational Site Number 7240002
  • Esplugues De Llobregat, Spain, 08950
    • Investigational Site Number 7240003
  • Sabadell, Spain, 08208
    • Investigational Site Number 7240004
  • Santa Cruz De Tenerife, Spain, 38320
    • Investigational Site Number 7240006
  • Vitoria, Spain, 01009
    • Investigational Site Number 7240001
• Sweden
  • Stockholm, Sweden, 118 83
    • Investigational Site Number 7520002
• United Kingdom
  • Doncaster, United Kingdom, DN2 5LT
    • Investigational Site Number 8260005
  • Ipswich, United Kingdom, IP4 5PD
    • Investigational Site Number 8260001
  • Kettering, United Kingdom, NN16 8UZ
    • Investigational Site Number 8260004
  • Salisbury, United Kingdom, SP2 8BJ
    • Investigational Site Number 8260002
• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • Investigational Site Number 8400008
  • Georgia
    • Atlanta, Georgia, United States, 30318
      • Investigational Site Number 8400037
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Investigational Site Number 8400032
  • New York
    • Buffalo, New York, United States, 14222
      • Investigational Site Number 8400015
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7295
      • Investigational Site Number 8400016
    • Morehead City, North Carolina, United States, 28557
      • Investigational Site Number 8400035
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • Investigational Site Number 8400038
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Investigational Site Number 8400030
  • South Dakota
    • Rapid City, South Dakota, United States, 57701
      • Investigational Site Number 8400010
  • Texas
    • Dallas, Texas, United States, 75231
      • Investigational Site Number 8400005
    • Dallas, Texas, United States, 75235
      • Investigational Site Number 8400021
    • Lufkin, Texas, United States, 75904
      • Investigational Site Number 8400029
  • Washington
    • Seattle, Washington, United States, 98105
      • Investigational Site Number 8400034

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria :

• Children and adolescents with type 1 diabetes mellitus (T1DM) for at least 1 year confirmed by typical symptoms at diagnosis and/or by antibody testing [presence of anti-GAD (glutamic acid decarboxylase) or anti-IA2 (islet antigen 2/tyrosine phosphatase) or anti-islet cell antibodies] and/or clinical features (eg, history of ketoacidosis)].
• Signed written informed consent obtained from parent(s)/legal guardian and written or oral assent obtained from participant.

Exclusion criteria:

• Age <6 years and >=18 years at randomization.
• Less than 1 year on insulin treatment prior to screening visit.
• Less than 6 months on basal plus mealtime insulin and self-monitoring of blood glucose prior to screening visit.
• Participants using premix insulins in the last 3 months before screening visit or participants using human regular insulin as mealtime insulin in the last 3 months before screening visit.
• Use of an insulin pump in the last 6 months before screening visit or plans to switch to pump within the next 6 months after screening visit.
• Any contraindication to use of insulin glargine as defined in the national product label.
• No willingness to inject insulin glargine (Lantus or HOE901-U300) once daily.
• HbA1c <7.5% or >11% at screening.
• Initiation of any glucose-lowering medications in the last 3 months before screening visit.
• Hospitalization or care in the emergency ward for diabetic ketoacidosis or history of severe hypoglycemia (as defined by need for glucagon or IV glucose) and accompanied by seizure and/or unconsciousness and/or coma in the last 3 months prior to screening visit.
• Postmenarchal girls not protected by highly-effective method(s) of birth control and/or who were unwilling or unable to be tested for pregnancy. Abstinence from sexual intercourse was considered as an acceptable form of birth control.
• Pregnant or breast-feeding adolescents, or adolescents who intended to become pregnant during the study period, or who were at risk of getting pregnant due to any psychosocial reason during the study period.

