Comparison of a New Formulation of Insulin Glargine With Lantus in Patients With Type 1 Diabetes Mellitus (EDITION IV)

A 6-Month, Multicenter, Randomized, Open-label, Parallel-group Study Comparing the Efficacy and Safety of a New Formulation of Insulin Glargine and Lantus® Injected in the Morning or Evening in Patients 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 and Lantus (overall, regardless the injection time) in terms of change of HbA1c from baseline to endpoint (scheduled Month 6) in participants with type 1 diabetes mellitus

Secondary Objective:

• To compare HOE901-U300 and Lantus when given in the morning or in the evening in terms of:
• Change of HbA1c from baseline to endpoint (scheduled Month 6)
• Change from baseline to endpoint (Month 6) in fasting plasma glucose (FPG), plasma glucose prior to injection of study drug, plasma glucose at 03:00 hours, mean plasma glucose (8-point profiles), glucose variability, treatment satisfaction and health related quality of life in participants with Type 1 Diabetes Mellitus (T1DM)
• Reaching target HbA1c values and controlled plasma glucose (all and reaching target without hypoglycemia)
• Frequency of occurrence and diurnal distribution of hypoglycemia by category of hypoglycemia (symptomatic, asymptomatic, nocturnal, severe, probable and relative)
• Safety and tolerability of HOE901-U300 including development of anti-insulin antibody (AIAs) during the 12-month study period

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes Mellitus
• Intervention / Treatment: Drug: HOE901-U300 (Insulin glargine new formulation); Drug: Lantus (Insulin glargine)

Detailed Description

The maximum study duration was up to approximately 54 weeks per participants:

• Up to 2-week screening period
• 6-month open-label comparative efficacy and safety treatment period
• 6-month open-label comparative safety extension period
• 48-hour post-treatment safety follow-up period

