Comparison of SAR341402 to NovoLog in Adult Patients With Type 1 Diabetes Mellitus Also Using Insulin Glargine (GEMELLI X)

Randomized, Open Label, Parallel-group Study Comparing the Pharmacokinetics and Immunogenicity of Alternating Use of SAR341402 and NovoLog® Versus Continuous Use of NovoLog in Participants With Type 1 Diabetes Mellitus Also Using Insulin Glargine

Primary Objective:

To demonstrate similarity in pharmacokinetics (PK) of SAR341402 and NovoLog after 4x4-week periods of alternating administration of SAR341402 and NovoLog compared to 16-week continuous use of NovoLog in participants with Type 1 diabetes mellitus (T1DM) also using insulin glargine.

Secondary Objectives:

• To compare the effects of alternating administration of SAR341402 and NovoLog with continuous use of NovoLog on immunogenicity.
• To evaluate the safety of alternating administration of SAR341402 and NovoLog versus continuous use of NovoLog.
• To compare other PK parameters between the two treatment arms (alternating administration of SAR341402 and NovoLog and continuous use of NovoLog).

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes Mellitus
• Intervention / Treatment: Drug: Insulin Aspart SAR341402; Drug: Insulin Aspart; Drug: Insulin glargine U100

Detailed Description

The study duration per participant was less than 19 weeks (for participants who did not require the run-in period) and less than 31 weeks (for participants who require the run-in period).

• Study Type: Interventional
• Enrollment (Actual): 210
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Concord, California, United States, 94520
      • Investigational Site Number 8400014
    • Temecula, California, United States, 92591
      • Investigational Site Number 8400001
    • Ventura, California, United States, 93003
      • Investigational Site Number 8400015
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Investigational Site Number 8400010
  • Connecticut
    • Waterbury, Connecticut, United States, 06708-3346
      • Investigational Site Number 8400029
  • Florida
    • Doral, Florida, United States, 33166
      • Investigational Site Number 8400038
    • Miami, Florida, United States, 33165
      • Investigational Site Number 8400030
    • New Port Richey, Florida, United States, 34652
      • Investigational Site Number 8400032
    • Ocoee, Florida, United States, 34761
      • Investigational Site Number 8400026
    • Palm Harbor, Florida, United States, 34684
      • Investigational Site Number 8400033
  • Georgia
    • Atlanta, Georgia, United States, 30318
      • Investigational Site Number 8400012
    • Columbus, Georgia, United States, 31904
      • Investigational Site Number 8400005
    • Roswell, Georgia, United States, 30076
      • Investigational Site Number 8400009
  • Illinois
    • Crystal Lake, Illinois, United States, 60012
      • Investigational Site Number 8400019
  • Iowa
    • Des Moines, Iowa, United States, 50314
      • Investigational Site Number 8400028
  • Kentucky
    • Lexington, Kentucky, United States, 40503
      • Investigational Site Number 8400018
  • Maryland
    • Baltimore, Maryland, United States, 21237
      • Investigational Site Number 8400023
    • Rockville, Maryland, United States, 20852-4267
      • Investigational Site Number 8400003
  • Massachusetts
    • Waltham, Massachusetts, United States, 02453
      • Investigational Site Number 8400013
  • Michigan
    • Flint, Michigan, United States, 48532
      • Investigational Site Number 8400004
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Investigational Site Number 8400021
    • Washington, Missouri, United States, 63090
      • Investigational Site Number 8400031
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Investigational Site Number 8400036
  • Nevada
    • Las Vegas, Nevada, United States, 89148
      • Investigational Site Number 8400017
  • New York
    • New York, New York, United States, 10001
      • Investigational Site Number 8400007
  • North Carolina
    • Morehead City, North Carolina, United States, 28557
      • Investigational Site Number 8400006
    • Rocky Mount, North Carolina, United States, 27804
      • Investigational Site Number 8400035
  • Tennessee
    • Jefferson City, Tennessee, United States, 37760
      • Investigational Site Number 8400034
  • Texas
    • Dallas, Texas, United States, 75235
      • Investigational Site Number 8400040
    • El Paso, Texas, United States, 79935
      • Investigational Site Number 8400042
    • Houston, Texas, United States, 77079
      • Investigational Site Number 8400027
    • Mesquite, Texas, United States, 75149
      • Investigational Site Number 8400016
    • Waco, Texas, United States, 76710
      • Investigational Site Number 8400041

Participation Criteria

Eligibility Criteria

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

Description

Inclusion criteria:

• Participants with T1DM.
• Participants on continuous insulin treatment for at least 12 months prior to screening.

