Tocilizumab (TCZ) in New-onset Type 1 Diabetes (EXTEND)

Preserving Beta-Cell Function With Tocilizumab in New-onset Type 1 Diabetes (ITN058AI)

Type 1 diabetes mellitus (T1DM) is an autoimmune disease. Based on previous research, study doctors think that giving medicines to affect the immune system soon after diabetes is diagnosed may stop, delay or decrease the destruction of beta cells, resulting in better glucose control.

Researchers believe that tocilizumab could have some effect on the cells in the immune system that are thought to be involved in the development of type 1 diabetes. This study will test whether tocilizumab can help preserve or delay destruction of remaining beta cells in people recently diagnosed type 1 diabetes.

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes Mellitus; T1DM; T1D; New-onset Type 1 Diabetes Mellitus
• Intervention / Treatment: Drug: Tocilizumab (TCZ); Other: Standard of Care; Drug: Placebo

Detailed Description

Staggered enrollment is planned for this trial.

Prior to initiating the study in the pediatric age group (6-17 years old), 30-99 eligible adults (ages 18-45 years) will be randomized 2:1 to tocilizumab or placebo, respectively. Once the first thirty adult participants have completed 12 weeks of treatment, the FDA and Data and Safety Monitoring Board (DSMB) will review available data (e.g., interim analysis) to weigh potential risks and benefits before opening the trial to pediatric participants.

As of ≥ May 15, 2017: Study enrollment limited to participants ages 6 to 17 years inclusive.

• Study Type: Interventional
• Enrollment (Actual): 136
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, Westmead 2145
      • The Children's Hospital at Westmead: Kids Research Institute
  • Queensland
    • South Brisbane, Queensland, Australia, 4101
      • Lady Cilento Children's Hospital: Department of Endocrinology
• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California San Francisco
    • Stanford, California, United States, 94305
      • Stanford University
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Yale University School of Medicine: Diabetes Endocrinology Research Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
    • Miami, Florida, United States, 33136
      • University of Miami: Diabetes Research Institute
    • Tampa, Florida, United States, 33612
      • University of South Florida: Diabetes Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Health - Riley Hospital for Children
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Massachusetts
    • Boston, Massachusetts, United States, 002215
      • Harvard University, Joslin Diabetes Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Children's Mercy Hospital
  • New York
    • New York, New York, United States, 10032
      • Columbia University, Naomi Berrie Diabetes Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57104
      • Sanford Research
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
  • Washington
    • Seattle, Washington, United States, 98101
      • Benaroya Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 13 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female aged 6-45 years*

   -*Current Institutional Review Board (IRB)-approved age eligibility criteria is restricted to subjects 6 to 17 years of age at time of study enrollment

2. Diagnosis of type 1 diabetes mellitus (T1DM), using the American Diabetes Association T1DM criteria, within 100 days of study enrollment

3. Positive for at least one diabetes-related autoantibody, including but not limited to:

   1. Glutamate decarboxylase (GAD-65)
   2. Insulin, if obtained within 10 days of the onset of exogenous insulin therapy
   3. Insulinoma antigen-2 (IA-2)
   4. Zinc transporter-8 (ZnT8)
4. Peak stimulated C-peptide level ≥ 0.2 pmol/mL following a mixed-meal tolerance test (MMTT) conducted at least 21 days from diagnosis and within 37 days of randomization (V0)
5. Signed informed consent (and informed assent of minor, if applicable).

Exclusion Criteria:

1. Severe reaction or anaphylaxis to human, humanized or murine monoclonal antibodies
2. History of malignancy or serious uncontrolled cardiovascular, nervous system, pulmonary, renal, or gastrointestinal disease, or significant dyslipidemia
3. Any history of recent serious bacterial, viral, fungal, or other opportunistic infections
4. Have serologic evidence of current or past HIV (Human immunodeficiency virus), Hepatitis B, or Hepatitis C
5. Positive QuantiFERON Tuberculosis (TB) test, history of TB, or active TB infection
6. Active infection with Epstein-Barr virus (EBV) as defined by EBV viral load ≥10,000 copies per mL of whole blood
7. Active infection with Cytomegalovirus (CMV) as defined by CMV viral load ≥10,000 copies per mL of whole blood
8. Diagnosis of liver disease or elevated hepatic enzymes, as defined by Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), or both > 1.5 x the upper limit of age-determined normal (ULN) or total bilirubin > ULN
9. Current or prior treatment that is known to cause a significant, ongoing change in the course of T1D or immunologic status
10. Current or prior (within last 30 days) use of drugs other than insulin to treat hyperglycemia (e.g. metformin, sulfonylureas, glinides, thiazolidinediones, exenatide, liraglutide, Dipeptidyl peptidase-4 Intravenous (DPP-IV) inhibitors, or amylin)
11. Current use of any medication known to significantly influence glucose tolerance (e.g., atypical antipsychotics, diphenylhydantoin, niacin)