• Study Type: Interventional
• Enrollment (Actual): 549
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Coquitlam, Canada, V3K 3P4
    • Investigational Site Number 124110
  • Laval, Canada, H7T 2P5
    • Investigational Site Number 124104
  • Mirabel, Canada, J7J 2K8
    • Investigational Site Number 124108
  • Montreal, Canada, H1Y 3L1
    • Investigational Site Number 124109
  • Thornhill, Canada, L4J 8L7
    • Investigational Site Number 124105
  • Toronto, Canada, M4R 2G4
    • Investigational Site Number 124101
• Czech Republic
  • Brno, Czech Republic, 62500
    • Investigational Site Number 203102
  • Praha 10, Czech Republic, 10034
    • Investigational Site Number 203104
  • Praha 8, Czech Republic, 18100
    • Investigational Site Number 203103
• Denmark
  • Esbjerg, Denmark, 6700
    • Investigational Site Number 208103
  • Gentofte, Denmark, 2900
    • Investigational Site Number 208105
  • København Nv, Denmark, 2400
    • Investigational Site Number 208104
  • Køge, Denmark, 4600
    • Investigational Site Number 208107
  • Ålborg, Denmark, 9100
    • Investigational Site Number 208102
• Estonia
  • Pärnu, Estonia, 80018
    • Investigational Site Number 233104
  • Tallinn, Estonia, 13419
    • Investigational Site Number 233105
  • Tartu, Estonia, 50406
    • Investigational Site Number 233106
  • Tartu, Estonia, 50410
    • Investigational Site Number 233101
  • Viljandimaa, Estonia, 71024
    • Investigational Site Number 233103
• Finland
  • Kokkola, Finland, 67100
    • Investigational Site Number 246102
  • Kuopio, Finland, 70210
    • Investigational Site Number 246101
  • Loimaa, Finland, 32200
    • Investigational Site Number 246106
  • Oulu, Finland, 90100
    • Investigational Site Number 246105
  • Tampere, Finland, 33100
    • Investigational Site Number 246103
• Hungary
  • Budapest, Hungary, 1036
    • Investigational Site Number 348103
  • Budapest, Hungary, 1083
    • Investigational Site Number 348108
  • Budapest, Hungary, 1088
    • Investigational Site Number 348107
  • Debrecen, Hungary, 4031
    • Investigational Site Number 348106
  • Gyula, Hungary, 5700
    • Investigational Site Number 348102
  • Urhida, Hungary, 8142
    • Investigational Site Number 348101
• Japan
  • Aisai-Shi, Japan
    • Investigational Site Number 392110
  • Ise-Shi, Japan
    • Investigational Site Number 392105
  • Karatsu-Shi, Japan
    • Investigational Site Number 392104
  • Kitakyushu-Shi, Japan
    • Investigational Site Number 392111
  • Matsumoto-Shi, Japan
    • Investigational Site Number 392112
  • Matumoto, Japan
    • Investigational Site Number 392108
  • Midori-Shi, Japan
    • Investigational Site Number 392103
  • Mito-Shi, Japan
    • Investigational Site Number 392107
  • Sakai-Shi, Japan
    • Investigational Site Number 392101
  • Tomishiro, Japan
    • Investigational Site Number 392102
  • Yamagata-Shi, Japan
    • Investigational Site Number 392106
• Latvia
  • Limbazi, Latvia, LV-4001
    • Investigational Site Number 428106
  • Riga, Latvia, LV-1002
    • Investigational Site Number 428103
  • Riga, Latvia, LV-1050
    • Investigational Site Number 428105
  • Sigulda, Latvia, LV-2150
    • Investigational Site Number 428102
  • Ventspils, Latvia, LV-3601
    • Investigational Site Number 428101
• Netherlands
  • Almere, Netherlands, 1311 RL
    • Investigational Site Number 528101
  • Beek, Netherlands, 6191 JW
    • Investigational Site Number 528103
  • Nijmegen, Netherlands, 6525 GA
    • Investigational Site Number 528105
  • Venlo, Netherlands, 5912 BL
    • Investigational Site Number 528104
  • Zwijndrecht, Netherlands, 3331 LZ
    • Investigational Site Number 528102
• Puerto Rico
  • Ponce, Puerto Rico, 00717
    • Investigational Site Number 840602
• Romania
  • Bacau, Romania, 600164
    • Investigational Site Number 642107
  • Brasov, Romania, 500365
    • Investigational Site Number 642103
  • Oradea, Romania, 410169
    • Investigational Site Number 642109
  • Resita, Romania, 320076
    • Investigational Site Number 642106
  • Sibiu, Romania, 550371
    • Investigational Site Number 642104
  • Targu Mures, Romania, 540142