• Participants exclusively on a multiple (greater than or equal to 3) daily injection insulin analogue regimen using:

  • NovoLog as mealtime insulin for at least 12 weeks prior to screening and
  • Insulin glargine (100 units per milliliter [U/mL]) as basal insulin for at least 12 weeks prior to screening. Note: Participants not meeting this criterion could also qualify, provided that they completed the run-in period during which NovoLog and Lantus was administered so that, at the time of randomization, the participants had been on NovoLog and insulin glargine (100 U/mL) for at least 12 weeks (including any potential pre-screening administration).
• Glycated hemoglobin (HbA1c) less than or equal to 10 percent (%) (85.79 millimoles per mole) at screening.
• Body mass index less than or equal to 35 kilograms per meter square (kg/m^2) at screening.

Exclusion criteria:

• Pancreatectomy and/or islet cell transplantation.
• Clinically significant laboratory findings, as defined by the protocol.
• Known presence of factors that interfered with the HbA1c measurement.
• History of severe hypoglycemia required emergency room admission or hospitalization within 3 months prior to screening.
• Hospitalization for recurrent diabetic ketoacidosis within 3 months prior to screening.
• Retinopathy or maculopathy with one of the following treatments, either recent (within 3 months of screening) or planned: intravitreal injections or laser or vitrectomy surgery.
• Use of glucose lowering treatments other than the multiple dose injections and basal insulin regimen (including use of insulin pump therapy), within 12 weeks prior to screening.
• Participants had received systemic glucocorticoids for one week or more within 3 months prior to screening (topical, nasal spray, inhaled or intra-articular applications are allowed).
• Participants had received systemic immunosuppressive agents within 6 months prior to screening.

The above information was 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: Switching: NovoLog/SAR341402; Participants self-administered subcutaneous (SC) injection daily prior to the start of a meal during the 16-week treatment period, starting with NovoLog (100 units per milliliters [U/mL]) for the first 4 weeks, then SAR341402 (100 U/mL) for 4 weeks, followed by NovoLog (at same dose) for 4 weeks and then SAR341402 (at same dose) for the last 4 weeks on top of mandatory background therapy with Lantus (Insulin glargine, 100 U/mL) as basal insulin.	Drug: Insulin Aspart SAR341402; Pharmaceutical form: Solution for injection Route of administration: Subcutaneous; Drug: Insulin Aspart; Pharmaceutical form: Solution for injection Route of administration: Subcutaneous; Other Names: NovoLog; Drug: Insulin glargine U100; Pharmaceutical form: Solution for injection Route of administration: Subcutaneous; Other Names: Lantus
Active Comparator: Non-Switching: NovoLog; Participants self-administered SC injection of NovoLog (100 U/mL) daily prior to the start of a meal during the 16-week treatment period on top of mandatory background therapy with Lantus (Insulin glargine, 100 U/mL) as basal insulin.	Drug: Insulin Aspart; Pharmaceutical form: Solution for injection Route of administration: Subcutaneous; Other Names: NovoLog; Drug: Insulin glargine U100; Pharmaceutical form: Solution for injection Route of administration: Subcutaneous; Other Names: Lantus