The above information is not intended to contain all considerations relevant to a participant'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: HOE901-U300; HOE901-U300 (Insulin glargine 300 Units/milliliter [U/mL]) Subcutaneous(SC) injection once daily for 12 months.	Drug: Insulin glargine,300 U/mL; Subcutaneous injection in the morning or evening using a prefilled pen. Dose titration to achieve fasting self-monitored plasma glucose (SMPG) from 90 to 130 milligram/deciliter (mg/dL) (5.0 to 7.2 millimol per liter [mmol/L]); Other Names: Toujeo ®; Drug: Background therapy; Fast-acting mealtime insulin analogs
Active Comparator: Lantus; Lantus (Insulin glargine 100 U/mL) SC injection once daily for 12 months.	Drug: Background therapy; Fast-acting mealtime insulin analogs; Drug: Insulin glargine (100 units /mL); Subcutaneous injection in the morning or evening using a prefilled pen. Dose titration to achieve fasting SMPG from 90 to 130 mg/dL (5.0 to 7.2 mmol/L)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in HbA1c to Month 6	Change in HbA1c was calculated by subtracting baseline value from Month 6 value. Adjusted least-square (LS) means and standard errors (SE) were obtained using analysis of covariance (ANCOVA) after multiple imputations of missing data using post-baseline HbA1c data available on the main 6-month randomized period.	Baseline to Month 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Fasting Plasma Glucose (FPG) to Month 6	Change in FPG was calculated by subtracting baseline value from Month 6 value. Adjusted LS means and SE were obtained using ANCOVA after multiple imputation to address missing data in the main 6 month randomized period.	Baseline to Month 6
Percentage of Participants With HbA1c Values of <7.5% at Month 6	Participants without any available HbA1c assessment at month 6 and/or with a premature study discontinuation during the main 6-month randomized period were considered as a failure (non-responders) in the analysis. Analysis was performed using Cochran-Mantel-Haenszel (CMH) method with randomization strata of screening HbA1c (<8.5%; >=8.5%) and randomization strata of age at screening (<12 years, >=12 years).	Month 6
Percentage of Participants With HbA1c Values of <7.5% Without Any Episode of Severe and/or Documented Self-Monitored Plasma Glucose ([SMPG] <54 mg/dL [3.0 mmol/L]) Symptomatic Hypoglycemia During the Last 3 Months of the Main 6-month Randomized Period	Participants without any available HbA1c assessment at month 6 and/or with a premature study discontinuation during the main 6-month randomized period were considered as a failure (non-responders) in the analysis. Analysis was performed using Cochran-Mantel-Haenszel (CMH) method with randomization strata of screening HbA1c (<8.5%; >=8.5%) and randomization strata of age at screening (<12 years, >=12 years).	upto Month 6
Percentage of Participants With FPG of <=130 mg/dL (7.2 mmol/L) at Month 6	Participants without any available FPG assessment at month 6 and/or with a premature study discontinuation during the main 6-month randomized period were considered as a failure (non-responders) in the analysis. Analysis was performed using Cochran-Mantel-Haenszel (CMH) method with randomization strata of screening HbA1c (<8.5%; >=8.5%) and randomization strata of age at screening (<12 years, >=12 years).	Month 6
Percentage of Participants With FPG of <=130 mg/dL (7.2 mmol/L) Without Any Episode of Severe and/or Documented (SMPG <54 mg/dL [3.0 mmol/L]) Symptomatic Hypoglycemia During the Last 3 Months of the Main 6-month Randomized Period	Participants without any available HbA1c assessment at month 6 and/or with a premature study discontinuation during the main 6-month randomized period were considered as a failure (non-responders) in the analysis. Analysis was performed using Cochran-Mantel-Haenszel (CMH) method with randomization strata of screening HbA1c (<8.5%; >=8.5%) and randomization strata of age at screening (<12 years, >=12 years).	upto Month 6
Change From Baseline in 24-Hour Mean Plasma Glucose Based on 8-point SMPG Profiles to Month 6	8-point SMPG profiles were measured at the following 8 points: between 01:00 and 04:00 (clock time) at night, pre-breakfast, 2 hours after breakfast, pre-lunch, 2 hours after lunch, pre-dinner, 2 hours after dinner, and bedtime. Analysis was performed using a ANCOVA model including the fixed categorical effects of treatment group, randomization strata of screening HbA1c (<8.5%; >=8.5%), randomization strata of age at screening (<12 years, >=12 years) and the baseline 24-hour average 8-point profile SMPG.	Baseline to Month 6
Change From Baseline in Variability of 24-Hour Mean Plasma Glucose Based on 8-point SMPG Profiles at Month 6	8-point SMPG profiles were measured at the following 8 points: between 01:00 and 04:00 (clock time) at night, pre-breakfast, 2 hours after breakfast, pre-lunch, 2 hours after lunch, pre-dinner, 2 hours after dinner, and bedtime. Variability was assessed by the coefficient of variation (standard deviation divided by mean) calculated over the 8-point SMPG. Analysis was performed using a ANCOVA model including the fixed categorical effects of treatment group, randomization strata of screening HbA1c (<8.5%; >=8.5%) and randomization strata of age at screening (<12 years, >=12 years).	Baseline, Month 6
Change From Baseline to Month 6 in 8-Point SMPG Profile Per Time Point	8-point SMPG profiles were measured for following 8 time points at Baseline and Month 6: between 01:00 and 04:00 (clock time) at night, pre-breakfast, 2 hours after breakfast, pre-lunch, 2 hours after lunch, pre-dinner, 2 hours after dinner, and bedtime.	Baseline to Month 6
Percentage of Participants With at Least One Hypoglycemic Events (Any Hypoglycemia, Severe Hypoglycemia, Documented Symptomatic, Probable Symptomatic, Asymptomatic Hypoglycemia, Pseudo-hypoglycemia and Severe and/or Confirmed Hypoglycemia) at Month 12	Severe hypoglycemia: an event in which the child/adolescent having altered mental status and cannot assist in their care, is semiconscious or unconscious, or in coma ± convulsions and may require parenteral therapy (glucagon or glucose). Documented symptomatic hypoglycemia: an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of <=70 mg/dL (3.9 mmol/L). Asymptomatic hypoglycemia: an event not accompanied by typical symptoms of hypoglycemia but with a measured plasma glucose concentration <=70 mg/dL. Probable symptomatic hypoglycemia: an event during which symptoms of hypoglycemia were not accompanied by plasma glucose determination but was presumably caused by a plasma glucose concentration <=70 mg/dL. Pseudo-hypoglycemia:an event with any of the typical symptoms of hypoglycaemia with plasma glucose concentration >70 mg/dL.	Month 12
Percentage of Participants With Any Hyperglycemia With Ketosis at Month 12	Hyperglycemia with ketosis was defined as SMPG >=252 mg/dL (14 mmol/L) with accompanying self-measured blood ketones >=1.5 mmol/L.	Month 12