12. Any of the following hematologic abnormalities, confirmed by repeat tests:

    1. White blood count <3,000/microL or >14,000/microL
    2. Lymphocyte count <500/microL
    3. Platelet count <150,000 /microL
    4. Hemoglobin <8.5 g/dL
    5. . Neutrophil count <2,000 cells/microL.
13. Females who are pregnant, lactating, or planning on pregnancy during the 2- year study period
14. History or diagnoses of other autoimmune diseases with the exception of stable thyroid or celiac disease
15. History of alcohol, drug or chemical abuse within 1 year prior to study eligibility screening evaluation
16. Any medical or psychological condition that in the opinion of the principal investigator would interfere with safe completion of the trial
17. Prior participation in a clinical trial that could increase risks associated with this clinical trial
18. Receipt of live vaccine (e.g. varicella, measles, mumps, rubella, cold-attenuated intranasal influenza vaccine, bacillus Calmette-Guérin, and small pox) in the 6 weeks before randomization
19. High lipid levels (fasting Low-density lipoprotein (LDL) cholesterol ≥160 mg/dL)
20. History of significant allergy (e.g. anaphylaxis) to milk or soy proteins.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tocilizumab (TCZ) + SOC; Subjects will receive intravenous (IV) infusions of either 8.0 mg/kg (body weight ≥30 kg) or 10.0 mg/kg (body weight <30kg) tocilizumab every 4 weeks for 24 weeks. Participants will also receive standard intensive diabetes management (in accordance with the American Diabetes Association guidelines [Standard of Care, SOC])	Drug: Tocilizumab (TCZ); Subjects assigned to this group will receive tocilizumab intravenous (IV) infusions of either 8.0 mg/kg (body weight ≥ 30kg) or 10.0 mg/kg (body weight <30kg) every 4 weeks for 24 weeks.; Other Names: Actemra®; Other: Standard of Care; Participants will also receive standard intensive diabetes management (in accordance with the American Diabetes Association guidelines [Standard of Care, SOC]); Other Names: SOC
Placebo Comparator: Tocilizumab Placebo Group + SOC; Subjects will receive IV infusions of either 8.0 mg/kg (body weight ≥ 30kg) or 10.0 mg/kg (body weight <30kg) placebo every 4 weeks for 24 weeks. Participants will also receive standard intensive diabetes management (in accordance with the American Diabetes Association guidelines [Standard of Care, SOC])	Other: Standard of Care; Participants will also receive standard intensive diabetes management (in accordance with the American Diabetes Association guidelines [Standard of Care, SOC]); Other Names: SOC; Drug: Placebo; Subjects assigned to this group will receive placebo intravenous (IV) infusions of either 8.0 mg/kg (body weight ≥ 30kg) or 10.0 mg/kg (body weight <30kg) every 4 weeks for 24 weeks.; Other Names: Placebo for Tocilizumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) in Pediatric Participants	C-peptide is a substance released by the pancreas into the bloodstream in equal amounts to insulin and reflects how much insulin pancreatic beta cells are making. The standardized MMTT evaluates whether beta cells are producing endogenous insulin. The MMTT was performed in the morning and blood samples for C-peptide collected at baseline (pre-meal) and 15, 30, 60, 90, 120, 150, 180, 210, and 240 minutes post-meal. C-peptide mAUC was calculated using the trapezoidal rule over the 2-hour time period. Larger numbers are preferable (better) in these mAUC results: more insulin being produced reflects less severe disease. C-peptide levels in the serum (e.g., mAUC following a standardized MMTT) compared to control group at 1 year post treatment initiation for the evaluation of investigational products intended to preserve endogenous beta-cell function in T1DM trials is recognized by the Center for Drug Evaluation and Research (CDER) at the FDA as a valid efficacy endpoint.	Baseline (Pre-treatment) to Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC)	C-peptide is a substance released by the pancreas into the bloodstream in equal amounts to insulin and reflects how much insulin pancreatic beta cells are making. The standardized MMTT evaluates whether beta cells are producing endogenous insulin. The MMTT was performed in the morning and blood samples for C-peptide collected at baseline (pre-meal) and 15, 30, 60, 90, 120, 150, 180, 210, and 240 minutes post-meal. C-peptide mAUC was calculated using the trapezoidal rule over the 2-hour time period. Larger numbers are preferable (better) in these mAUC results: more insulin being produced reflects less severe disease. C-peptide levels in the serum (e.g., mAUC following a standardized MMTT) compared to control group at 1 year post treatment initiation for the evaluation of investigational products intended to preserve endogenous beta-cell function in T1DM trials is recognized by the Center for Drug Evaluation and Research (CDER) at the FDA as a valid efficacy endpoint.	Baseline (Pre-treatment) to Weeks 24, 52, and 104