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve From Time Zero to Last Measurable Timepoint (AUClast) of Insulin Aspart Following Administration of Either SAR341402 (Switching Arm) or NovoLog (Non-switching Arm)	AUClast was defined as area under the plasma concentration versus time curve from time zero to last measurable timepoint. Insulin aspart was the active ingredient of SAR341402 and NovoLog.	0 hour (hr)(Pre-dose), 10, 20, 30, 40 & 50 minutes (min), 1hr, 1hr-10, 20, 30, 40 & 50min, 2hr, 2hr-15, 30 & 45min, 3hr, 3hr-15, 30 & 45min, 4hr, 4hr-20 & 40min, 5hr, 5hr-20 & 40min, 6hr, 6hr-30min, 7hr, 7hr-30min & 8hr post-dose on Day 112
Pharmacokinetics: Area Under the Plasma Concentration Versus Time Curve (AUC) of Insulin Aspart Following Administration of Either SAR341402 (Switching Arm) or NovoLog (Non-switching Arm)	AUC was defined as area under the concentration versus time curve. Insulin aspart is the active ingredient of SAR341402 and NovoLog.	0 hr (pre-dose), 10, 20, 30, 40 & 50 min, 1 hr, 1 hr-10, 20, 30, 40 & 50 min, 2 hr, 2 hr-15, 30 & 45 min, 3 hr, 3 hr-15, 30 & 45 min, 4 hr, 4 hr-20 & 40 min, 5 hr, 5 hr-20 & 40 min, 6 hr, 6 hr-30 min, 7 hr, 7 hr-30 min & 8 hr post-dose on Day 112
Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Insulin Aspart Following Administration of Either SAR341402 (Switching Arm) or NovoLog (Non-switching Arm)	Cmax was defined as the maximum observed plasma concentration. Insulin aspart is the active ingredient of SAR341402 and NovoLog.	0 hr (pre-dose), 10, 20, 30, 40 & 50 min, 1 hr, 1 hr-10, 20, 30, 40 & 50 min, 2 hr, 2hr-15, 30 & 45 min, 3 hr, 3 hr-15, 30 & 45 min, 4 hr, 4 hr-20 & 40 min, 5 hr, 5 hr-20 & 40 min, 6 hr, 6 hr-30 min, 7 hr, 7 hr-30 min & 8 hr post-dose on Day 112

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-emergent Anti-Insulin Aspart Antibodies (AIAs)	AIA was categorized as: treatment-induced AIA, treatment-boosted AIA, and treatment-emergent AIA. Treatment-induced AIAs: participants who developed AIA following investigational medicinal product (IMP) administration (participants with at least one positive AIA sample at any time during on-treatment period, in those participants without pre-existing AIA or with missing Baseline sample). Treatment-boosted AIAs: participants with pre-existing AIAs that were boosted to a significant higher titer following IMP administration (participants with at least one AIA sample with at least a 4-fold increase in titers compared to Baseline value at any time during on-treatment period, in those participants with pre-existing AIA). Participants with treatment-emergent AIA were defined as participants with treatment-induced, or treatment-boosted AIAs. On-treatment period was defined as the time from the first injection of IMP up to the last injection of IMP + 1 day.	From first injection of IMP (Day 1) up to 1 day after the last injection of IMP (i.e., up to Day 113)
Number of Participants With at Least One Hypoglycemic Event	Severe hypoglycemia: event in which participant required assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions, because participant was not capable of helping self. Documented symptomatic hypoglycemia: event in which typical symptoms of hypoglycemia (SOH) were accompanied by measured plasma glucose concentration (PGC) less than or equal to (<=) 3.9 millimoles per liter (mmol/L)(<70 milligrams per deciliter [mg/dL]) or <3.0 mmol/L(<54 mg/dL). Asymptomatic hypoglycemia: event without SOH and with measured PGC of <=3.9 mmol/L (<70 mg/dL) or <3.0 mmol/L (<54 mg/dL). Probable symptomatic hypoglycemia: event with SOH not accompanied by plasma glucose determination but was presumably caused by PGC <=3.9 mmol/L (70 mg/dL). Relative hypoglycemia: event with SOH but with measured PGC greater than (>) 3.9 mmol/L (70 mg/dL).	From first injection of IMP (Day 1) up to 1 day after the last injection of IMP (i.e., up to Day 113)
Number of Hypoglycemic Events Per Participant-year	Number of hypoglycemia events (any, severe, documented [both threshold], asymptomatic [both threshold], probable symptomatic and relative) per participant-year of exposure were reported. Severe hypoglycemia: event in which participant required assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions, because participant wasn't capable of helping self. Documented symptomatic hypoglycemia: event in which typical SOH were accompanied by measured PGC of <=3.9 mmol/L (<70 mg/dL) or <3.0 mmol/L(<54 mg/dL). Asymptomatic hypoglycemia: event without SOH and measured PGC of <=3.9 mmol/L (<70 mg/dL) or <3.0 mmol/L(<54 mg/dL). Probable symptomatic hypoglycemia: event with SOH not accompanied by plasma glucose determination but was presumably caused by PGC <=3.9 mmol/L (70 mg/dL). Relative hypoglycemia: event with SOH but with measured PGC >3.9 mmol/L (70 mg/dL).	From first injection of IMP (Day 1) up to 1 day after the last injection of IMP (i.e., up to Day 113)
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)	An Adverse Event (AE) was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. Serious adverse events (SAEs) were defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/ incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were defined as AEs that developed, worsened or became serious during the on-treatment period (from first injection of IMP up to 1 day after the last injection of IMP).	From first injection of IMP (Day 1) up to 1 day after the last injection of IMP (i.e., up to Day 113)
Pharmacokinetics: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Insulin Aspart Following Administration of Either SAR341402 (Switching Arm) or NovoLog (Non-switching Arm)	Tmax was defined as the time taken to reach the maximum observed plasma concentration. Insulin aspart is the active ingredient of SAR341402 and NovoLog.	0 hr (pre-dose), 10, 20, 30, 40 & 50 min, 1 hr, 1 hr-10, 20, 30, 40 & 50 min, 2 hr, 2hr-15, 30 & 45 min, 3 hr, 3 hr-15, 30 & 45 min, 4 hr, 4 hr-20 & 40 min, 5 hr, 5 hr-20 & 40 min, 6 hr, 6 hr-30 min, 7 hr, 7 hr-30 min & 8 hr post-dose on Day 112