Collaborators and Investigators

• Sponsor: Sanofi

Publications and helpful links

General Publications

• Danne T, Tamborlane WV, Malievsky OA, Franco DR, Kawamura T, Demissie M, Niemoeller E, Goyeau H, Wardecki M, Battelino T. Efficacy and Safety of Insulin Glargine 300 Units/mL (Gla-300) Versus Insulin Glargine 100 Units/mL (Gla-100) in Children and Adolescents (6-17 years) With Type 1 Diabetes: Results of the EDITION JUNIOR Randomized Controlled Trial. Diabetes Care. 2020 Jul;43(7):1512-1519. doi: 10.2337/dc19-1926. Epub 2020 May 19.

Study record dates

Study Major Dates

• Study Start (Actual): April 14, 2016
• Primary Completion (Actual): May 31, 2018
• Study Completion (Actual): December 20, 2018

Study Registration Dates

• First Submitted: March 30, 2016
• First Submitted That Met QC Criteria: April 6, 2016
• First Posted (Estimate): April 12, 2016

Study Record Updates

• Last Update Posted (Actual): March 25, 2022
• Last Update Submitted That Met QC Criteria: March 15, 2022
• Last Verified: March 1, 2022

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; Insulin; Insulin, Globin Zinc; Insulin Glargine
• Other Study ID Numbers: EFC13957; 2015-002084-42 (EudraCT Number); U1111-1168-4546 (Other Identifier: UTN)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org