2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model	C-peptide is a substance released by the pancreas into the bloodstream in equal amounts to insulin and reflects how much insulin pancreatic beta cells are making. The standardized MMTT evaluates whether beta cells are producing endogenous insulin. The MMTT was performed in the morning and blood samples for C-peptide collected at baseline (pre-meal) and 15, 30, 60, 90, 120, 150, 180, 210, and 240 minutes post-meal. C-peptide mAUC was calculated using the trapezoidal rule over the 2-hour time period. Larger numbers are preferable (better) in these mAUC results: more insulin being produced reflects less severe disease. C-peptide levels in the serum (e.g., mAUC following a standardized MMTT) compared to control group at 1 year post treatment initiation for the evaluation of investigational products intended to preserve endogenous beta-cell function in T1DM trials is recognized by the Center for Drug Evaluation and Research (CDER) at the FDA as a valid efficacy endpoint.	Baseline (Pre-treatment), Weeks 12, 24, 39, 52, 78, and 104
Change From Baseline in 4-Hour C-peptide Mean Area Under the Curve (mAUC)	C-peptide is a substance released by the pancreas into the bloodstream in equal amounts to insulin and reflects how much insulin pancreatic beta cells are making. The standardized MMTT evaluates whether beta cells are producing endogenous insulin. The MMTT was performed in the morning and blood samples for C-peptide collected at baseline (pre-meal) and 15, 30, 60, 90, 120, 150, 180, 210, and 240 minutes post-meal. C-peptide mAUC was calculated using the trapezoidal rule over the 4-hour time period. Larger numbers are preferable (better) in these mAUC results: more insulin being produced reflects less severe disease. C-peptide levels in the serum (e.g., mAUC following a standardized MMTT) compared to control group at 1 year post treatment initiation for the evaluation of investigational products intended to preserve endogenous beta-cell function in T1DM trials is recognized by the Center for Drug Evaluation and Research (CDER) at the FDA as a valid efficacy endpoint.	Baseline (Pre-treatment) to Weeks 52 and 104
Change From Baseline in Average Insulin Use in Units Per Kilogram Body Weight Per Day	The need to use exogenous insulin is an indication that the body is not producing enough endogenous insulin. Higher amounts of insulin use indicate higher disease activity. Insulin use was collected each day for 5 days prior to the visit. Average insulin use per kg is the average insulin use over the 5 days prior to the visit divided by the participant's weight in kg.	Baseline (Pre-treatment) to Weeks 24, 52, and 104
Change From Baseline in Average Insulin Use Per Kg, Mixed Model	The need to use exogenous insulin is an indication that the body is not producing enough endogenous insulin. Higher amounts of insulin use indicate higher disease activity. Insulin use was collected each day for 5 days prior to the visit. Average insulin use per kg is the average insulin use over the 5 days prior to the visit divided by the participant's weight in kg.	Baseline (Pre-treatment) to Weeks 12, 24, 39, 52, 78, and 104
Change From Baseline in Hemoglobin A1c	Glycosylated hemoglobin (HbA1c) is a measure of the average plasma concentration of blood sugar (glucose) over the previous three months and measures the level of optimal management of underlying disease. An HbA1c of 5.6% or less is considered normal. HbA1c of 6.5% or higher is typical for individuals with Type 1 Diabetes mellitus (T1DM). The closer HbA1c levels are to normal, the better controlled the disease is.	Baseline (Pre-treatment) to Weeks 24, 52, and 104
Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model	Glycosylated hemoglobin (HbA1c) is a measure of the average plasma concentration of blood sugar (glucose) over the previous three months and measures the level of optimal management of underlying disease. An HbA1c of 5.6% or less is considered normal. HbA1c of 6.5% or higher is typical for individuals with Type 1 Diabetes mellitus (T1DM). The closer HbA1c levels are to normal, the better controlled the disease is.	Baseline (Pre-treatment) to Weeks 12, 24, 39, 52, 78, and 104
Number of Participants Who Experienced at Least One Major Hypoglycemic Event After Treatment Initiation	Major hypoglycemic adverse events are defined as: Blood glucose concentration < 40 mg/dL (Grades 3-5, NCI-CTCAE version 4.03*), or hypoglycemic events involving seizure or loss of consciousness (coma) or requiring assistance from another individual in order to recover. *NCI-CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events	Day 0 (Treatment Initiation) to Weeks 52 and 104
Number of Participants Who Experienced Infusion-Related Adverse Events	An infusion/dose reaction is defined as an adverse event occurring during and within 24 hours after the infusion or subcutaneous injection of tocilizumab. This may include hypersensitivity reactions or anaphylactic reactions.	Day 0 (Treatment Initiation) to Week 52
Number of Participants Who Experienced Hypersensitivity Adverse Events	Signs of a possible hypersensitivity reaction to the study drug include but are not limited to: Fever, chills, pruritus, urticaria, angioedema, and skin rash; Cardiopulmonary reactions, including chest pain, dyspnea, hypotension or hypertension	Day 0 (Treatment Initiation) to Week 52