    • Investigational Site Number 642101
  • Targu Mures, Romania, 540142
    • Investigational Site Number 642102
  • Timisoara, Romania, 300133
    • Investigational Site Number 642105
  • Timisoara, Romania, 300456
    • Investigational Site Number 642108
• Sweden
  • Goteborg, Sweden, 41345
    • Investigational Site Number 752103
  • Kristianstad, Sweden, 29185
    • Investigational Site Number 752105
  • Stockholm, Sweden, 11526
    • Investigational Site Number 752101
  • Vällingby, Sweden, 16268
    • Investigational Site Number 752104
• United States
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Investigational Site Number 840156
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Investigational Site Number 840177
  • California
    • Bell Gardens, California, United States, 90201
      • Investigational Site Number 840430
    • Escondido, California, United States, 92025
      • Investigational Site Number 840131
    • Fresno, California, United States, 93720
      • Investigational Site Number 840140
    • Greenbrae, California, United States, 94904
      • Investigational Site Number 840107
    • Huntington Beach, California, United States, 92648
      • Investigational Site Number 840149
    • La Jolla, California, United States, 92037
      • Investigational Site Number 840120
    • La Mesa, California, United States, 91942
      • Investigational Site Number 840123
    • La Mesa, California, United States, 91942
      • Investigational Site Number 840159
    • Long Beach, California, United States, 90806
      • Investigational Site Number 840114
    • Mission Hills, California, United States, 91345
      • Investigational Site Number 840189
    • Temecula, California, United States, 92591
      • Investigational Site Number 840105
    • Tustin, California, United States, 92780
      • Investigational Site Number 840155
    • Walnut Creek, California, United States, 94598
      • Investigational Site Number 840115
  • Colorado
    • Denver, Colorado, United States, 80239
      • Investigational Site Number 840160
    • Denver, Colorado, United States, 80262
      • Investigational Site Number 840188
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Investigational Site Number 840196
  • Florida
    • Bradenton, Florida, United States, 34208
      • Investigational Site Number 840113
    • Hialeah, Florida, United States, 33012
      • Investigational Site Number 840102
    • Hollywood, Florida, United States, 33021
      • Investigational Site Number 840134
    • Jacksonville, Florida, United States, 32216
      • Investigational Site Number 840185
    • Jacksonville, Florida, United States, 32258
      • Investigational Site Number 840116
    • Miami, Florida, United States, 33144
      • Investigational Site Number 840126
    • Miami, Florida, United States, 33176
      • Investigational Site Number 840179
    • New Port Richey, Florida, United States, 34652
      • Investigational Site Number 840117
    • Orlando, Florida, United States, 32806
      • Investigational Site Number 840174
    • Oviedo, Florida, United States, 32765
      • Investigational Site Number 840110
    • Palm Harbor, Florida, United States, 34684
      • Investigational Site Number 840178
    • Tampa, Florida, United States, 33613
      • Investigational Site Number 840181
    • West Palm Beach, Florida, United States, 33401
      • Investigational Site Number 840420
  • Georgia
    • Atlanta, Georgia, United States, 30318
      • Investigational Site Number 840195
  • Hawaii
    • Honolulu, Hawaii, United States, 96814
      • Investigational Site Number 840124
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • Investigational Site Number 840167
    • Nampa, Idaho, United States, 83686
      • Investigational Site Number 840163
  • Illinois
    • Springfield, Illinois, United States, 62704
      • Investigational Site Number 840162
  • Indiana
    • Avon, Indiana, United States, 46123
      • Investigational Site Number 840172
    • Indianapolis, Indiana, United States, 46202
      • Investigational Site Number 840197
  • Iowa
    • Des Moines, Iowa, United States, 50314