Collaborators and Investigators

• Sponsor: Sanofi
• Investigators: Study Director: Clinical Sciences & Operations, Sanofi

Publications and helpful links

General Publications

• Shah VN, Al-Karadsheh A, Barnes C, Mandry J, Nakhle S, Wernicke-Panten K, Kramer D, Schmider W, Pierre S, Teichert L, Rotthaeuser B, Mukherjee B, Bailey TS. Pharmacokinetic similarity of switching SAR341402 insulin aspart biosimilar and NovoLog insulin aspart versus continuous use of NovoLog in adults with type 1 diabetes: The GEMELLI X trial. Diabetes Obes Metab. 2024 Feb;26(2):540-547. doi: 10.1111/dom.15341. Epub 2023 Oct 25.
• Shah VN, Al-Karadsheh A, Barnes C, Mandry J, Nakhle S, Wernicke-Panten K, Kramer D, Schmider W, Pierre S, Teichert L, Rotthaeuser B, Mukherjee B, Bailey TS. Safety and Efficacy of Switching SAR341402 Insulin Aspart and Originator Insulin Aspart vs Continuous Use of Originator Insulin Aspart in Adults With Type 1 Diabetes: The GEMELLI X Trial. J Diabetes Sci Technol. 2024 Feb 29:19322968241232709. doi: 10.1177/19322968241232709. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): March 11, 2019
• Primary Completion (Actual): July 8, 2020
• Study Completion (Actual): July 8, 2020

Study Registration Dates

• First Submitted: March 12, 2019
• First Submitted That Met QC Criteria: March 12, 2019
• First Posted (Actual): March 14, 2019

Study Record Updates

• Last Update Posted (Actual): April 17, 2024
• Last Update Submitted That Met QC Criteria: March 21, 2024
• Last Verified: March 1, 2024

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 Aspart; Insulin, Long-Acting; Insulin degludec, insulin aspart drug combination; Insulin Glargine
• Other Study ID Numbers: EFC15178; U1111-1197-7811 (Other Identifier: UTN); 136342 (Other Identifier: IND)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No