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: PPD; Rho Federal Systems Division, Inc.; Immune Tolerance Network (ITN)
• Investigators: Study Chair: Carla Greenbaum, Benaroya Research Institute at Virginia Mason: Diabetes Research Program; Study Chair: Jane Buckner, M.D., Benaroya Research Institute at Virginia Mason: Diabetes Research Program

Publications and helpful links

General Publications

• Greenbaum CJ, Serti E, Lambert K, Weiner LJ, Kanaparthi S, Lord S, Gitelman SE, Wilson DM, Gaglia JL, Griffin KJ, Russell WE, Raskin P, Moran A, Willi SM, Tsalikian E, DiMeglio LA, Herold KC, Moore WV, Goland R, Harris M, Craig ME, Schatz DA, Baidal DA, Rodriguez H, Utzschneider KM, Nel HJ, Soppe CL, Boyle KD, Cerosaletti K, Keyes-Elstein L, Long SA, Thomas R, McNamara JG, Buckner JH, Sanda S; ITN058AI EXTEND Study Team. IL-6 receptor blockade does not slow beta cell loss in new-onset type 1 diabetes. JCI Insight. 2021 Nov 8;6(21):e150074. doi: 10.1172/jci.insight.150074.
• Hundhausen C, Roth A, Whalen E, Chen J, Schneider A, Long SA, Wei S, Rawlings R, Kinsman M, Evanko SP, Wight TN, Greenbaum CJ, Cerosaletti K, Buckner JH. Enhanced T cell responses to IL-6 in type 1 diabetes are associated with early clinical disease and increased IL-6 receptor expression. Sci Transl Med. 2016 Sep 14;8(356):356ra119. doi: 10.1126/scitranslmed.aad9943.

Helpful Links

• National Institute of Allergy and Infectious Diseases (NIAID) website
• Division of Allergy, Immunology, and Transplantation (DAIT) website
• Immune Tolerance Network (ITN) website
• EXTEND's study-specific ITN website
• American Diabetes Association information on Type 1 Diabetes

Study record dates

Study Major Dates

• Study Start (Actual): March 12, 2015
• Primary Completion (Actual): July 10, 2019
• Study Completion (Actual): August 31, 2020

Study Registration Dates

• First Submitted: November 13, 2014
• First Submitted That Met QC Criteria: November 17, 2014
• First Posted (Estimate): November 18, 2014

Study Record Updates

• Last Update Posted (Actual): September 8, 2021
• Last Update Submitted That Met QC Criteria: August 16, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: interleukin-6 (IL-6) receptor inhibitor
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1
• Other Study ID Numbers: DAIT ITN058AI

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: The plan is to share data upon completion of the study in: Immunology Database and Analysis Portal (ImmPort), a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts.
• IPD Sharing Time Frame: On average, within 24 months after database lock for the trial.
• IPD Sharing Access Criteria: Open access.