      • Investigational Site Number 840108
    • Iowa City, Iowa, United States
      • Investigational Site Number 840407
  • Kansas
    • Topeka, Kansas, United States, 66606
      • Investigational Site Number 840170
  • Kentucky
    • Lexington, Kentucky, United States, 40503
      • Investigational Site Number 840421
  • Louisiana
    • Metairie, Louisiana, United States, 70006
      • Investigational Site Number 840426
  • Maryland
    • Baltimore, Maryland, United States, 21237
      • Investigational Site Number 840104
    • Rockville, Maryland, United States, 20852
      • Investigational Site Number 840180
  • Massachusetts
    • Haverhill, Massachusetts, United States, 1830
      • Investigational Site Number 840137
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Investigational Site Number 840408
    • Madison Heights, Michigan, United States, 48071
      • Investigational Site Number 840153
  • Minnesota
    • St Louis Park, Minnesota, United States, 55416
      • Investigational Site Number 840171
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Investigational Site Number 840184
  • Nebraska
    • Omaha, Nebraska, United States, 68131
      • Investigational Site Number 840106
    • Omaha, Nebraska, United States, 68131
      • Investigational Site Number 840145
  • Nevada
    • Las Vegas, Nevada, United States, 89148
      • Investigational Site Number 840139
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • Investigational Site Number 840151
  • New York
    • New Hyde Park, New York, United States, 11042
      • Investigational Site Number 840191
    • Syracuse, New York, United States, 13210
      • Investigational Site Number 840173
  • North Carolina
    • Asheville, North Carolina, United States, 28803
      • Investigational Site Number 840133
    • Chapel Hill, North Carolina, United States, 27599-7295
      • Investigational Site Number 840175
    • Morganton, North Carolina, United States, 28655
      • Investigational Site Number 840161
  • Ohio
    • Mentor, Ohio, United States, 44060
      • Investigational Site Number 840169
  • Oklahoma
    • Norman, Oklahoma, United States, 73069
      • Investigational Site Number 840119
  • Oregon
    • Bend, Oregon, United States, 97701
      • Investigational Site Number 840112
  • South Carolina
    • Greer, South Carolina, United States, 29651
      • Investigational Site Number 840136
  • South Dakota
    • Dakota Dunes, South Dakota, United States, 57049
      • Investigational Site Number 840122
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Investigational Site Number 840144
    • Nashville, Tennessee, United States, 37232
      • Investigational Site Number 840187
  • Texas
    • Austin, Texas, United States, 78731
      • Investigational Site Number 840109
    • Austin, Texas, United States, 78731
      • Investigational Site Number 840157
    • Dallas, Texas, United States, 75230
      • Investigational Site Number 840150
    • Dallas, Texas, United States, 75231
      • Investigational Site Number 840412
    • Houston, Texas, United States, 77030
      • Investigational Site Number 840130
    • Houston, Texas, United States, 77095
      • Investigational Site Number 840141
    • San Antonio, Texas, United States, 78229
      • Investigational Site Number 840166
  • Utah
    • Murray, Utah, United States, 84123
      • Investigational Site Number 840101
  • Virginia
    • Burke, Virginia, United States, 22015
      • Investigational Site Number 840125
    • Chesapeake, Virginia, United States, 23321
      • Investigational Site Number 840427
    • Manassas, Virginia, United States, 20110
      • Investigational Site Number 840103
  • Washington
    • Renton, Washington, United States, 98055
      • Investigational Site Number 840132
    • Seattle, Washington, United States, 98195
      • Investigational Site Number 840403
    • Spokane, Washington, United States, 99220
      • Investigational Site Number 840402
    • Tacoma, Washington, United States, 98415-0299
      • Investigational Site Number 840127
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53209-0996
      • Investigational Site Number 840411

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• Adult participants with type 1 diabetes mellitus

Exclusion criteria:

• HbA1c less than (<) 7.0% (53 mmol/mol) or greater than (>) 10% (86 mmol/mol) at screening
• Less than 1 year on any basal plus mealtime insulin and self-monitoring of blood glucose before screening visit
• Participants not on stable insulin dose (+/-20 percent total basal insulin dose) in the last 30 days prior to screening visit
• Participants using pre-mix insulins, human regular insulin as mealtime insulin and/or any glucose-lowering drugs other than basal insulin and mealtime analogue insulin in the last 3 months before screening visit
• Use of an insulin pump in the last 6 months before screening visit and no plan to switch to insulin pump in the next 12 months
• Not willing to inject insulin glargine as assigned by the randomization process once daily in the morning or evening;
• Severe hypoglycemia resulting in coma/seizures, and/or hospitalization for diabetic ketoacidosis in the last 6 months before screening visit
• Unstable proliferative diabetic retinopathy or any other rapidly progressive diabetic retinopathy or macular edema likely to require treatment (example laser, surgical treatment or injectable drugs) 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 (new insulin glargine 300 units per milliliter [U/mL]) subcutaneous (SC) injection once daily in morning or evening for 12 months on top of mealtime insulin analogue. Dose titration seeking fasting plasma glucose 4.4-5.6 millimole per liter (mmol/L) (80 - 100 milligram per deciliter [mg/dL]).	Drug: HOE901-U300 (Insulin glargine new formulation)
Active Comparator: Lantus; Lantus (HOE901-U100, insulin glargine 100 U/mL) SC injection once daily in morning or evening for 12 months on top of mealtime insulin analogue. Dose titration seeking fasting plasma glucose 4.4-5.6 mmol/L (80 - 100 mg/dL).	Drug: Lantus (Insulin glargine)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change In HbA1c From Baseline to Month 6 Endpoint	Baseline, Month 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With HbA1c <7% at Month 6 Endpoint		Month 6
Percentage of Participants With HbA1c Less Than or Equal to 6.5% at Month 6 Endpoint		Month 6
Change In Average Pre-Injection Self-Monitored Plasma Glucose (SMPG) From Baseline Month 6 Endpoint	Pre-injection SMPG was measured within 30 minutes prior to the injection of the study drug. Average was assessed by the mean of at least 3 SMPG calculated over the 7 days preceding the assessment visit.	Baseline, Month 6
Change in Variability of Pre-injection SMPG From Baseline to Month 6 Endpoint	Pre-injection SMPG was measured within 30 minutes prior to the injection of the study drug. Variability was assessed by the mean of coefficient of variation calculated as 100 multiplied by (standard deviation/mean) over at least 3 SMPG measured during the 7 days preceding the assessment visit.	Baseline, Month 6
Change in Fasting Plasma Glucose From Baseline to Month 6 Endpoint		Baseline, Month 6
Percentage of Participants With Fasting Plasma Glucose (FPG) <5.6 mmol/L (100 mg/dL) At Month 6		Month 6
Percentage of Participants With FPG <7.2 mmol/L (130 mg/dL) at Month 6 Endpoint		Month 6
Change in 8--Point SMPG Profiles Per Time Point From Baseline to Month 6 Endpoint	Change in each time-point of 8-point SMPG profile: 03:00 hours (clock time) at night; before and 2 hours after breakfast; before and 2 hours after lunch; before and 2 hours after dinner; and at bedtime.	Baseline, Month 6
Change in Daily Average Total Insulin Dose From Baseline to Month 6 Endpoint		Baseline, Month 6
Change in Total Treatment Satisfaction Score Using The Diabetes Treatment Satisfaction Questionnaire (DTSQs) From Baseline to Month 6 Endpoint	DTSQ is a validated measure to assess how satisfied participants with diabetes are with their treatment and how they perceive hyper- and hypoglycemia. It consists of 8 questions which are answered on a Likert scale from 0 to 6. DTSQ treatment satisfaction score is the sum of question 1 and 4-8 scores and ranges between 0 and 36, where higher scores indicate more treatment satisfaction.	Baseline, Month 6
Percentage of Participants With Hypoglycemia (All and Nocturnal) Events From Baseline to Month 12	Hypoglycemia events were Severe hypoglycemia (an event that required assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions); Documented symptomatic hypoglycemia (typical symptoms of hypoglycemia with plasma glucose level of <=3.9 mmol/L [70 mg/dL]); Asymptomatic hypoglycemia (no typical symptoms of hypoglycemia but plasma glucose level <=3.9 mmol/L); Probable symptomatic hypoglycemia (an event during which symptoms of hypoglycemia were not accompanied by a plasma glucose determination, but was presumably caused by a plasma glucose level <=3.9 mmol/L, symptoms treated with oral carbohydrate without a test of plasma glucose); Relative hypoglycemia (an event during which the person with diabetes reported any of the typical symptoms of hypoglycemia, and interpreted the symptoms as indicative of hypoglycemia, but plasma glucose level >3.9 mmol/L); Severe and/or confirmed a hypoglycemia (plasma glucose <=3.9 mmol/L).	Up to Month 12

Collaborators and Investigators

• Sponsor: Sanofi

Publications and helpful links

General Publications

• Home PD, Bergenstal RM, Bolli GB, Ziemen M, Rojeski M, Espinasse M, Riddle MC. Glycaemic control and hypoglycaemia during 12 months of randomized treatment with insulin glargine 300 U/mL versus glargine 100 U/mL in people with type 1 diabetes (EDITION 4). Diabetes Obes Metab. 2018 Jan;20(1):121-128. doi: 10.1111/dom.13048. Epub 2017 Aug 8.

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (Actual): September 1, 2013
• Study Completion (Actual): March 1, 2014

Study Registration Dates

• First Submitted: September 7, 2012
• First Submitted That Met QC Criteria: September 10, 2012
• First Posted (Estimate): September 11, 2012

Study Record Updates

• Last Update Posted (Estimate): June 24, 2015
• Last Update Submitted That Met QC Criteria: May 28, 2015
• Last Verified: May 1, 2015

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: EFC12456; 2012-001524-35 (EudraCT Number); U1111-1128-5517 (Other Identifier: UTN)